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Du Y, Zhao M, Zeng X, Wang S, Wang Q, Chen L, Yang X, Feng X, Lu M, Dittmer U, Sutter K, Zheng X, Yang D, Xu C, Liu J. Regulatory T cells suppress TLR9-induced formation of intrahepatic myeloid-cell aggregates for T cell population expansion in liver. Med Microbiol Immunol 2025; 214:24. [PMID: 40366446 DOI: 10.1007/s00430-025-00834-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Accepted: 05/04/2025] [Indexed: 05/15/2025]
Abstract
Toll-like receptor (TLR) 9 ligand has been reported to induce the formation of intrahepatic myeloid-cell aggregates for T cell population expansion (iMATEs), which enhances responses of cytotoxic T lymphocytes (CTLs). However, little is known about how the formation of iMATEs is regulated. Previously, various studies have demonstrated that regulatory T cells (Tregs) can suppress CTL responses through soluble cytokines or co-inhibitory molecules. It's unclear whether and how Tregs regulate the formation of iMATEs. In this study, we investigated whether Tregs are involved in regulating TLR9-induced iMATEs formation and the mechanisms behind it by using different gene knockout mice and blocking antibodies. We observed that intravenous injection of TLR9 ligand CpG induced significant iMATEs formation, accompanied by a marked increase in the number of Tregs infiltrating the liver as well as upregulation of IL-10 in both peripheral blood and liver. Importantly, depletion of Tregs either by anti-CD4, anti-CD25 blocking antibodies or diphtheria toxin (DT) in DEREG transgenic mice resulted in enhanced CpG-induced iMATEs formation. Conversely, knocking out IL-10 led to increased intrahepatic Treg infiltration and decreased CpG ODN-induced iMATEs formation. Consistently, depleting Kupffer cells (KCs), one of the main source of IL-10, also resulted in reduced formation of iMATEs. In conclusion, our results suggest that IL-10 suppresses Treg infiltration in the liver and thus promote CpG ODN-induced iMATEs formation. These results fill the gap in our understanding of the intrahepatic regulation mechanism of iMATEs formation.
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Affiliation(s)
- Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengxiao Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaoqing Zeng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shichuan Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
| | - Liwei Chen
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Kathrin Sutter
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chunli Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China.
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China.
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Hsu CY, Chandramoorthy HC, Mohammed JS, Al-Hasnaawei S, Yaqob M, Kundlas M, Samikan K, Sahoo S, Sunori SK, Abbas ZA. Exosomes as key mediators in immune and cancer cell interactions: insights in melanoma progression and therapy. Arch Dermatol Res 2025; 317:729. [PMID: 40252131 DOI: 10.1007/s00403-025-04237-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/25/2025] [Accepted: 04/02/2025] [Indexed: 04/21/2025]
Abstract
Exosomes (30-150 nm) are small extracellular vesicles that are secreted by cells into the extracellular environment and are known to mediate cell-to-cell communication. Exosomes contain proteins, lipids, and RNA molecules in relative abundance, capable of modifying the activity of target cells. Melanoma-derived exosomes (MEXs) promote the transfer of oncogenic signals and immunosuppressive factors into immune cells, resulting in a bias of the immune response towards tumor-promoting processes. MEXs could suppress the activation and proliferation of T cells and dendritic cells and induce differentiation of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). They can induce apoptosis of antigen-specific CD8 + T cells and promote the transfer of tumor antigens, resulting in immune evasion. Specifically, MEXs can shuttle cytokines like interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) to immune cells or express programmed death-ligand 1 (PD-L1 or CD274), creating an immune-suppressive microenvironment that promotes tumorigenesis. Since exosomes preferentially accumulate in melanoma tissues, this targeted delivery could enhance the bioavailability of treatments while limiting side effects. Here, we review the molecular composition of melanoma-derived exosomes, their mechanisms of action, and their potential as therapeutic targets or biomarkers in melanoma. The summarizations of these mechanisms to appropriately influence exosome-mediated interactions could yield new tactics to elicit anti-melanoma immunity or augment the therapeutic effects of current therapies.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University, Tempe Campus, Phoenix, AZ, 85004, USA.
| | - Harish C Chandramoorthy
- Department of Microbiology and Clinical Parasitology, College of Medicine and Central Research Laboratories, King Khalid University, Abha, Saudi Arabia
| | | | - Shaker Al-Hasnaawei
- College of Pharmacy, the Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| | - Mohammed Yaqob
- Department of Biology, Mazaya University College, Dhiqar, Iraq
| | - Mayank Kundlas
- Centre for Research Impact and Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Krishnakumar Samikan
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Samir Sahoo
- Department of General Medicine, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - S K Sunori
- Graphic Era Hill University, Bhimtal, Uttarakhand, India
- Graphic Era Deemed to be University, Dehradun, Uttarakhand, 248002, India
| | - Zainab Ahmed Abbas
- College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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Stacchiotti C, Mazzella di Regnella S, Cinotti M, Spalloni A, Volpe E. Neuroinflammation and Amyotrophic Lateral Sclerosis: Recent Advances in Anti-Inflammatory Cytokines as Therapeutic Strategies. Int J Mol Sci 2025; 26:3854. [PMID: 40332510 PMCID: PMC12028049 DOI: 10.3390/ijms26083854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.
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Affiliation(s)
- Costanza Stacchiotti
- Molecular Neuroimmunology Unit, Santa Lucia Foundation, 00143 Rome, Italy; (C.S.); (S.M.d.R.); (M.C.); (E.V.)
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Simona Mazzella di Regnella
- Molecular Neuroimmunology Unit, Santa Lucia Foundation, 00143 Rome, Italy; (C.S.); (S.M.d.R.); (M.C.); (E.V.)
| | - Miriam Cinotti
- Molecular Neuroimmunology Unit, Santa Lucia Foundation, 00143 Rome, Italy; (C.S.); (S.M.d.R.); (M.C.); (E.V.)
- Department of Biology and Biotechnology Charles Darwin, Sapienza University, 00185 Rome, Italy
| | - Alida Spalloni
- Molecular Neurobiology Unit, Santa Lucia Foundation, 00143 Rome, Italy
| | - Elisabetta Volpe
- Molecular Neuroimmunology Unit, Santa Lucia Foundation, 00143 Rome, Italy; (C.S.); (S.M.d.R.); (M.C.); (E.V.)
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Zhang F, Wang B, Wu M, Zhang L, Ji M. Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review. Front Immunol 2025; 16:1509173. [PMID: 40303413 PMCID: PMC12037499 DOI: 10.3389/fimmu.2025.1509173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 03/26/2025] [Indexed: 05/02/2025] Open
Abstract
In recent years, precision medicine for non-small cell lung cancer (NSCLC) has made significant strides, particularly with advancements in diagnostic and therapeutic technologies. Targeted 7therapies and Anti-PD-(L)1 Therapies have emerged as vital treatment options, yet KRAS mutations, especially KRAS G12C, have been historically difficult to address. Due to the unique activation mechanism of KRAS G12C has led to the development of specific inhibitors, such as AMG 510 and MRTX849, which show promising therapeutic potential. However, results from the CodeBreaK 200 Phase III trial indicated that AMG 510 did not significantly improve overall survival compared to docetaxel. Resistance after prolonged use of KRAS G12C inhibitors continues to pose a challenge, prompting interest in new drugs and combination strategies. KRAS mutations can impair tumor-infiltrating T cell function and create an immunosuppressive tumor microenvironment, making the combination of KRAS G12C inhibitors with anti-PD-(L)1 therapies particularly appealing. Preliminary data suggest these combinations may enhance both survival and quality of life, though safety concerns remain a barrier. Ongoing research is crucial to refine treatment regimens and identify suitable patient populations. This review focuses on the development of KRAS G12C inhibitors in monotherapy and combination therapies for NSCLC, discussing major clinical trials and future research directions.
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Affiliation(s)
| | | | | | | | - Mei Ji
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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5
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Cosola S, Fanelli SM, Sinesi A, Lasala R, Oldoini G, Genovesi A, Butera A, Scribante A. A Descriptive Observational Survey on Italian Women’s Awareness of the Association Between Periodontal Disease and Pregnancy. HYGIENE 2025; 5:10. [DOI: 10.3390/hygiene5010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2025]
Abstract
The literature has identified several common acute and chronic complications associated with periodontal health during pregnancy, such as gingivitis, recession, periodontitis, and changes in systemic health, such as gestational diabetes, which may act as additional risk factors for chronic periodontal disease. Are the general public and health care providers aware of the potential risks of systemic and intrauterine inflammation caused by bacteria from the oral microbiota entering the bloodstream through inflamed gingival tissue and affecting the fetoplacental unit, leading to complications, such as preterm birth and reduced prenatal growth? A questionnaire-based survey, conducted between January 2023 and June 2023, aimed to assess patients’ personal oral hygiene practices and their understanding of the link between pregnancy and periodontal health. A total of 826 people completed a questionnaire for this study. The majority of women surveyed (86.9%) were not pregnant, but 77.7% had at least one child. The majority of women believed in good oral hygiene during pregnancy but lacked knowledge about how oral care can affect pregnancy outcomes.
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Affiliation(s)
- Saverio Cosola
- Department of Stomatology, Tuscan Stomatologic Institute, Foundation for Dental Clinic, Research and Continuing Education, 55041 Camaiore, Italy
- Department of Dentistry, Unicamillus—Saint Camillus International University of Health and Medical Sciences, 00100 Rome, Italy
| | - Sandy Manuela Fanelli
- Department of Stomatology, Tuscan Stomatologic Institute, Foundation for Dental Clinic, Research and Continuing Education, 55041 Camaiore, Italy
- Unit of Dentistry and Dental Hygiene, ASL, 74100 Taranto, Italy
| | - Antonia Sinesi
- Unit of Dentistry and Dental Hygiene, ASL, 74100 Taranto, Italy
| | | | - Giacomo Oldoini
- Department of Stomatology, Tuscan Stomatologic Institute, Foundation for Dental Clinic, Research and Continuing Education, 55041 Camaiore, Italy
| | - Annamaria Genovesi
- Department of Stomatology, Tuscan Stomatologic Institute, Foundation for Dental Clinic, Research and Continuing Education, 55041 Camaiore, Italy
- Department of Dentistry, Unicamillus—Saint Camillus International University of Health and Medical Sciences, 00100 Rome, Italy
| | - Andrea Butera
- Unit of Dental Hygiene, Section of Dentistry, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Andrea Scribante
- Unit of Dental Hygiene, Section of Dentistry, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy
- Unit of Orthodontics and Paediatric Dentistry, Section of Dentistry, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy
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Su X, Zhang M, Zhu H, Cai J, Wang Z, Xu Y, Wang L, Shen C, Cai M. Mechanisms of T-cell Depletion in Tumors and Advances in Clinical Research. Biol Proced Online 2025; 27:5. [PMID: 39905296 PMCID: PMC11792740 DOI: 10.1186/s12575-025-00265-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025] Open
Abstract
T lymphocytes (T cells) are essential components of the adaptive immune system that play a vital role in identifying and eliminating infected and tumor cells. In tumor immunotherapy, T cells have emerged as a promising therapeutic strategy due to their high specificity, potent cytotoxic capability, long-lasting immune memory, and adaptability within immunotherapeutic approaches. However, tumors can evade the immune system by depleting T cells through various mechanisms, such as inhibitory receptor signaling, metabolic exhaustion, and physical barriers within the tumor microenvironment. This review provided an overview of the mechanisms underlying T-cell depletion in tumors and discussed recent advances in clinical research related to T-cell immunotherapy for tumors. It highlighted the need for in-depth studies on key issues such as indications, dosage, and sequencing of combined therapeutic strategies tailored to different patients and tumor types, providing practical guidance for individualized treatment. Future research on T-cell depletion would be necessary to uncover the fundamental mechanisms and laws of T-cell depletion, offering both theoretical insights and practical guidance for the selection and optimization of tumor immunotherapy. Furthermore, interdisciplinary, cross-disciplinary, and international collaborative innovations are necessary for developing more effective and safer treatments for tumor patients.
