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1
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Wei L, Zhu W, Dong C, Kim JK, Ma Y, Denning TL, Kang SM, Wang BZ. Lipid nanoparticles encapsulating both adjuvant and antigen mRNA improve influenza immune cross-protection in mice. Biomaterials 2025; 317:123039. [PMID: 39724768 DOI: 10.1016/j.biomaterials.2024.123039] [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: 10/08/2024] [Revised: 11/26/2024] [Accepted: 12/21/2024] [Indexed: 12/28/2024]
Abstract
The rapid approval of SARS-CoV-2 mRNA lipid nanoparticle (LNP) vaccines indicates the versatility of mRNA LNPs in an urgent vaccine need. However, the mRNA vaccines do not induce mucosal cellular responses or broad protection against recent variants. To improve cross-protection of mRNA vaccines, here we engineered a pioneered mRNA LNP encapsulating with mRNA constructs encoding cytokine adjuvant and influenza A hemagglutinin (HA) antigen for intradermal vaccination. The adjuvant mRNA encodes a novel fusion cytokine GIFT4 comprising GM-CSF and IL-4. We found that the adjuvanted mRNA LNP vaccine induced high levels of humoral antibodies and systemic T cell responses against heterologous influenza antigens and protected immunized mice against influenza A viral infections. Also, the adjuvanted mRNA LNP vaccine elicited early germinal center reactions in draining lymph nodes and promoted antibody-secreting B cell responses. In addition, we generated another adjuvant mRNA encoding CCL27, which enhanced systemic immune responses. We found the two adjuvant mRNAs both showed effective adjuvanticity in enhancing humoral and cellular responses in mice. Interestingly, intradermal immunizations of GIFT4 or CCL27 mRNA adjuvanted mRNA LNP vaccines induced significant lung tissue-resident T cells. Our findings demonstrate that the cytokine mRNA can be a promising adjuvant flexibly formulated into mRNA LNP vaccines to provoke strong immunity against viral variants.
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Affiliation(s)
- Lai Wei
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Wandi Zhu
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Chunhong Dong
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Joo Kyung Kim
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Yao Ma
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Timothy L Denning
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Sang-Moo Kang
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA
| | - Bao-Zhong Wang
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Science, Georgia State University, Atlanta, GA, USA.
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2
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Kim M, Kong D, Kim NG, Kim MJ, Kim HY, Choi JJ, Choi YS, Lee HE, Farzaneh KS, Kwon D, Lee S, Kang KS. Therapeutic effect of long-interval repeated subcutaneous administration of canine amniotic membrane-derived mesenchymal stem cells in atopic dermatitis mouse model. BMC Vet Res 2025; 21:115. [PMID: 40011929 DOI: 10.1186/s12917-025-04554-w] [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: 03/21/2024] [Accepted: 01/31/2025] [Indexed: 02/28/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic and inflammatory disease. According to a recent study, administration of canine MSCs is a potential therapy for immunological diseases. However, most related studies involve short-term experiments and acute atopic dermatitis animal models. Thus, studies of repeated subcutaneous injection of canine MSCs for ameliorating long-term inflammatory skin disorders have not yet been established. In this study, we evaluated the effects of long-term canine amniotic mesenchymal stem cells (cAM-MSCs) and calcineurin inhibitors (CNIs) treatments in mouse AD model for up to 8 weeks and compared the differences in therapeutic effect through canine peripheral blood mononuclear cells (PBMCs). Using a mouse model, we validated the therapeutic impact of cAM-MSCs in comparison to pimecrolimus (Pime), the most widely used CNIs, as a therapy for canine AD. Based on our results, we verified that the cAM-MSC treatment group exhibited substantially lower scores for tissue pathologic alterations, inflammatory cytokines, and dermatologic symptoms than the PBS control group. Importantly, compared with Pime, cAM-MSCs were more effective at preventing wound dysfunction and regulating mast cell activity. Additionally, we confirmed that immune modulation proteins (TGF-β1, IDO1, and COX-2) were increased in the cAM-MSCs treatment group. Furthermore, we examined the immunoregulatory effect of cAM-MSCs through the proliferation of T lymphocytes from activated canine PBMCs. As a result, cAM-MSCs suppressed the proliferative capacity of effector T cells from canine PBMCs more effectively than Pime. In conclusion, this study suggested that the cAM-MSCS could be an effective canine treatment for long-term canine AD through regeneration and immunomodulation.