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Affiliation(s)
- Xiangfei Su
- China Association of Chinese Medicine, Beijing, China
| | - Mi Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Chinese Medicine, No. 300, Shouchun Road, Hefei, Anhui, 230061, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Hong Zhu
- Tongling People's Hospital, Tongling, Anhui, China
| | - Jingwen Cai
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhen Wang
- Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Yuewei Xu
- Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Chinese Medicine, No. 300, Shouchun Road, Hefei, Anhui, 230061, China
| | - Li Wang
- Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Chinese Medicine, No. 300, Shouchun Road, Hefei, Anhui, 230061, China
| | - Chen Shen
- Key Laboratory of Data Science and Innovation and Development of Traditional Chinese Medicine and Social Sciences of Anhui Province, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Hefei, Anhui, 230012, China.
| | - Ming Cai
- Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Chinese Medicine, No. 300, Shouchun Road, Hefei, Anhui, 230061, China.
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, China.
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Nejabat S, Khomartash MS, Mohammadimehr M, Adloo Z, Zanchi FB, Ghorbani M, Nezafat N. Immunoinformatics approach: Developing a multi-epitope vaccine with novel carriers targeting monkeypox virus. FASEB J 2024; 38:e70257. [PMID: 39679938 DOI: 10.1096/fj.202400757rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 10/12/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024]
Abstract
Since May 2022, the global spread of monkeypox virus (MPXV) has presented a significant threat to public health. Despite this, there are limited preventive measures available. In this study, different computational tools were employed to design a multi-epitope vaccine targeting MPXV. Three key MPXV proteins, M1R, B6R, and F3L, were chosen for epitope selection, guided by bioinformatic analyses to identify immunodominant epitopes for T- and B-cell activation. To enhance immune stimulation and facilitate targeted delivery of the vaccine to specific cells, the selected epitopes were linked to novel carriers, including the extracellular domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a 12-mer Clec9a binding peptide (CBP-12), and a Toll-like receptor 2 (TLR2) peptide ligand. The designed vaccine construct exhibited strong antigenicity along with nonallergenic and nontoxic properties, with favorable physicochemical characteristics. The validated vaccine's tertiary structure underwent evaluation for interactions with CD80/86, Clec9a, and TLR2 through molecular docking and molecular dynamics simulation. The results ensured the vaccine's stability and high affinity for the aforementioned receptors. In silico immune simulations studies revealed robust innate and adaptive immune responses, including enhanced mucosal immunity essential for protection against MPXV. Ultimately, the DNA sequence of the vaccine construct was synthesized and successfully cloned into the pET-22b(+) vector. Our study, through integration of computational predictions, suggests the proposed vaccine's potential efficacy in safeguarding against MPXV; however, further in vitro and in vivo validations are imperative to assess real-world effectiveness and safety.
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Affiliation(s)
- Sajjad Nejabat
- Science and Technology Research Center, AJA University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mojgan Mohammadimehr
- Infectious Diseases Research Center, AJA University of Medical Sciences, Tehran, Iran
- Department of Laboratory Sciences, Faculty of Paramedicine, AJA University of Medical Sciences, Tehran, Iran
| | - Zahra Adloo
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fernando Berton Zanchi
- Laboratório de Bioinformática e Química Medicinal (LABIOQUIM), Fundação Oswaldo Cruz Rondônia, Porto Velho, Brazil
| | - Mahdi Ghorbani
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, AJA University of Medical Sciences, Tehran, Iran
| | - Navid Nezafat
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Bido S, Nannoni M, Muggeo S, Gambarè D, Ruffini G, Bellini E, Passeri L, Iaia S, Luoni M, Provinciali M, Giannelli SG, Giannese F, Lazarevic D, Gregori S, Broccoli V. Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease. Sci Transl Med 2024; 16:eadm8563. [PMID: 39167665 DOI: 10.1126/scitranslmed.adm8563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 04/23/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024]
Abstract
Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson's disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human SNCA gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing SNCA. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8+ T cells. In summary, our results show that local and microglia-specific IL-10 transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects.
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Affiliation(s)
- Simone Bido
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Melania Nannoni
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Sharon Muggeo
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Diana Gambarè
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Giorgia Ruffini
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Edoardo Bellini
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Laura Passeri
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Silvia Iaia
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Mirko Luoni
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- CNR Institute of Neuroscience, 20129 Milan, Italy
| | - Martino Provinciali
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Serena Gea Giannelli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Francesca Giannese
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Dejan Lazarevic
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Silvia Gregori
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Vania Broccoli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- CNR Institute of Neuroscience, 20129 Milan, Italy
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9
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Gois LL, Ribeiro-Soares B, Regis-Silva CG, Zanette DL, Lisboa R, Nascimento RS, Coutinho Junior R, Galvão-Castro B, Grassi MFR. Imbalanced IL10/TGF-β production by regulatory T-lymphocytes in patients with HTLV-1-associated myelopathy/ tropical spastic paraparesis. BMC Infect Dis 2024; 24:652. [PMID: 38943078 PMCID: PMC11214226 DOI: 10.1186/s12879-024-09494-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 06/11/2024] [Indexed: 07/01/2024] Open
Abstract
BACKGROUND Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-β. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. METHODS Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-β-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. RESULTS Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. CONCLUSIONS A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-β may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.
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Affiliation(s)
- Luana Leandro Gois
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador-Bahia, Brazil
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
- Departamento de Ciências da Biointeração, Instituto de Ciências da Saúde, Universidade Federal da Bahia (ICS/UFBA), Salvador-Bahia, Brazil
| | - Bárbara Ribeiro-Soares
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador-Bahia, Brazil
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
| | - Carlos Gustavo Regis-Silva
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
| | - Dalila L Zanette
- Laboratório de Ciências e Tecnologias Aplicadas a Saúde, Instituto Carlos Chagas, Fundação Oswaldo Cruz (ICC/FIOCRUZ-PR), Curitiba-Paraná, Brazil
| | - Raphaella Lisboa
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador-Bahia, Brazil
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
| | - Regina Santos Nascimento
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
| | - Raimundo Coutinho Junior
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador-Bahia, Brazil
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
| | - Bernardo Galvão-Castro
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador-Bahia, Brazil
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil
| | - Maria Fernanda Rios Grassi
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador-Bahia, Brazil.
- Laboratório Avançado de Saúde Pública, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (LASP, IGM, FIOCRUZ), Salvador-Bahia, Brazil.
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Verma Y, Perera Molligoda Arachchige AS. Advances in Tumor Management: Harnessing the Potential of Histotripsy. Radiol Imaging Cancer 2024; 6:e230159. [PMID: 38639585 PMCID: PMC11148838 DOI: 10.1148/rycan.230159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 02/22/2024] [Accepted: 03/01/2024] [Indexed: 04/20/2024]
Abstract
Tissue ablation techniques have long been used in clinical settings to treat various oncologic diseases. However, many of these techniques are invasive and can cause substantial adverse effects. Histotripsy is a noninvasive, nonionizing, nonthermal tissue ablation technique that has the potential to replace surgical interventions in various clinical settings. Histotripsy works by delivering high-intensity focused ultrasound waves to target tissue. These waves create cavitation bubbles within tissues that rapidly expand and collapse, thereby mechanically fractionating the tissue into acellular debris that is subsequently absorbed by the body's immune system. Preclinical and clinical studies have demonstrated the efficacy of histotripsy in treating a range of diseases, including liver, pancreatic, renal, and prostate tumors. Safety outcomes of histotripsy have been generally favorable, with minimal adverse effects reported. However, further studies are needed to optimize the technique and understand its long-term effects. This review aims to discuss the importance of histotripsy as a noninvasive tissue ablation technique, the preclinical and clinical literature on histotripsy and its safety, and the potential applications of histotripsy in clinical practice. Keywords: Tumor Microenvironment, Ultrasound-High-Intensity Focused (HIFU), Ablation Techniques, Abdomen/GI, Genital/Reproductive, Nonthermal Tissue Ablation, Histotripsy, Clinical Trials, Preclinical Applications, Focused Ultrasound © RSNA, 2024.
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11
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Benne N, Ter Braake D, Porenta D, Lau CYJ, Mastrobattista E, Broere F. Autoantigen-Dexamethasone Conjugate-Loaded Liposomes Halt Arthritis Development in Mice. Adv Healthc Mater 2024; 13:e2304238. [PMID: 38295848 DOI: 10.1002/adhm.202304238] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/23/2024] [Indexed: 02/13/2024]
Abstract
There is no curative treatment for chronic auto-inflammatory diseases including rheumatoid arthritis, and current treatments can induce off-target side effects due to systemic immune suppression. This work has previously shown that dexamethasone-pulsed tolerogenic dendritic cells loaded with the arthritis-specific antigen human proteoglycan can suppress arthritis development in a proteoglycan-induced arthritis mouse model. To circumvent ex vivo dendritic cell culture, and enhance antigen-specific effects, drug delivery vehicles, such as liposomes, provide an interesting approach. Here, this work uses anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol liposomes with enhanced loading of human proteoglycan-dexamethasone conjugates by cationic lysine tetramer addition. Antigen-pulsed tolerogenic dendritic cells induced by liposomal dexamethasone in vitro enhanced antigen-specific regulatory T cells to a similar extent as dexamethasone-induced tolerogenic dendritic cells. In an inflammatory adoptive transfer model, mice injected with antigen-dexamethasone liposomes have significantly higher antigen-specific type 1 regulatory T cells than mice injected with antigen only. The liposomes significantly inhibit the progression of arthritis compared to controls in preventative and therapeutic proteoglycan-induced arthritis mouse models. This coincides with systemic tolerance induction and an increase in IL10 expression in the paws of mice. In conclusion, a single administration of autoantigen and dexamethasone-loaded liposomes seems to be a promising antigen-specific treatment strategy for arthritis in mice.
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Affiliation(s)
- Naomi Benne
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584 CL, The Netherlands
| | - Daniëlle Ter Braake
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584 CL, The Netherlands
| | - Deja Porenta
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584 CL, The Netherlands
- Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Faculty of Science, Utrecht University, Utrecht, 3584 CG, The Netherlands
| | - Chun Yin Jerry Lau
- Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Faculty of Science, Utrecht University, Utrecht, 3584 CG, The Netherlands
- Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Enrico Mastrobattista
- Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Faculty of Science, Utrecht University, Utrecht, 3584 CG, The Netherlands
| | - Femke Broere
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584 CL, The Netherlands
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12
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Li QH, Zhao QY, Yang WJ, Jiang AF, Ren CE, Meng YH. Beyond Immune Balance: The Pivotal Role of Decidual Regulatory T Cells in Unexplained Recurrent Spontaneous Abortion. J Inflamm Res 2024; 17:2697-2710. [PMID: 38707955 PMCID: PMC11070170 DOI: 10.2147/jir.s459263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024] Open
Abstract
Recurrent spontaneous abortion (RSA) is defined as two or more consecutive pregnancy failures, which brings tremendous stress to women of childbearing age and seriously affects family well-being. However, the reason in about 50% of cases remains unknown and is defined as unexplained recurrent spontaneous abortion (URSA). The immunological perspective in URSA has attracted widespread attention in recent years. The embryo is regarded as a semi-allogeneic graft to the mother. A successful pregnancy requires transition to an immune environment conducive to embryo survival at the maternal-fetal interface. As an important member of regulatory immunity, regulatory T (Treg) cells play a key role in regulating immune tolerance at the maternal-fetal interface. This review will focus on the phenotypic plasticity and lineage stability of Treg cells to illustrate its relationship with URSA.
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Affiliation(s)
- Qing-Hui Li
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261021, People’s Republic of China
- Center of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Qiu-Yan Zhao
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261021, People’s Republic of China
| | - Wei-Jing Yang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261021, People’s Republic of China
| | - Ai-Fang Jiang
- Center of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Chun-E Ren
- Center of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Yu-Han Meng
- Center of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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14
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Verma Y, Perera Molligoda Arachchige AS. Revolutionizing brain interventions: the multifaceted potential of histotripsy. Neurosurg Rev 2024; 47:124. [PMID: 38509320 DOI: 10.1007/s10143-024-02353-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 02/26/2024] [Accepted: 03/12/2024] [Indexed: 03/22/2024]
Abstract
Histotripsy, a non-thermal ultrasound technique, holds significant promise in various applications within the realm of brain interventions. While its use for treating brain tumors is somewhat limited, focused ultrasound technology has been extensively investigated for a wide range of purposes within the brain, including disrupting the blood-brain barrier, supporting immunotherapy, addressing conditions like essential tremor, Parkinson's disease, Alzheimer's disease, epilepsy, and neuropathic pain. Research findings indicate that histotripsy can reduce tumor cells with fewer pulses, minimizing the risk of bleeding and cellular injury. The use of MRI sequences such as T2 and T2* enhances the evaluation of the effects of histotripsy treatment, facilitating non-invasive assessment of treated areas. Furthermore, histotripsy displays promise in creating precise brain lesions with minimal edema and inflammation, particularly in porcine models, suggesting considerable progress in the treatment of brain lesions. Moreover, studies confirm its feasibility, safety, and effectiveness in treating intracerebral hemorrhage by safely liquefying clots without causing significant harm to surrounding brain tissue., opening exciting possibilities for clinical applications. The development of transcranial MR-guided focused ultrasound systems based on histotripsy represents a significant breakthrough in overcoming the limitations associated with thermal ablation techniques. Histotripsy's ability to efficiently liquefy clots, minimize skull heating, and target shallow lesions near the skull establishes it as a promising alternative for various brain treatments. In conclusion, histotripsy offers diverse potential in the field of brain interventions, encompassing applications ranging from tumor treatment to the management of intracerebral hemorrhage. While challenges such as accurate monitoring and differentiation of treatment effects persist, ongoing research efforts and technological advancements continue to expand the role of histotripsy in both neurology and neurosurgery.
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Affiliation(s)
- Yash Verma
- Norfolk and Norwich University Hospital, Norwich, UK
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15
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Shao TY, Jiang TT, Stevens J, Russi AE, Troutman TD, Bernieh A, Pham G, Erickson JJ, Eshleman EM, Alenghat T, Jameson SC, Hogquist KA, Weaver CT, Haslam DB, Deshmukh H, Way SS. Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation. Cell Rep 2023; 42:113323. [PMID: 37889750 PMCID: PMC10822050 DOI: 10.1016/j.celrep.2023.113323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 09/05/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.
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Affiliation(s)
- Tzu-Yu Shao
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Tony T Jiang
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Joseph Stevens
- Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Abigail E Russi
- Division of Gastroenterology, Hepatology and Advanced Nutrition, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Ty D Troutman
- Division of Allergy and Immunology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Anas Bernieh
- Division of Pathology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Giang Pham
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - John J Erickson
- Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Emily M Eshleman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Theresa Alenghat
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Stephen C Jameson
- Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Kristin A Hogquist
- Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Casey T Weaver
- Program in Immunology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - David B Haslam
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Hitesh Deshmukh
- Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Sing Sing Way
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA.
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16
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Alsalloum A, Alrhmoun S, Shevchenko J, Fisher M, Philippova J, Perik-Zavodskii R, Perik-Zavodskaia O, Lopatnikova J, Kurilin V, Volynets M, Akahori Y, Shiku H, Silkov A, Sennikov S. TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. Biomedicines 2023; 11:2805. [PMID: 37893178 PMCID: PMC10604587 DOI: 10.3390/biomedicines11102805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/13/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
Adoptive T-cell therapies tailored for the treatment of solid tumors encounter intricate challenges, necessitating the meticulous selection of specific target antigens and the engineering of highly specific T-cell receptors (TCRs). This study delves into the cytotoxicity and functional characteristics of in vitro-cultured T-lymphocytes, equipped with a TCR designed to precisely target the cancer-testis antigen NY-ESO-1. Flow cytometry analysis unveiled a notable increase in the population of cells expressing activation markers upon encountering the NY-ESO-1-positive tumor cell line, SK-Mel-37. Employing the NanoString platform, immune transcriptome profiling revealed the upregulation of genes enriched in Gene Ontology Biological Processes associated with the IFN-γ signaling pathway, regulation of T-cell activation, and proliferation. Furthermore, the modified T cells exhibited robust cytotoxicity in an antigen-dependent manner, as confirmed by the LDH assay results. Multiplex immunoassays, including LEGENDplex™, additionally demonstrated the elevated production of cytotoxicity-associated cytokines driven by granzymes and soluble Fas ligand (sFasL). Our findings underscore the specific targeting potential of engineered TCR T cells against NY-ESO-1-positive tumors. Further comprehensive in vivo investigations are essential to thoroughly validate these results and effectively harness the intrinsic potential of genetically engineered T cells for combating cancer.
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Affiliation(s)
- Alaa Alsalloum
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
| | - Saleh Alrhmoun
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
| | - Julia Shevchenko
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Marina Fisher
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Julia Philippova
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Roman Perik-Zavodskii
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Olga Perik-Zavodskaia
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Julia Lopatnikova
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Vasily Kurilin
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Marina Volynets
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
| | - Yasushi Akahori
- Department of Personalized Cancer Immunotherapy, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan;
| | - Hiroshi Shiku
- Department of Personalized Cancer Immunotherapy, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan;
| | - Alexander Silkov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
| | - Sergey Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (A.A.); (S.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (J.L.); (V.K.); (M.V.); (A.S.)
- Department of Immunology, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Novosibirsk 630090, Russia
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Alsalloum A, Shevchenko J, Fisher M, Philippova J, Perik-Zavodskii R, Perik-Zavodskaia O, Alrhmoun S, Lopatnikova J, Vasily K, Volynets M, Zavjalov E, Solovjeva O, Akahori Y, Shiku H, Silkov A, Sennikov S. Exploring TCR-like CAR-Engineered Lymphocyte Cytotoxicity against MAGE-A4. Int J Mol Sci 2023; 24:15134. [PMID: 37894816 PMCID: PMC10606439 DOI: 10.3390/ijms242015134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/05/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
TCR-like chimeric antigen receptor (CAR-T) cell therapy has emerged as a game-changing strategy in cancer immunotherapy, offering a broad spectrum of potential antigen targets, particularly in solid tumors containing intracellular antigens. In this study, we investigated the cytotoxicity and functional attributes of in vitro-generated T-lymphocytes, engineered with a TCR-like CAR receptor precisely targeting the cancer testis antigen MAGE-A4. Through viral transduction, T-cells were genetically modified to express the TCR-like CAR receptor and co-cultured with MAGE-A4-expressing tumor cells. Flow cytometry analysis revealed a significant surge in cells expressing activation markers CD69, CD107a, and FasL upon encountering tumor cells, indicating robust T-cell activation and cytotoxicity. Moreover, immune transcriptome profiling unveiled heightened expression of pivotal T-effector genes involved in immune response and cell proliferation regulation. Additionally, multiplex assays also revealed increased cytokine production and cytotoxicity driven by granzymes and soluble Fas ligand (sFasL), suggesting enhanced anti-tumor immune responses. Preliminary in vivo investigations revealed a significant deceleration in tumor growth, highlighting the therapeutic potential of these TCR-like CAR-T cells. Further investigations are warranted to validate these revelations fully and harness the complete potential of TCR-like CAR-T cells in overcoming cancer's resilient defenses.
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Affiliation(s)
- Alaa Alsalloum
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Julia Shevchenko
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Marina Fisher
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Julia Philippova
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Roman Perik-Zavodskii
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Olga Perik-Zavodskaia
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Saleh Alrhmoun
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Julia Lopatnikova
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Kurilin Vasily
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Marina Volynets
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Evgenii Zavjalov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Ministry of Science and High Education of Russian Federation, 630090 Novosibirsk, Russia
| | - Olga Solovjeva
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Ministry of Science and High Education of Russian Federation, 630090 Novosibirsk, Russia
| | - Yasushi Akahori
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan;
| | - Hiroshi Shiku
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan;
| | - Alexander Silkov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
| | - Sergey Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (A.A.); (J.S.); (M.F.); (J.P.); (R.P.-Z.); (O.P.-Z.); (S.A.); (J.L.); (K.V.); (M.V.); (E.Z.); (O.S.); (A.S.)
- Department of Immunology, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia
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18
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Yoo S, Jeong YH, Choi HH, Chae S, Hwang D, Shin SJ, Ha SJ. Chronic LCMV infection regulates the effector T cell response by inducing the generation of less immunogenic dendritic cells. Exp Mol Med 2023:10.1038/s12276-023-00991-5. [PMID: 37121977 DOI: 10.1038/s12276-023-00991-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 05/02/2023] Open
Abstract
Chronic viral infection impairs systemic immunity in the host; however, the mechanism underlying the dysfunction of immune cells in chronic viral infection is incompletely understood. In this study, we studied the lineage differentiation of hematopoietic stem cells (HSCs) during chronic viral infection to elucidate the changes in dendritic cell (DC) differentiation and subsequent impact on T cell functionality using a chronic lymphocytic choriomeningitis virus (LCMV) infection model. We first investigated the lineage differentiation of HSCs in the bone marrow (BM) to elucidate the modulation of immune cell differentiation and found that the populations highly restrained in their differentiation were common myeloid progenitors (CMPs) and common dendritic cell progenitors (CDPs). Of interest, the main immune cells infected with LCMV Clone 13 (CL13) in the BM were CD11b/c+ myeloid DCs. We next characterized CD11b+ DCs that differentiated during chronic LCMV infection. These DCs displayed a less immunogenic phenotype than DCs in naive or acutely infected mice, showing low expression of CD80 but high expression of PD-L1, B7-H4, IDO, TGF-β, and IL-10. Consequently, these CD11b+ DCs induced less effective CD8+ T cells and more Foxp3+ regulatory T (Treg) cells. Furthermore, CD11b+ DCs generated during CL13 infection could not induce effective CD8+ T cells specific to the antigens of newly invading pathogens. Our findings demonstrate that DCs generated from the BM during chronic viral infection cannot activate fully functional effector CD8+ T cells specific to newly incoming antigens as well as persistent antigens themselves, suggesting a potential cause of the functional alterations in the T cell immune response during chronic viral infection.
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Affiliation(s)
- Seungbo Yoo
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
- Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, 03722, Republic of Korea
| | - Yun Hee Jeong
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
- Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, 03722, Republic of Korea
| | - Hong-Hee Choi
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sehyun Chae
- Korea Brain Bank, Korea Brain Research Institute (KBRI), Daegu, 41062, Republic of Korea
| | - Daehee Hwang
- Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sung Jae Shin
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang-Jun Ha
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
- Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, 03722, Republic of Korea.
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19
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van der Elst G, Varol H, Hermans M, Baan CC, Duong-van Huyen JP, Hesselink DA, Kramann R, Rabant M, Reinders MEJ, von der Thüsen JH, van den Bosch TPP, Clahsen-van Groningen MC. The mast cell: A Janus in kidney transplants. Front Immunol 2023; 14:1122409. [PMID: 36891297 PMCID: PMC9986315 DOI: 10.3389/fimmu.2023.1122409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
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Affiliation(s)
- G van der Elst
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - H Varol
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M Hermans
- Department of Internal Medicine, Division of Allergy and Clinical Immunology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - C C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | - D A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - R Kramann
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.,Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - M Rabant
- Department of Pathology, Necker Hospital, APHP, Paris, France
| | - M E J Reinders
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - J H von der Thüsen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - T P P van den Bosch
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M C Clahsen-van Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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20
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Vij S, Thakur R, Kumari L, Suri CR, Rishi P. Potential of a novel flagellin epitope as a broad-spectrum vaccine candidate against enteric fever. Microb Pathog 2023; 174:105936. [PMID: 36494021 DOI: 10.1016/j.micpath.2022.105936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/24/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
Relentless emergence of antibiotic resistant Salmonella strains, coupled with the drawbacks associated with currently available vaccines against enteric fever, warrants an urgent need to look for new vaccine candidates. Out of the multiple virulence factors harbored by Salmonella, flagella are regarded as one of the most important targets of innate as well as adaptive immune response. Individual Salmonella serotypes alternate between expression of two different antigenic forms encoded by fliC and fljB genes, respectively thereby employing this as a strategy to escape the host immune response. In the present study, using various immunoinformatic approaches, a flagellin epitope, present in both antigenic forms of typhoidal Salmonellae has been targeted. Following B-cell epitope and B-cell derived T-cell epitope prediction and interaction studies with major histocompatibility complexes using molecular docking, a peptide epitope was selected. Further, it was screened for its presence in majority of typhoidal serovars along with other useful attributes, in silico. Thereafter, safety studies were performed with the synthesized peptide. Subsequently, immunization studies were carried out using S. Typhi as well as S. Paratyphi A induced murine peritonitis model. Active immunization with peptide-BSA conjugate resulted in 75% and 80% mice survival following lethal challenge with S. Typhi and S. Paratyphi A respectively, along with a significant IgG antibody titer, thereby highlighting its immunogenic potential. Reduced bacterial burden in vital organs along with improved histoarchitecture and cytokine levels further substantiated the protective efficacy of the proposed candidate. Passive immunization studies with the candidate verified the protective efficacy of the generated antibodies against lethal challenge of bacteria in mice. Given the endemic nature of enteric fever and the antigenic variability observed in Salmonella serotypes, present study highlights the importance of using a vaccine candidate, which, along with generating a strong immune response, also exhibits a broad coverage against both, S. Typhi as well as S. Paratyphi A strains.