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Grants
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
- 23A0101L1 The Ministry of Science and ICT, the Ministry of Health & Welfare
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Affiliation(s)
- Minsoo Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Dasom Kong
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Nam Gyo Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Min-Ji Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hee-Yeong Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jung-Ju Choi
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yu-Seung Choi
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ha-Eun Lee
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Khaligh Seyedeh Farzaneh
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Dohyung Kwon
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Kyung-Sun Kang
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.
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3
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Guo H, Yuan H, Yu Y, Sun J, Sun Y, Tang Y, Zheng F. Role of skin-homing t-cells in recurrent episodes of atopic dermatitis: a review. Front Immunol 2025; 16:1489277. [PMID: 40040698 PMCID: PMC11876967 DOI: 10.3389/fimmu.2025.1489277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 01/30/2025] [Indexed: 03/06/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic relapsing disease with complex pathogenesis. Among them, inflammation is one of the primary pathogenesis of AD. AD is characterized by infiltration of lymphocytes into the skin's dermis, and the skin homing of lymphocytes plays an essential role in the recurrence of AD. Currently, there is more and more evidence to support this view. This article reviews the relevant role of T lymphocyte skin-homing-related molecules in the recurrence of AD to provide a reference for the cure of AD.
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Affiliation(s)
- Huimin Guo
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Huimin Yuan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yanru Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jingwei Sun
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Sun
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Tang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fengjie Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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4
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Cutilli A, Jansen SA, Paolucci F, van Hoesel M, Frederiks CL, Mulder TAM, Chalkiadakis T, Mokry M, Prekovic S, Mocholi E, Lindemans CA, Coffer PJ. Interferon-gamma induces epithelial reprogramming driving CXCL11-mediated T-cell migration. J Leukoc Biol 2025; 117:qiae205. [PMID: 39302156 DOI: 10.1093/jleuko/qiae205] [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: 07/03/2024] [Revised: 08/20/2024] [Accepted: 09/19/2024] [Indexed: 09/22/2024] Open
Abstract
The cytokine interferon-gamma plays a multifaceted role in intestinal immune responses ranging from anti- to proinflammatory depending on the setting. Here, using a 3D co-culture system based on human intestinal epithelial organoids, we explore the capacity of interferon-gamma exposure to reprogram intestinal epithelia and thereby directly modulate lymphocyte responses. Interferon-gamma treatment of organoids led to transcriptional reprogramming, marked by a switch to a proinflammatory gene expression profile, including transcriptional upregulation of the chemokines CXCL9, CXCL10, and CXCL11. Proteomic analysis of organoid-conditioned medium posttreatment confirmed chemokine secretion. Interferon-gamma treatment of organoids led to enhanced T-cell migration in a CXCL11-dependent manner without affecting T-cell activation status. Taken together, our results suggest a specific role for CXCL11 in T-cell recruitment that could be targeted to prevent T-cell trafficking to the inflamed intestine.