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Affiliation(s)
- Shania Vij
- Department of Microbiology, Basic Medical Sciences, Block I, South Campus, Panjab University, Chandigarh, India
| | - Reena Thakur
- Department of Microbiology, Basic Medical Sciences, Block I, South Campus, Panjab University, Chandigarh, India
| | - Laxmi Kumari
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | | | - Praveen Rishi
- Department of Microbiology, Basic Medical Sciences, Block I, South Campus, Panjab University, Chandigarh, India.
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21
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Imran KM, Ganguly A, Paul T, Powar M, Vlaisavljevich E, Cho CS, Allen IC. Magic bubbles: utilizing histotripsy to modulate the tumor microenvironment and improve systemic anti-tumor immune responses. Int J Hyperthermia 2023; 40:2244206. [PMID: 37580047 PMCID: PMC10430775 DOI: 10.1080/02656736.2023.2244206] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/28/2023] [Accepted: 07/29/2023] [Indexed: 08/16/2023] Open
Abstract
Focused Ultrasound (FUS) is emerging as a promising primary and adjunct therapy for the treatment of cancer. This includes histotripsy, which is a noninvasive, non-ionizing, non-thermal ultrasound guided ablation modality. As histotripsy has progressed from bench-to-bedside, it has become evident that this therapy has benefits beyond local tumor ablation. Specifically, histotripsy has the potential to shift the local tumor microenvironment from immunologically 'cold' to 'hot'. This is associated with the production of damage associated molecular patterns, the release of a selection of proinflammatory mediators, and the induction of inflammatory forms of cell death in cells just outside of the treatment zone. In addition to the induction of this innate immune response, histotripsy can also improve engagement of the adaptive immune system and promote systemic anti-tumor immunity targeting distal tumors and metastatic lesions. These tantalizing observations suggest that, in settings of widely metastatic disease burden, selective histotripsy of a limited number of accessible tumors could be a means of maximizing responsiveness to systemic immunotherapy. More work is certainly needed to optimize treatment strategies that best synergize histotripsy parameters with innate and adaptive immune responses. Likewise, rigorous clinical studies are still necessary to verify the presence and repeatability of these phenomena in human patients. As this technology nears regulatory approval for clinical use, it is our expectation that the insights and immunomodulatory mechanisms summarized in this review will serve as directional guides for rational clinical studies to validate and optimize the potential immunotherapeutic role of histotripsy tumor ablation.
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Affiliation(s)
- Khan M. Imran
- Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, USA
| | - Anutosh Ganguly
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Tamalika Paul
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA
| | - Manali Powar
- Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, USA
| | - Eli Vlaisavljevich
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, USA
- Institute for Critical and Applied Science Center for Engineered Health, Virginia Tech, Blacksburg, VA, USA
| | - Clifford S. Cho
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
- Research Service, Ann Arbor VA Healthcare, Ann Arbor, MI, USA
| | - Irving C. Allen
- Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, USA
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA
- Institute for Critical and Applied Science Center for Engineered Health, Virginia Tech, Blacksburg, VA, USA
- Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
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22
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Arenas-Luna VM, Montesinos JJ, Cortés-Morales VA, Navarro-Betancourt JR, Peralta-Ildefonso J, Cisneros B, Hernández-Gutiérrez S. In Vitro Evidence of Differential Immunoregulatory Response between MDA-MB-231 and BT-474 Breast Cancer Cells Induced by Bone Marrow-Derived Mesenchymal Stromal Cells Conditioned Medium. Curr Issues Mol Biol 2022; 45:268-285. [PMID: 36661506 PMCID: PMC9857683 DOI: 10.3390/cimb45010020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 01/04/2023] Open
Abstract
Inside tumors, cancer cells display several mechanisms to create an immunosuppressive environment. On the other hand, by migration processes, mesenchymal stromal cells (MSCs) can be recruited by different cancer tumor types from tissues as distant as bone marrow and contribute to tumor pathogenesis. However, the impact of the immunoregulatory role of MSCs associated with the aggressiveness of breast cancer cells by soluble molecules has not been fully elucidated. Therefore, this in vitro work aimed to study the effect of the conditioned medium of human bone marrow-derived-MSCs (hBM-MSC-cm) on the immunoregulatory capability of MDA-MB-231 and BT-474 breast cancer cells. The hBM-MSC-cm on MDA-MB-231 cells induced the overexpression of TGF-β, IDO, and IL-10 genes. Additionally, immunoregulation assays of mononuclear cells (MNCs) in co-culture with MDA-MB-231 and hBM-MSC-cm decreased lymphocyte proliferation, and increased proteins IL-10, TGF-β, and IDO while also reducing TNF levels, shooting the proportion of regulatory T cells. Conversely, the hBM-MSC-cm did not affect the immunomodulatory capacity of BT-474 cells. Thus, a differential immunoregulatory effect was observed between both representative breast cancer cell lines from different origins. Thus, understanding the immune response in a broader tumor context could help to design therapeutic strategies based on the aggressive behavior of tumor cells.
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Affiliation(s)
- Víctor M. Arenas-Luna
- Molecular Biology Laboratory, School of Medicine, Panamerican University, Mexico City 03920, Mexico
- Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City 04740, Mexico
| | - Juan J. Montesinos
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Víctor A. Cortés-Morales
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City 06720, Mexico
| | | | | | - Bulmaro Cisneros
- Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City 04740, Mexico
| | - Salomón Hernández-Gutiérrez
- Molecular Biology Laboratory, School of Medicine, Panamerican University, Mexico City 03920, Mexico
- Correspondence:
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23
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Cheong PK, Ho TM, Chan KL, Lo CW, Leung SB, Hon KL, Leung KC, Siu THC, Song TH, Zhang H, Ching JYL, Chow TY, Sum CH, Chia CP, Lin ZX. The efficacy and safety of Yupingfeng Powder with variation in the treatment of allergic rhinitis: Study protocol for a randomized, double-blind, placebo-controlled trial. Front Pharmacol 2022; 13:1058176. [PMID: 36588672 PMCID: PMC9800420 DOI: 10.3389/fphar.2022.1058176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Background: Allergic rhinitis (AR) is an upper airways chronic inflammatory disease mediated by IgE, which affects 10%-20% of the population. The mainstay for allergic rhinitis nowadays include steroids and antihistamines, but their effects are less than ideal. Many patients therefore seek Chinese medicine for treatment and Yupingfeng Powder is one of the most common formulae prescribed. In this study, we aim to investigate the efficacy and safety of Yupingfeng Powder with variation for the treatment of allergic rhinitis. Study design: This is a double-blind, randomized, placebo-controlled trial. A 2-week screening period will be implemented, and then eligible subjects with allergic rhinitis will receive interventions of either "Yupingfeng Powder with variation" granules or placebo granules for 8 weeks, followed by post treatment visits at weeks 12 and 16. The change in the Total Nasal Symptom Score (TNSS) will be used as the primary outcome. Discussion: This trail will evaluate the efficacy and safety of Yupingfeng Powder in treating allergic rhinitis. The study may provide the solid evidence of Yupingfeng Powder with variation can produce better clinical efficacy than the placebo granules. Trial registration: ClinicalTrials.gov, identifier NCT04976023.
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Affiliation(s)
- Pui Kuan Cheong
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,S. H. Ho Centre for Digestive Health, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tin Muk Ho
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Kam Leung Chan
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Cho Wing Lo
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,S. H. Ho Centre for Digestive Health, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Sin Bond Leung
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China,Department of Medicine and Geriatric, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China
| | - Kam Lun Hon
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka Chun Leung
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tony Hon Chung Siu
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tian-He Song
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Hongwei Zhang
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jessica Yuet Ling Ching
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,S. H. Ho Centre for Digestive Health, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tak Yee Chow
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi Him Sum
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Chon Pin Chia
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhi-Xiu Lin
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China,School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China,*Correspondence: Zhi-Xiu Lin,
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Babaahmadi M, Tayebi B, Gholipour NM, Bendele P, Pheneger J, Kheimeh A, Kamali A, Molazem M, Baharvand H, Eslaminejad MB, Hajizadeh-Saffar E, Hassani SN. Long-term passages of human clonal mesenchymal stromal cells can alleviate the disease in the rat model of collagen-induced arthritis resembling early passages of different heterogeneous cells. J Tissue Eng Regen Med 2022; 16:1261-1275. [PMID: 36437574 DOI: 10.1002/term.3368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/26/2022] [Accepted: 11/01/2022] [Indexed: 11/29/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown cause. The interaction of immune system cells and the secretion of inflammatory cytokines with synovial cells leads to severe inflammation in the affected joints. Currently, medications, including non-steroidal anti-inflammatory drugs, glucocorticoids, and more recently, disease-modifying anti-rheumatic drugs, are used to reduce inflammation. However, long-term use of these drugs causes adverse effects or resistance in a considerable number of RA patients. Recent findings revealed the safety and efficacy of mesenchymal stromal cells (MSCs)-based therapies both in RA animal models and clinical trials. Here, the beneficial effects of bone marrow-derived heterogeneous MSCs (BM-hMSCs) and Wharton jelly-derived MSCs (WJ-MSCs) at early passages were compared to BM-derived clonal MSCs (BM-cMSCs) at high passage number on a rat model of collagen-induced arthritis. Results showed that systemic delivery of MSCs significantly reversed adverse changes in body weight, paw swelling, and arthritis score in all MSC-treated groups. Radiological images and histological evaluation demonstrated the therapeutic effects of MSCs. There was a decrease in serum level of anti-collagen type II immunoglobulin G and the inflammatory cytokines interleukin (IL)-1β, IL-6, IL-17, and tumor necrosis factor-α in all MSC-treated groups. In contrast, an increase in inhibitory cytokines transforming growth factor-β and IL-10 was seen. Notably, the long-term passages of BM-cMSCs could alleviate RA symptoms similar to the early passages of WJ-MSCs and BM-hMSCs. The importance of BM-cMSCs is the potential to establish cell banks with billions of cells derived from a single donor that could be a competitive cell-based therapy to treat RA.
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Affiliation(s)
- Mahnaz Babaahmadi
- Department of Applied Cell Sciences, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Behnoosh Tayebi
- Department of Applied Cell Sciences, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nima Makvand Gholipour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | | | | | - Abolfazl Kheimeh
- Animal Core Facility, Reproductive Biomedicine Research Center, Royan Institute for Animal Biotechnology, ACECR, Tehran, Iran
| | | | - Mohammad Molazem
- Department of Radiology and Surgery, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Seyedeh-Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Wen Y, Zhu Y, Zhang C, Yang X, Gao Y, Li M, Yang H, Liu T, Tang H. Chronic inflammation, cancer development and immunotherapy. Front Pharmacol 2022; 13:1040163. [PMID: 36313280 PMCID: PMC9614255 DOI: 10.3389/fphar.2022.1040163] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/03/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic inflammation plays a pivotal role in cancer development. Cancer cells interact with adjacent cellular components (pro-inflammatory cells, intrinsic immune cells, stromal cells, etc.) and non-cellular components to form the inflammatory tumor microenvironment (TME). Interleukin 6 (IL-6), macrophage migration inhibitory factor (MIF), immune checkpoint factors and other pro-inflammatory cytokines produced by intrinsic immune cells in TME are the main mediators of intercellular communication in TME, which link chronic inflammation to cancer by stimulating different oncogenic signaling pathways and improving immune escape to promote cancer development. In parallel, the ability of monocytes, T regulatory cells (Tregs) and B regulatory cells (Bregs) to perform homeostatic tolerogenic functions is hijacked by cancer cells, leading to local or systemic immunosuppression. Standard treatments for advanced malignancies such as chemotherapy and radiotherapy have improved in the last decades. However, clinical outcomes of certain malignant cancers are not satisfactory due to drug resistance and side effects. The clinical application of immune checkpoint therapy (ICT) has brought hope to cancer treatment, although therapeutic efficacy are still limited due to the immunosuppressive microenvironment. Emerging evidences reveal that ideal therapies including clearance of tumor cells, disruption of tumor-induced immunosuppression by targeting suppressive TME as well as reactivation of anti-tumor T cells by ICT. Here, we review the impacts of the major pro-inflammatory cells, mediators and their downstream signaling molecules in TME on cancer development. We also discuss the application of targeting important components in the TME in the clinical management of cancer.
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Affiliation(s)
- Yalei Wen
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Yingjie Zhu
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Caishi Zhang
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Xiao Yang
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Yuchen Gao
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Mei Li
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Hongyan Yang
- Department of Central Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, China,*Correspondence: Hongyan Yang, ; Tongzheng Liu, ; Hui Tang,
| | - Tongzheng Liu
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China,*Correspondence: Hongyan Yang, ; Tongzheng Liu, ; Hui Tang,
| | - Hui Tang
- Department of Central Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, China,Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University (Heyuan Shenhe People’s Hospital), Heyuan, China,*Correspondence: Hongyan Yang, ; Tongzheng Liu, ; Hui Tang,
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Lopatina T, Sarcinella A, Brizzi MF. Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion. Cancers (Basel) 2022; 14:cancers14164020. [PMID: 36011012 PMCID: PMC9406972 DOI: 10.3390/cancers14164020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/12/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumour onset and development occur because of specific immune support. The immune system, which is originally able to perceive and eliminate incipient cancer cells, becomes suppressed and hijacked by cancer. For these purposes, tumour cells use extracellular vesicles (TEVs). Specific molecular composition allows TEVs to reprogram immune cells towards tumour tolerance. Circulating TEVs move from their site of origin to other organs, preparing “a fertile soil” for metastasis formation. This implies that TEV molecular content can provide a valuable tool for cancer biomarker discovery and potential targets to reshape the immune system into tumour recognition and eradication. Abstract Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different immune cells. Tumour-surrounding tissues also contribute to tumour immune editing and evasion, tumour progression, and drug resistance via locally released TEV. Moreover, the increase in circulating TEV has suggested their underpinning role in tumour dissemination. This review brings together data referring to TEV-driven immune regulation and antitumour immune suppression. Attention was also dedicated to TEV-mediated drug resistance.
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Svanberg C, Nyström S, Govender M, Bhattacharya P, Che KF, Ellegård R, Shankar EM, Larsson M. HIV-1 induction of tolerogenic dendritic cells is mediated by cellular interaction with suppressive T cells. Front Immunol 2022; 13:790276. [PMID: 36032117 PMCID: PMC9399885 DOI: 10.3389/fimmu.2022.790276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
HIV-1 infection gives rise to a multi-layered immune impairment in most infected individuals. The chronic presence of HIV-1 during the priming and activation of T cells by dendritic cells (DCs) promotes the expansion of suppressive T cells in a contact-dependent manner. The mechanism behind the T cell side of this HIV-induced impairment is well studied, whereas little is known about the reverse effects exerted on the DCs. Herein we assessed the phenotype and transcriptome profile of mature DCs that have been in contact with suppressive T cells. The HIV exposed DCs from cocultures between DCs and T cells resulted in a more tolerogenic phenotype with increased expression of e.g., PDL1, Gal-9, HVEM, and B7H3, mediated by interaction with T cells. Transcriptomic analysis of the DCs separated from the DC-T cell coculture revealed a type I IFN response profile as well as an activation of pathways involved in T cell exhaustion. Taken together, our data indicate that the prolonged and strong type I IFN signaling in DCs, induced by the presence of HIV during DC-T cell cross talk, could play an important role in the induction of tolerogenic DCs and suppressed immune responses seen in HIV-1 infected individuals.
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Affiliation(s)
- Cecilia Svanberg
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Sofia Nyström
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Clinical Immunology and Transfusion Medicine, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Melissa Govender
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Pradyot Bhattacharya
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Karlhans F. Che
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Rada Ellegård
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Division of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Esaki M. Shankar
- Infection Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Marie Larsson
- Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- *Correspondence: Marie Larsson,
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Sana M, Rashid M, Rashid I, Akbar H, Gomez-Marin JE, Dimier-Poisson I. Immune response against toxoplasmosis-some recent updates RH: Toxoplasma gondii immune response. Int J Immunopathol Pharmacol 2022; 36:3946320221078436. [PMID: 35227108 PMCID: PMC8891885 DOI: 10.1177/03946320221078436] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AIMS Cytokines, soluble mediators of immunity, are key factors of the innate and adaptive immune system. They are secreted from and interact with various types of immune cells to manipulate host body's immune cell physiology for a counter-attack on the foreign body. A study was designed to explore the mechanism of Toxoplasma gondii (T. gondii) resistance from host immune response. METHODS AND RESULTS The published data on aspect of host (murine and human) immune response against T. gondii was taken from Google scholar and PubMed. Most relevant literature was included in this study. The basic mechanism of immune response starts from the interactions of antigens with host immune cells to trigger the production of cytokines (pro-inflammatory and anti-inflammatory) which then act by forming a cytokinome (network of cytokine). Their secretory equilibrium is essential for endowing resistance to the host against infectious diseases, particularly toxoplasmosis. A narrow balance lying between Th1, Th2, and Th17 cytokines (as demonstrated until now) is essential for the development of resistance against T. gondii as well as for the survival of host. Excessive production of pro-inflammatory cytokines leads to tissue damage resulting in the production of anti-inflammatory cytokines which enhances the proliferation of Toxoplasma. Stress and other infectious diseases (human immunodeficiency virus (HIV)) that weaken the host immunity particularly the cellular component, make the host susceptible to toxoplasmosis especially in pregnant women. CONCLUSION The current review findings state that in vitro harvesting of IL12 from DCs, Np and MΦ upon exposure with T. gondii might be a source for therapeutic use in toxoplasmosis. Current review also suggests that therapeutic interventions leading to up-regulation/supplementation of SOCS-3, IL12, and IFNγ to the infected host could be a solution to sterile immunity against T. gondii infection. This would be of interest particularly in patients passing through immunosuppression owing to any reason like the ones receiving anti-cancer therapy, the ones undergoing immunosuppressive therapy for graft/transplantation, the ones suffering from immunodeficiency virus (HIV) or having AIDS. Another imortant suggestion is to launch the efforts for a vaccine based on GRA6Nt or other similar antigens of T. gondii as a probable tool to destroy tissue cysts.
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Affiliation(s)
- Madiha Sana
- Department of Parasitology, 66920University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Muhammad Rashid
- Department of Parasitology, Faculty of Veterinary and Animal Sciences, 66920The Islamia University of Bahawalpur, Pakistan
| | - Imran Rashid
- Department of Parasitology, 66920University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Haroon Akbar
- Department of Parasitology, 66920University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Jorge E Gomez-Marin
- Grupo Gepamol, Centro de Investigaciones Biomedicas, Universidad del Quindio, Armenia, CO, South America
| | - Isabelle Dimier-Poisson
- Université de Tours, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Unité mixte de recherche 1282 (UMR1282), Infectiologie et santé publique (ISP), Tours, France
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Hu G, Zhou X. Gallic Acid Ameliorates Atopic Dermatitis-Like Skin Inflammation Through Immune Regulation in a Mouse Model. Clin Cosmet Investig Dermatol 2021; 14:1675-1683. [PMID: 34815684 PMCID: PMC8605796 DOI: 10.2147/ccid.s327825] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/12/2021] [Indexed: 12/17/2022]
Abstract
Background Gallic acid (GA) has an anti-inflammatory effect by regulating inflammatory molecules. This study aimed to investigate the effect of GA on atopic dermatitis (AD)-like skin inflammation. Methods 4-dinitrochlorobenzene (DNCB) was used to induce an AD-like skin inflammation model. The effect of GA on DNCB-induced inflammation was assessed by measuring the thickness and histopathological examination of the ear. Serum IgE and TNF-α levels were detected. The effect of GA on lymph nodes was determined by measuring the weights and mRNA/protein expression levels of TNF-α, IL-4, IFN-γ and IL-17. Ratio of Treg cells and Th17 cells was also analyzed. Results It was found that the thickness and pathology of the ear were significantly improved by GA in the DNCB-induced mice. Serum IgE and TNF-α levels were significantly reduced in GA-treated model mice compared to the model group. GA treatment lowered the weight of lymph node and the expression of mRNAs of TNF-α, IL-4, IFN-γ, and IL-17 of lymph node. In the ear, inflammatory factors (IL-4, IL-5, IL-17, or IL-23) showed a significant decrease in GA-treated model mice versus model mice, while the expression levels of IL-10 and TGF-β showed a great increase in GA-treated model mice. ROR-γt showed a decrease in GA-treated model group, along with an increase expression of SOCS3. Conclusion GA could ameliorate AD-like skin inflammation possibly through Th17 mediated immune regulation in a DNCB-induced mouse model.
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Affiliation(s)
- Guohong Hu
- Dermatology Hospital of Jiangxi Province, Nanchang, 330001, Jiangxi, People's Republic of China
| | - Xiansheng Zhou
- Dermatology Hospital of Jiangxi Province, Nanchang, 330001, Jiangxi, People's Republic of China
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Xiang Y, Dai J, Xu L, Li X, Jiang J, Xu J. Research progress in immune microenvironment regulation of muscle atrophy induced by peripheral nerve injury. Life Sci 2021; 287:120117. [PMID: 34740577 DOI: 10.1016/j.lfs.2021.120117] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 09/18/2021] [Accepted: 10/28/2021] [Indexed: 01/08/2023]
Abstract
Denervated skeletal muscular atrophy is primarily characterized by loss of muscle strength and mass and an unideal functional recovery of the muscle after extended denervation. This review emphasizes the interaction between the immune system and the denervated skeletal muscle. Immune cells such as neutrophils, macrophages and T-cells are activated and migrate to denervated muscle, where they release a high concentration of cytokines and chemokines. The migration of these immune cells, the transformation of different functional immune cell subtypes, and the cytokine network in the immune microenvironment may be involved in the regulatory process of muscle atrophy or repair. However, the exact mechanisms of the interaction between these immune cells and immune molecules in skeletal muscles are unclear. In this paper, the immune microenvironment regulation of muscle atrophy induced by peripheral nerve injury is reviewed.
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Affiliation(s)
- Yaoxian Xiang
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai, China; Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China
| | - Junxi Dai
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai, China; Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China
| | - Lei Xu
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai, China; Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China
| | - Xiaokang Li
- Natl Res Inst Child Hlth & Dev, Div Transplantat Immunol, Tokyo, Japan
| | - Junjian Jiang
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai, China; Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China.
| | - Jianguang Xu
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai, China; Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Hot or cold: Bioengineering immune contextures into in vitro patient-derived tumor models. Adv Drug Deliv Rev 2021; 175:113791. [PMID: 33965462 DOI: 10.1016/j.addr.2021.05.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/02/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
In the past decade, immune checkpoint inhibitors (ICI) have proven to be tremendously effective for a subset of cancer patients. However, it is difficult to predict the response of individual patients and efforts are now directed at understanding the mechanisms of ICI resistance. Current models of patient tumors poorly recapitulate the immune contexture, which describe immune parameters that are associated with patient survival. In this Review, we discuss parameters that influence the induction of different immune contextures found within tumors and how engineering strategies may be leveraged to recapitulate these contextures to develop the next generation of immune-competent patient-derived in vitro models.