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Affiliation(s)
- Alessandro Cutilli
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Suze A Jansen
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Division of Pediatrics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - Francesca Paolucci
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Marliek van Hoesel
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Division of Pediatrics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - Cynthia L Frederiks
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Tessa A M Mulder
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Theofilos Chalkiadakis
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Michal Mokry
- Division of Pediatrics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
- Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
| | - Stefan Prekovic
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Enric Mocholi
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
| | - Caroline A Lindemans
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Division of Pediatrics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - Paul J Coffer
- Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Center of Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
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5
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Sun Z, Qin Y, Zhang X. Identification and validation of five ferroptosis-related molecular signatures in keloids based on multiple transcriptome data analysis. Front Mol Biosci 2025; 11:1490745. [PMID: 39834787 PMCID: PMC11743277 DOI: 10.3389/fmolb.2024.1490745] [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: 09/03/2024] [Accepted: 11/27/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Keloids are a common skin disorder characterized by excessive fibrous tissue proliferation, which can significantly impact patients' health. Ferroptosis, a form of regulated cell death, plays a crucial role in the development of fibrosis; however, its role in the mechanisms of keloid formation remains poorly understood. Methods This study aimed to identify key genes associated with ferroptosis in keloid formation. Data from the NCBI GEO database, including GSE145725, GSE7890, and GSE44270, were analyzed, comprising a total of 24 keloid and 17 normal skin samples. Additionally, single-cell data from GSE181316, which included 8 samples with complete expression profiles, were also evaluated. Differentially expressed genes were identified, and ferroptosis-related genes were extracted from the GeneCards database. LASSO regression was used to select key genes associated with keloids. Validation was performed using qRT-PCR and Western blot (WB) analysis on tissue samples from five keloid and five normal skin biopsies. Results A total of 471 differentially expressed genes were identified in the GSE145725 dataset, including 225 upregulated and 246 downregulated genes. Five ferroptosis-related genes were selected through gene intersection and LASSO regression. Two of these genes were upregulated, while three were downregulated in keloid tissue. Further analysis through GSEA pathway enrichment, GSVA gene set variation, immune cell infiltration analysis, and single-cell sequencing revealed that these genes were primarily involved in the fibrotic process. The qRT-PCR and WB results confirmed the expression patterns of these genes. Discussion This study provides novel insights into the molecular mechanisms of ferroptosis in keloid formation. The identified ferroptosis-related genes could serve as potential biomarkers or therapeutic targets for treating keloids.
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Affiliation(s)
| | - Yonghong Qin
- Department of Plastic Surgery, Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Xuanfen Zhang
- Department of Plastic Surgery, Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China
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6
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Jonczyk A, Gottschalk M, Mangan MS, Majlesain Y, Thiem MW, Burbaum LC, Weighardt H, Latz E, Mayer G, Förster I. Topical application of a CCL22-binding aptamer suppresses contact allergy. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102254. [PMID: 39071952 PMCID: PMC11278340 DOI: 10.1016/j.omtn.2024.102254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/13/2024] [Indexed: 07/30/2024]
Abstract
Allergic contact dermatitis is a prevalent occupational disease with limited therapeutic options. The chemokine CCL22, a ligand of the chemokine receptor CCR4, directs the migration of immune cells. Here, it is shown that genetic deficiency of CCL22 effectively ameliorated allergic reactions in contact hypersensitivity (CHS), a commonly used mouse model of allergic contact dermatitis. For the pharmacological inhibition of CCL22, DNA aptamers specific for murine CCL22 were generated by the systematic evolution of ligands by exponential enrichment (SELEX). Nine CCL22-binding aptamers were initially selected and functionally tested in vitro. The 29-nt DNA aptamer AJ102.29m profoundly inhibited CCL22-dependent T cell migration and did not elicit undesired Toll-like receptor-dependent immune activation. AJ102.29m efficiently ameliorated CHS in vivo after systemic application. Moreover, CHS-associated allergic symptoms were also reduced following topical application of the aptamer on the skin. Microscopic analysis of skin treated with AJ102.29m ex vivo demonstrated that the aptamer could penetrate into the epidermis and dermis. The finding that epicutaneous application of the aptamer AJ102.29m in a cream was as effective in suppressing the allergic reaction as intraperitoneal injection paves the way for therapeutic use of aptamers beyond the current routes of systemic administration.