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Cuesta C, Arévalo-Alameda C, Castellano E. The Importance of Being PI3K in the RAS Signaling Network. Genes (Basel) 2021; 12:1094. [PMID: 34356110 PMCID: PMC8303222 DOI: 10.3390/genes12071094] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/06/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.
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Affiliation(s)
| | | | - Esther Castellano
- Tumour-Stroma Signalling Laboratory, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain; (C.C.); (C.A.-A.)
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Hendricks-Wenger A, Hutchison R, Vlaisavljevich E, Allen IC. Immunological Effects of Histotripsy for Cancer Therapy. Front Oncol 2021; 11:681629. [PMID: 34136405 PMCID: PMC8200675 DOI: 10.3389/fonc.2021.681629] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.
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Affiliation(s)
- Alissa Hendricks-Wenger
- Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, United States
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United States
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, United States
| | - Ruby Hutchison
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, United States
| | - Eli Vlaisavljevich
- Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, United States
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, United States
- Institute for Critical Technology and Applied Sciences Center for Engineered Health, Virginia Tech, Blacksburg, VA, United States
| | - Irving Coy Allen
- Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, United States
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United States
- Institute for Critical Technology and Applied Sciences Center for Engineered Health, Virginia Tech, Blacksburg, VA, United States
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
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Kolobarić N, Drenjančević I, Matić A, Šušnjara P, Mihaljević Z, Mihalj M. Dietary Intake of n-3 PUFA-Enriched Hen Eggs Changes Inflammatory Markers' Concentration and Treg/Th17 Cells Distribution in Blood of Young Healthy Adults-A Randomised Study. Nutrients 2021; 13:nu13061851. [PMID: 34071714 PMCID: PMC8229500 DOI: 10.3390/nu13061851] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/28/2022] Open
Abstract
In the present study, we aimed to determine the effects of n-3 polyunsaturated acid (PUFA) supplementation (~1053 mg/per day), i.e., α-linolenic (~230 mg), eicosapentaenoic (~15 mg), and docosahexaenoic acid (~105 mg), through hen eggs, on pro- and anti-inflammatory parameters in healthy individuals (23.8 ± 2.57 years old). Here, we demonstrate differential effects of regular hen eggs (N = 21; W/M = 10/11) and n-3 PUFA-enriched hen eggs (N = 19; W/M = 10/9) consumption on the serum levels of lipid mediators, representation of peripheral T helper cell subsets (recently activated T-helper cells, nTreg, Th17 and non-Th17-IL-17A secreting T-helper lymphocytes) and their functional capacity for cytokine secretion. Both diets significantly altered systemic levels of pro-inflammatory and inflammation resolving lipid mediators; however, only the n-3 PUFAs group showed a significant shift towards anti-inflammatory prostanoids and increased levels of pro-resolving oxylipins. Both study groups showed reduced frequencies of peripheral nTreg lymphocytes and decreased rates of peripheral Th17 cells. Their functional capacity for cytokine secretion was significantly altered only in the n-3 PUFAs group in terms of increased transforming growth factor β-1 and reduced interleukin 6 secretion. Diet supplemented with n-3 PUFAs alters immune response towards inflammation resolving conditions through effects on lipid mediators and cytokine secretion by T lymphocytes in human model without underlying comorbidities.
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Affiliation(s)
- Nikolina Kolobarić
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (N.K.); (I.D.); (A.M.); (P.Š.); (Z.M.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia
| | - Ines Drenjančević
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (N.K.); (I.D.); (A.M.); (P.Š.); (Z.M.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia
| | - Anita Matić
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (N.K.); (I.D.); (A.M.); (P.Š.); (Z.M.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia
| | - Petar Šušnjara
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (N.K.); (I.D.); (A.M.); (P.Š.); (Z.M.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia
| | - Zrinka Mihaljević
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (N.K.); (I.D.); (A.M.); (P.Š.); (Z.M.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia
| | - Martina Mihalj
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (N.K.); (I.D.); (A.M.); (P.Š.); (Z.M.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia
- Department of Dermatology and Venereology, Osijek University Hospital, J. Huttlera 4, 31000 Osijek, Croatia
- Correspondence: ; Tel.: +385-3151-2800
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Xu S, Ma Y, Chen Y, Pan F. Role of Forkhead box O3a transcription factor in autoimmune diseases. Int Immunopharmacol 2021; 92:107338. [PMID: 33412391 DOI: 10.1016/j.intimp.2020.107338] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/05/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
Forkhead box O3a (FOXO3a) transcription factor, the most important member of Forkhead box O family, is closely related to cell proliferation, apoptosis, autophagy, oxidative stress and aging. The downregulation of FOXO3a has been verified to be associated with the poor prognosis, severer malignancy and chemoresistance in several human cancers. The activity of FOXO3a mainly regulated by phosphorylation of protein kinase B. FOXO3a plays a vital role in promoting the apoptosis of immune cells. FOXO3a could also modulate the activation, differentiation and function of T cells, regulate the proliferation and function of B cells, and mediate dendritic cells tolerance and immunity. FOXO3a accommodates the immune response through targeting nuclear factor kappa-B and FOXP3, as well as regulating the expression of cytokines. Besides, FOXO3a participates in intercellular interactions. FOXO3a inhibits dendritic cells from producing interleukin-6, which inhibits B-cell lymphoma-2 (BCL-2) and BCL-XL expression, thereby sparing resting T cells from apoptosis and increasing the survival of antigen-stimulated T cells. Recently, plentiful evidences further illustrated the significance of FOXO3a in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, myositis, multiple sclerosis, and systemic sclerosis. In this review, we focused on the biological function of FOXO3a and related signaling pathways regarding immune system, and summarized the potential role of FOXO3a in the pathogenesis, progress and therapeutic potential of autoimmune diseases.
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Affiliation(s)
- Shanshan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yuting Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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36
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Song HY, Kim WS, Han JM, Seo HS, Lim ST, Byun EB. Galangin treatment during dendritic cell differentiation confers tolerogenic properties in response to lipopolysaccharide stimulation. J Nutr Biochem 2021; 87:108524. [PMID: 33039583 DOI: 10.1016/j.jnutbio.2020.108524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 09/15/2020] [Accepted: 09/30/2020] [Indexed: 12/28/2022]
Abstract
Tolerogenic dendritic cells (tolDCs) can induce the differentiation of immunosuppressive regulatory T cells and are therefore candidates for the prevention or treatment of various inflammatory diseases. Galangin, a major component of propolis and Alpinia officinarum, has well-established anti-inflammatory effects, but its ability to induce a tolerogenic state in DCs has not been demonstrated. In this study, we investigated the effects of galangin on DC differentiation and immune responses. In particular, we compared phenotypic and functional differences between DCs (Gal-DCs) generated by galangin treatment during DC differentiation and bone marrow-derived DCs. Gal-DCs were generated by adding culture medium containing various doses of galangin (1.8-18.5 µM) on 3 and 6 day. Upon lipopolysaccharide (100 ng/mL) stimulation for 24 h, Gal-DCs generated with 7.4 µM galangin treatment showed lower levels of CD86 and lower major histocompatibility complex class II antigen-presentation than those of bone marrow-derived DCs. Furthermore, Gal-DCs showed markedly increased programmed death ligand 1 expression and IL-10 production via the activation of mitogen-activated protein kinases. Interestingly, Gal-DCs co-cultured with allogeneic CD4 T cells exhibited the reduced cell proliferation and differentiation into Th1-, Th2-, and Th17-type cell; instead, Gal-DCs contributed to the induction of CD4+CD25+Foxp3+ Tregs. Taken together, our data suggest that exposure to galangin during DC differentiation confers tolerogenic properties, efficiently inducing Th cell differentiation to immunosuppressive Tregs. These findings provide new insights into the molecular mechanism underlying the anti-inflammatory effects of galangin on DCs.
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Affiliation(s)
- Ha-Yeon Song
- Research Division for Radiation Science, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea; Department of Biotechnology, College of Life science and Biotechnology, Korea University, Seoul, Republic of Korea.
| | - Woo Sik Kim
- Research Division for Radiation Science, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea
| | - Jeong Moo Han
- Research Division for Radiation Science, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea; Department of Biotechnology, College of Life science and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Ho Seong Seo
- Research Division for Radiation Science, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea
| | - Seung-Taik Lim
- Department of Biotechnology, College of Life science and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Eui-Baek Byun
- Research Division for Radiation Science, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea
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Alonso-Guallart P, Llore N, Lopes E, Kofman SB, Ho SH, Stern J, Pierre G, Bruestle K, Tang Q, Sykes M, Griesemer A. CD40L-stimulated B cells for ex-vivo expansion of polyspecific non-human primate regulatory T cells for translational studies. Clin Exp Immunol 2020; 203:480-492. [PMID: 33058141 DOI: 10.1111/cei.13537] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 08/31/2020] [Accepted: 10/01/2020] [Indexed: 12/14/2022] Open
Abstract
The therapeutic applications of regulatory T cells (Tregs ) include treating autoimmune diseases, graft-versus-host disease and induction of transplantation tolerance. For ex-vivo expanded Tregs to be used in deceased donor transplantation, they must be able to suppress T cell responses to a broad range of human leukocyte antigen (HLA). Here, we present a novel approach for the expansion of polyspecific Tregs in cynomolgus macaques that was adapted from a good manufacturing practice-compliant protocol. Tregs were isolated by fluorescence-activated cell sorting (FACS) and expanded in the presence of a panel of CD40L-stimulated B cells (CD40L-sBc). Prior to Treg culture, CD40L-sBc were expanded in vitro from multiple major histocompatibility complex (MHC)-disparate macaques. Expanded Tregs expressed high levels of forkhead box protein 3 (FoxP3) and Helios, a high percentage of Treg -specific demethylated region (TSDR) demethylation and strong suppression of naïve T cell responses in vitro. In addition, these Tregs produced low levels of inflammatory cytokines and were able to expand post-cryopreservation. Specificity assays confirmed that these Tregs were suppressive upon activation by any antigen-presenting cells (APCs) whose MHC was shared by CD40L-sBc used during expansion, proving that they are polyspecific. We developed an approach for the expansion of highly suppressive cynomolgus macaque polyspecific Tregs through the use of a combination of CD40L-engineered B cells with the potential to be translated to clinical studies. To our knowledge, this is the first report that uses a pool of MHC-mismatched CD40L-sBc to create polyspecific Tregs suitable for use in deceased-donor transplants.
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Affiliation(s)
- P Alonso-Guallart
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - N Llore
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - E Lopes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - S-B Kofman
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - S-H Ho
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - J Stern
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - G Pierre
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - K Bruestle
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Q Tang
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - M Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.,Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA.,Department of Surgery, Columbia University Medical Center, New York, NY, USA
| | - A Griesemer
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.,Department of Surgery, Columbia University Medical Center, New York, NY, USA
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Janssens I, Cools N. Regulating the regulators: Is introduction of an antigen-specific approach in regulatory T cells the next step to treat autoimmunity? Cell Immunol 2020; 358:104236. [PMID: 33137651 DOI: 10.1016/j.cellimm.2020.104236] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/28/2020] [Accepted: 10/04/2020] [Indexed: 12/22/2022]
Abstract
In autoimmunity, the important and fragile balance between immunity and tolerance is disturbed, resulting in abnormal immune responses to the body's own tissues and cells. CD4+CD25hiFoxP3+ regulatory T cells (Tregs) induce peripheral tolerance in vivo by means of direct cell-cell contact and release of soluble factors, or indirectly through antigen-presenting cells (APC), thereby controlling auto-reactive effector T cells. Based on these unique capacities of Tregs, preclinical studies delivered proof-of-principle for the clinical use of Tregs for the treatment of autoimmune diseases. To date, the first clinical trials using ex vivo expanded polyclonal Tregs have been completed. These pioneering studies demonstrate the feasibility of generating large numbers of polyclonal Tregs in a good manufacturing practices (GMP)-compliant manner, and that infusion of Tregs is well tolerated by patients with no evidence of general immunosuppression. Nonetheless, only modest clinical results were observed, arguing that a more antigen-specific approach might be needed to foster a durable patient-specific clinical cell therapy without the risk for general immunosuppression. In this review, we discuss current knowledge, applications and future goals of adoptive immune-modulatory Treg therapy for the treatment of autoimmune disease and transplant rejection. We describe the key advances and prospects of the potential use of T cell receptor (TCR)- and chimeric antigen receptor (CAR)-engineered Tregs in future clinical applications. These approaches could deliver the long-awaited breakthrough in stopping undesired autoimmune responses and transplant rejections.
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Affiliation(s)
- Ibo Janssens
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium.
| | - Nathalie Cools
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium
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Enhancement of Immune Activities of Mixtures with Sasa quelpaertensis Nakai and Ficus erecta var. sieboldii. Foods 2020; 9:foods9070868. [PMID: 32630826 PMCID: PMC7404794 DOI: 10.3390/foods9070868] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/25/2020] [Accepted: 06/28/2020] [Indexed: 12/02/2022] Open
Abstract
The objective of the present study was to develop a concoction of natural products that could dramatically improve immune function with minimal possible side effects. Sasa quelpaertensis Nakai and Ficus erecta var. sieboldii are plants that are native to Jeju Island, Korea and are known to be rich in physiologically active substances. We prepared a mixture of different proportions and extraction conditions using two natural plants and determined their optimum mixing ratio and extraction method by assessing immune function-related biomarkers in RAW264.7 macrophages. Optimal extract (HR02/04(8:2)-W) was selected from in vitro experiments and its immunity-enhancing efficacy was evaluated in mice. After oral administration of extract to BALB/c mice for 2 weeks, nitric oxide production in the peritoneal exudate cells, natural killer cell cytotoxicity, cytokine expression in splenocytes, and total cell number of immune tissues and phenotype analysis were evaluated. Our results demonstrated that HR02/04(8:2)-W significantly enhanced the immune system by increasing natural killer cell activity, cytokine expression, and total number of cells in immune tissues. In conclusion, our study validates the role of HR02/04(8:2)-W in enhancing immunity and its potential development as a functional food.
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40
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Krop J, Heidt S, Claas FHJ, Eikmans M. Regulatory T Cells in Pregnancy: It Is Not All About FoxP3. Front Immunol 2020; 11:1182. [PMID: 32655556 PMCID: PMC7324675 DOI: 10.3389/fimmu.2020.01182] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 05/13/2020] [Indexed: 12/15/2022] Open
Abstract
In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed.
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Affiliation(s)
- Juliette Krop
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Sebastiaan Heidt
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Frans H J Claas
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Michael Eikmans
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
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Chulpanova DS, Kitaeva KV, Green AR, Rizvanov AA, Solovyeva VV. Molecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy. Front Cell Dev Biol 2020; 8:402. [PMID: 32582698 PMCID: PMC7283917 DOI: 10.3389/fcell.2020.00402] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 05/01/2020] [Indexed: 12/11/2022] Open
Abstract
Cytokine-based immunotherapy is a promising field in the cancer treatment, since cytokines, as proteins of the immune system, are able to modulate the host immune response toward cancer cell, as well as directly induce tumor cell death. Since a low dose monotherapy with some cytokines has no significant therapeutic results and a high dose treatment leads to a number of side effects caused by the pleiotropic effect of cytokines, the problem of understanding the influence of cytokines on the immune cells involved in the pro- and anti-tumor immune response remains a pressing one. Immune system cells carry CD makers on their surface which can be used to identify various populations of cells of the immune system that play different roles in pro- and anti-tumor immune responses. This review discusses the functions and specific CD markers of various immune cell populations which are reported to participate in the regulation of the immune response against the tumor. The results of research studies and clinical trials investigating the effect of cytokine therapy on the regulation of immune cell populations and their surface markers are also discussed. Current trends in the development of cancer immunotherapy, as well as the role of cytokines in combination with other therapeutic agents, are also discussed.
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Affiliation(s)
- Daria S Chulpanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Kristina V Kitaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Andrew R Green
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, United Kingdom
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, United Kingdom
| | - Valeriya V Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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42
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Fuhler GM. The immune system and microbiome in pregnancy. Best Pract Res Clin Gastroenterol 2020; 44-45:101671. [PMID: 32359685 DOI: 10.1016/j.bpg.2020.101671] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/19/2020] [Accepted: 03/05/2020] [Indexed: 01/31/2023]
Abstract
Hormonal changes during pregnancy instigate numerous physiological changes aimed at the growth and delivery of a healthy baby. A careful balance between immunological tolerance against fetal antigens and immunity against infectious agents needs to be maintained. A three-way interaction between pregnancy hormones, the immune system and our microbiota is now emerging. Recent evidence suggests that microbial alterations seen during pregnancy may help maintain homeostasis and aid the required physiological changes occurring in pregnancy. However, these same immunological and microbial alterations may also make women more vulnerable during pregnancy and the post-partum period, especially regarding immunological and infectious diseases. Thus, a further understanding of the host-microbial interactions taking place during pregnancy may improve identification of populations at risk for adverse pregnancy outcomes.
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Affiliation(s)
- G M Fuhler
- Erasmus MC University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Erasmus Medical Center, Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
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Kim HW, Ju DB, Kye YC, Ju YJ, Kim CG, Lee IK, Park SM, Choi IS, Cho KK, Lee SH, Kim SC, Jung ID, Han SH, Yun CH. Galectin-9 Induced by Dietary Probiotic Mixture Regulates Immune Balance to Reduce Atopic Dermatitis Symptoms in Mice. Front Immunol 2020; 10:3063. [PMID: 32038618 PMCID: PMC6987441 DOI: 10.3389/fimmu.2019.03063] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/16/2019] [Indexed: 12/22/2022] Open
Abstract
Probiotics can be an effective treatment for atopic dermatitis (AD), while their mechanism of action is still unclear. Here, we induced AD in mice with 2,4-dinitrochlorobenzene and administrated YK4, a probiotic mixture consisting of Lactobacillus acidophilus CBT LA1, L. plantarum CBT LP3, Bifidobacterium breve CBT BR3, and B. lactis CBT BL3. Then, we have validated the underlying mechanism for the alleviation of AD by YK4 from the intestinal and systematic immunological perspectives. Administration of YK4 in AD mice alleviated the symptoms of AD by suppressing the expression of skin thymic stromal lymphopoietin and serum immunoglobulin E eliciting excessive T-helper (Th) 2 cell-mediated responses. YK4 inhibited Th2 cell population through induce the proportion of Th1 cells in spleen and Treg cells in Peyer's patches and mesenteric lymph node (mLN). CD103+ dendritic cells (DCs) in mLN and the spleen were significantly increased in AD mice administered with YK4 when compared to AD mice. Furthermore, galectin-9 was significantly increased in the gut of AD mice administered with YK4. In vitro experiments were performed using bone marrow-derived DCs (BMDC) and CD4+ T cells to confirm the immune mechanisms of YK4 and galectin-9. The expression of CD44, a receptor of galectin-9, together with programmed death-ligand 1 was significantly upregulated in BMDCs following treatment with YK4. IL-10 and IL-12 were upregulated when BMDCs were treated with YK4. Cytokines together with co-receptors from DCs play a major role in the differentiation and activation of CD4+ T cells. Proliferation of Tregs and Th1 cell activation were enhanced when CD4+T cells were co-cultured with YK4-treated BMDCs. Galectin-9 appeared to contribute at least partially to the proliferation of Tregs. The results further suggested that DCs treated with YK4 induced the differentiation of naïve T cells toward Th1 and Tregs. At the same time, YK4 alleviated AD symptoms by inhibiting Th2 response. Thus, the present study suggested a potential role of YK4 as an effective immunomodulatory agent in AD patients.
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Affiliation(s)
- Han Wool Kim
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - Do Bin Ju
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - Yoon-Chul Kye
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - Young-Jun Ju
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - Cheol Gyun Kim
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - In Kyu Lee
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - Sung-Moo Park
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
| | - In Soon Choi
- Department of Biological Science, College of Medical and Life Sciences, Silla University, Busan, South Korea
| | - Kwang Keun Cho
- Department of Animal Resources Technology, Gyeongnam National University of Science and Technology, Jinju, South Korea
| | - Seung Ho Lee
- Department of Nano-Bioengineering, Incheon National University, Incheon, South Korea
| | - Sung Chan Kim
- Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon, South Korea
| | - In Duk Jung
- Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Chungju, South Korea
| | - Seung Hyun Han
- Department of Oral Microbiology and Immunology, Dental Research Institute and Brain Korea 21 Plus Program, School of Dentistry, Seoul National University, Seoul, South Korea
| | - Cheol-Heui Yun
- Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea.,Institute of Green Bio Science Technology, Seoul National University, Seoul, South Korea.,Center for Food and Bioconvergence, Seoul National University, Seoul, South Korea
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44
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Horwitz DA, Fahmy TM, Piccirillo CA, La Cava A. Rebalancing Immune Homeostasis to Treat Autoimmune Diseases. Trends Immunol 2019; 40:888-908. [PMID: 31601519 DOI: 10.1016/j.it.2019.08.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 08/01/2019] [Accepted: 08/14/2019] [Indexed: 12/18/2022]
Abstract
During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.
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Affiliation(s)
- David A Horwitz
- General Nanotherapeutics, LLC, Santa Monica, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Tarek M Fahmy
- Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA; Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada; Program in Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montréal, QC, Canada; Centre of Excellence in Translational Immunology (CETI), Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Antonio La Cava
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
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Al-Dabbagh S, McPhee JS, Piasecki M, Stewart CE, Al-Shanti N. Soluble Factors Released From Activated T Lymphocytes Regulate C2C12 Myoblast Proliferation and Cellular Signaling, but Effects Are Blunted in the Elderly. J Gerontol A Biol Sci Med Sci 2019; 74:1375-1385. [PMID: 30329021 DOI: 10.1093/gerona/gly238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Indexed: 12/11/2022] Open
Abstract
The key objective of this work was to investigate the impact of young and old human lymphocyte secretomes on C2C12 myoblasts regeneration. Conditioned media were harvested from isolated young and older lymphocytes treated with (activated [AC]) or without (nonactivated [NA]), anti-CD3/CD28 activators for 4 days. AC conditioned media from older lymphocytes had decreased levels of amphiregulin (367 ± 208 pg/mL vs 904 ± 323 pg/mL; p = .018) and IGF-I (845 ± 88 ng/mL vs 1100 ± 48 ng/mL; p = .032) compared with younger AC lymphocytes. AC older versus younger lymphocytes had reduced expression of CD25 (24.6 ± 5.5%; p = .0003) and increased expression of FoxP3 (35 ± 15.7%; p = .032). Treatment of C2C12 myoblasts with young AC lymphocytes resulted in decreased expression of MyoD (0.46 ± 0.12; p =.004) and Myogenin (0.34 ± 0.05; p = .010) mRNA, increased activation of MEk1 (724 ± 140 mean fluorescent intensity [MFI]; p =.001) and ERK1/2 (3768 ± 314 MFI; p =.001), and a decreased activation of Akt (74.5 ± 4 MFI; p = .009) and mTOR (61.8 ± 7 MFI; p = .001) compared with old AC lymphocytes. By contrast, C2C12 myoblasts treated with older AC lymphocytes displayed increased expression of MyoD (0.7 ± 0.08; p =.004) and Myogenin (0.68 ± 0.05; p =.010) mRNA, decreased phosphorylation of MEk1 and ERK1/2 (528 ± 80 MFI; p = .008, and 1141 ± 668 MFI; p = .001, respectively), and increased Akt/mTOR activation (171 ± 35 MFI; p = .009, and 184 ± 33 MFI; p = .001, respectively). These data provide new evidence that differences between older and younger lymphocyte secretomes contribute to differential responses of C2C12 myoblasts in culture.
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Affiliation(s)
- Sarah Al-Dabbagh
- School of Healthcare Science, Manchester Metropolitan University
| | - Jamie S McPhee
- Department of Sport and Exercise Sciences, Faculty of Science and Engineering, Manchester Metropolitan University
| | - Mathew Piasecki
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute of Health Research, Biomedical Research Centre, School of Medicine, University of Nottingham
| | - Claire E Stewart
- Research Institute for Sport and Exercise Sciences, School of Sport and Exercise Sciences, Faculty of Science, Liverpool John Moores University
| | - Nasser Al-Shanti
- School of Healthcare Science, Manchester Metropolitan University
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Alonso-Guallart P, Zitsman JS, Stern J, Kofman SB, Woodland D, Ho SH, Sondermeijer HP, Bühler L, Griesemer A, Sykes M, Duran-Struuck R. Characterization, biology, and expansion of regulatory T cells in the Cynomolgus macaque for preclinical studies. Am J Transplant 2019; 19:2186-2198. [PMID: 30768842 PMCID: PMC6658340 DOI: 10.1111/ajt.15313] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 01/16/2019] [Accepted: 02/04/2019] [Indexed: 01/25/2023]
Abstract
Reliable in vitro expansion protocols of regulatory T cells (Tregs) are needed for clinical use. We studied the biology of Mauritian Cynomolgus macaque (MCM) Tregs and developed four in vitro Treg expansion protocols for translational studies. Tregs expanded 3000-fold when artificial antigen presenting cells (aAPCs) expressing human CD80, CD58 and CD32 were used throughout the culture. When donor peripheral blood mononuclear cells (PBMCs) were used as the single source of APCs followed by aAPCs, Tregs expanded 2000-fold. Tregs from all protocols suppressed the proliferation of anti-CD2CD3CD28 bead-stimulated autologous PBMCs albeit with different potencies, varying from 1:2-1:4 Treg:PBMC ratios, up to >1:32. Reculture of cryopreserved Tregs permitted reexpansion with improved suppressive activity. Occasionally, CD8 contamination was observed and resolved by resorting. Specificity studies showed greater suppression of stimulation by anti-CD2CD3CD28 beads of PBMCs from the same donor used for stimulation during the Treg cultures and of autologous cells than of third-party PBMC responders. Similar to humans, the Treg-specific demethylated region (TSDR) within the Foxp3 locus correlated with suppressive activity and expression of Foxp3. Contrary to humans, FoxP3 expression did not correlate with CD45RA or CD127 expression. In summary, we have characterized MCM Tregs and developed four Treg expansion protocols that can be used for preclinical applications.
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Affiliation(s)
- Paula Alonso-Guallart
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Jonah S. Zitsman
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Jeffrey Stern
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Sigal B. Kofman
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - David Woodland
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Siu-Hong Ho
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Hugo P. Sondermeijer
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States.,Current address; Department of Physiology, Maastricht University, Maastricht, The Netherlands
| | - Leo Bühler
- Current address; Department of Surgery, University Hospital of Geneva, Switzerland
| | - Adam Griesemer
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States.,Department of Surgery, Columbia University Medical Center, New York, NY, United States
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States.,Department of Surgery, Columbia University Medical Center, New York, NY, United States.,Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, United States
| | - Raimon Duran-Struuck
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, United States.,Current address; Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, United States
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Hyun KH, Gil KC, Kim SG, Park SY, Hwang KW. Delphinidin Chloride and Its Hydrolytic Metabolite Gallic Acid Promote Differentiation of Regulatory T cells and Have an Anti-inflammatory Effect on the Allograft Model. J Food Sci 2019; 84:920-930. [PMID: 30977922 DOI: 10.1111/1750-3841.14490] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/21/2018] [Accepted: 02/07/2019] [Indexed: 01/10/2023]
Abstract
Regulatory T cells (Tregs) control the reactivity of other T cells to prevent excessive inflammatory responses. They also plays a role in preventing autoimmune diseases; but when they are overproduced, they decreased vital immunity, which can lead to invasion of external pathogens. Therefore, it is most important in preventing the development of immune diseases to maintain the homeostasis of these cells. Delphinidin chloride is an anthocyanidin and known to have anti-oxidant activities. However, its structure is very unstable and easily decomposed. One of these degradation products is gallic acid, which also has anti-oxidant effects. In this study, we examined the effect of these materials on Tregs in controlling immune response. It was found that these materials further promote differentiation into Tregs, and TGF-β and IL-2 related signals are involved in this process. Furthermore, it was verified that a variety of immunosuppressive proteins were secreted more, and the function of induced Tregs was also increased. Finally, in the allograft model, we could find a decrease in activated T cells when these materials were treated because they increased differentiation into Tregs. Therefore, these two materials are expected to become new candidates for the treatment of diseases caused by excessive activation of immune cells, such as autoimmune diseases. PRACTICAL APPLICATION: Delphinidin, a kind of anthocyanin rich in pigmented fruits, and its hydrolytic metabolite, gallic acid, are known to have antimicrobial and anti-oxidant properties. In this experiment, it was shown that delphinidin and gallic acid had an effect of increasing the differentiation of regulatory T cells, and the effect of suppressing the function of memory T cells was also observed. Due to these functions, delphinidin and gallic acid might have the potential to be used as immune suppressive agents in organ transplant and autoimmune disease patients or be a model for food development associated with the immune system.
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Affiliation(s)
- Ki Hyeob Hyun
- Host Defense Modulation Lab, College of Pharmacy Chung-Ang Univ., Heukseok-ro 84, Dongjak-gu, Seoul, 06974, Republic of Korea
| | - Ki Cheol Gil
- Host Defense Modulation Lab, College of Pharmacy Chung-Ang Univ., Heukseok-ro 84, Dongjak-gu, Seoul, 06974, Republic of Korea
| | - Sung Gun Kim
- Laboratory of Pharmacology, College of Pharmacy, Dankook Univ., Cheonan, 31116, Republic of Korea
| | - So-Young Park
- Laboratory of Pharmacology, College of Pharmacy, Dankook Univ., Cheonan, 31116, Republic of Korea
| | - Kwang Woo Hwang
- Host Defense Modulation Lab, College of Pharmacy Chung-Ang Univ., Heukseok-ro 84, Dongjak-gu, Seoul, 06974, Republic of Korea
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48
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Jørgensen N, Persson G, Hviid TVF. The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer. Front Immunol 2019; 10:911. [PMID: 31134056 PMCID: PMC6517506 DOI: 10.3389/fimmu.2019.00911] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/09/2019] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells, a subpopulation of suppressive T cells, are potent mediators of self-tolerance and essential for the suppression of triggered immune responses. The immune modulating capacity of these cells play a major role in both transplantation, autoimmune disease, allergy, cancer and pregnancy. During pregnancy, low numbers of regulatory T cells are associated with pregnancy failure and pregnancy complications such as pre-eclampsia. On the other hand, in cancer, low numbers of immunosuppressive T cells are correlated with better prognosis. Hence, maternal immune tolerance toward the fetus during pregnancy and the escape from host immunosurveillance by cancer seem to be based on similar immunological mechanisms being highly dependent on the balance between immune activation and suppression. As regulatory T cells hold a crucial role in several biological processes, they may also be promising subjects for therapeutic use. Especially in the field of cancer, cell therapy and checkpoint inhibitors have demonstrated that immune-based therapies have a very promising potential in treatment of human malignancies. However, these therapies are often accompanied by adverse autoimmune side effects. Therefore, expanding the knowledge to recognize the complexities of immune regulation pathways shared across different immunological scenarios is extremely important in order to improve and develop new strategies for immune-based therapy. The intent of this review is to highlight the functional characteristics of regulatory T cells in the context of mechanisms of immune regulation in pregnancy and cancer, and how manipulation of these mechanisms potentially may improve therapeutic options.
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Affiliation(s)
| | | | - Thomas Vauvert F. Hviid
- Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Consortium ZUH, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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49
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Bracks IV, Espaladori MC, Barros P, de Brito LCN, Vieira LQ, Ribeiro Sobrinho AP. Effect of ethylenediaminetetraacetic acid irrigation on immune-inflammatory response in teeth submitted to regenerative endodontic therapy. Int Endod J 2019; 52:1457-1465. [PMID: 31046128 DOI: 10.1111/iej.13136] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 04/29/2019] [Indexed: 12/28/2022]
Abstract
AIM To analyse longitudinally the immune-inflammatory response in teeth of mice that underwent a regenerative protocol with or without the use of ethylenediaminetetraacetic acid (EDTA) to irrigate the root canal system. METHODOLOGY First maxillary molars of mice were devitalized using size 10 and 15 files. Teeth were divided into the following groups: Empty - the canals were left empty; Blood Clot (BC) - the canals were filled with a blood clot; and EDTA + Blood - the canals were irrigated with 0.06 mL of 17% EDTA for 1 min and filled with a blood clot. Access cavities were restored with Coltosol® . Animals were sacrificed at 7, 14 or 21 days after the operative procedures, and teeth were collected. RNA was extracted, mRNA expression of the cytokines IGF, NGF, IL-1α, IL-10, TGF and VEGF was assessed using real-time PCR, and the anova Kruskal-Wallis test was used. RESULTS IL-1 mRNA expression was significantly higher in the EDTA + BC group than in the Empty and BC groups at the 7th and 14th days of evaluation (P < 0.05). IL-10 mRNA expression was similar across the three groups at all time periods. TGF-β mRNA expression in the EDTA + BC group was significantly higher on the 7th and 21st days than on the 14th (P < 0.05); at day 21, TGF-β mRNA expression was similar between the BC and EDTA + BC groups but significantly higher than in the Empty group (P < 0.05). IGF mRNA expression was significantly higher in the EDTA + BC group than in the other groups at all time periods. VEGF mRNA expression remained unchanged throughout the experimental period in all groups (P > 0.05). NGF mRNA expression was similar amongst all groups at the 7th and 21st days (P > 0.05). At the 14th day, however, there was a significant increase in NGF mRNA expression in the EDTA + Blood group (P < 0.05) when compared with the expression in the other groups. CONCLUSION EDTA promoted increased expression of factors that have the potential to improve the outcome of regenerative endodontic treatment.
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Affiliation(s)
- I V Bracks
- Department of Operative Dentistry, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - M C Espaladori
- Department of Operative Dentistry, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - P Barros
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - L C N de Brito
- Department of Endodontics, School of Dentistry, Itaúna University, Itaúna, MG, Brazil
| | - L Q Vieira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - A P Ribeiro Sobrinho
- Department of Operative Dentistry, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
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50
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Acharya S, Timilshina M, Chang JH. Mevalonate promotes differentiation of regulatory T cells. J Mol Med (Berl) 2019; 97:927-936. [PMID: 31020340 DOI: 10.1007/s00109-019-01784-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 03/25/2019] [Accepted: 04/01/2019] [Indexed: 12/13/2022]
Abstract
Mevalonate is a precursor in a biosynthetic pathway that is important for the coordination of regulatory T cell (Treg) proliferation and upregulation of the suppressive function that establishes the functional competency of Tregs. The extensive role of mevalonate and its underlying effect on Treg differentiation are still unclear. We found that mevalonate increases in vitro differentiation of induced Tregs (iTregs) without broadly affecting Th1 and Th17 cell differentiation. Furthermore, an adoptive transfer study showed that mevalonate enhanced peripherally induced Treg cells (pTregs) in mesenteric lymphocytes in vivo. Mevalonate-treated iTregs exhibited greater suppressive activity against effector cells than untreated Tregs. Mechanistically, mevalonate enhanced transforming growth factor (TGF)-β signaling by increasing the phosphorylation of Smad3, but not Smad2, and by promoting Foxp3 expression. Furthermore, we demonstrated that mevalonate treatment ameliorated dextran sulfate sodium (DSS)-induced colitis and resulted in an increased percentage of Tregs in vivo. Our results suggest that mevalonate enhanced Treg differentiation and ameliorated DSS colitis, indicating its potential for treatment of inflammatory diseases.
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Affiliation(s)
- Suman Acharya
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, South Korea
| | | | - Jae-Hoon Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, South Korea.
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