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Affiliation(s)
- Anna Jonczyk
- Chemical Biology and Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53121 Bonn, Germany
| | - Marlene Gottschalk
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
| | | | - Yasmin Majlesain
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
| | - Manja W. Thiem
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Lea-Corinna Burbaum
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
| | - Heike Weighardt
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany
| | - Günter Mayer
- Centre of Aptamer Research and Development, University of Bonn, 53121 Bonn, Germany
| | - Irmgard Förster
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
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7
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Zhang J, Yao Z. Immune cell trafficking: a novel perspective on the gut-skin axis. Inflamm Regen 2024; 44:21. [PMID: 38654394 DOI: 10.1186/s41232-024-00334-5] [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: 02/05/2024] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
Immune cell trafficking, an essential mechanism for maintaining immunological homeostasis and mounting effective responses to infections, operates under a stringent regulatory framework. Recent advances have shed light on the perturbation of cell migration patterns, highlighting how such disturbances can propagate inflammatory diseases from their origin to distal organs. This review collates and discusses current evidence that demonstrates atypical communication between the gut and skin, which are conventionally viewed as distinct immunological spheres, in the milieu of inflammation. We focus on the aberrant, reciprocal translocation of immune cells along the gut-skin axis as a pivotal factor linking intestinal and dermatological inflammatory conditions. Recognizing that the translation of these findings into clinical practices is nascent, we suggest that therapeutic strategies aimed at modulating the axis may offer substantial benefits in mitigating the widespread impact of inflammatory diseases.
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Affiliation(s)
- Jiayan Zhang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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8
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Murakami M. Tissue-resident memory T cells: decoding intra-organ diversity with a gut perspective. Inflamm Regen 2024; 44:19. [PMID: 38632596 PMCID: PMC11022361 DOI: 10.1186/s41232-024-00333-6] [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: 02/08/2024] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
Tissue-resident memory T cells (TRM) serve as the frontline of host defense, playing a critical role in protection against invading pathogens. This emphasizes their role in providing rapid on-site immune responses across various organs. The physiological significance of TRM is not just confined to infection control; accumulating evidence has revealed that TRM also determine the pathology of diseases such as autoimmune disorders, inflammatory bowel disease, and cancer. Intensive studies on the origin, mechanisms of formation and maintenance, and physiological significance of TRM have elucidated the transcriptional and functional diversity of these cells, which are often affected by local cues associated with their presence. These were further confirmed by the recent remarkable advancements of next-generation sequencing and single-cell technologies, which allow the transcriptional and phenotypic characterization of each TRM subset induced in different microenvironments. This review first overviews the current knowledge of the cell fate, molecular features, transcriptional and metabolic regulation, and biological importance of TRM in health and disease. Finally, this article presents a variety of recent studies on disease-associated TRM, particularly focusing and elaborating on the TRM in the gut, which constitute the largest and most intricate immune network in the body, and their pathological relevance to gut inflammation in humans.
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Affiliation(s)
- Mari Murakami
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
- Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.
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9
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Migayron L, Merhi R, Seneschal J, Boniface K. Resident memory T cells in nonlesional skin and healed lesions of patients with chronic inflammatory diseases: Appearances can be deceptive. J Allergy Clin Immunol 2024; 153:606-614. [PMID: 37995858 DOI: 10.1016/j.jaci.2023.11.017] [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: 09/12/2023] [Revised: 10/30/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023]
Abstract
Tissue-resident memory T (TRM) cells serve as a first line of defense in peripheral tissues to protect the organism against foreign pathogens. However, autoreactive TRM cells are increasingly implicated in autoimmunity, as evidenced in chronic autoimmune and inflammatory skin conditions. This highlights the need to characterize their phenotype and understand their role for the purpose of targeting them specifically without affecting local immunity. To date, the investigation of TRM cells in human skin diseases has focused mainly on lesional tissues of patients. Accumulating evidence suggests that self-reactive TRM cells are still present in clinically healed lesions of patients and play a role in disease flares, but TRM cells also populate skin that is apparently normal. This review discusses the ontogeny of TRM cells in the skin as well as recent insights regarding the presence of self-reactive TRM cells in both clinically healed skin and nonlesional skin of patients with autoimmune and inflammatory skin conditions, with a particular focus on psoriasis, atopic dermatitis, and vitiligo.
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Affiliation(s)
- Laure Migayron
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR5164, F-33000, Bordeaux, France; R&D Department, SILAB, Brive-la-Gaillarde, France
| | - Ribal Merhi
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR5164, F-33000, Bordeaux, France
| | - Julien Seneschal
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR5164, F-33000, Bordeaux, France; CHU de Bordeaux, Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, UMR Bordeaux, Bordeaux, France
| | - Katia Boniface
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR5164, F-33000, Bordeaux, France.
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10
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Cutilli A, Jansen SA, Paolucci F, Mokry M, Mocholi E, Lindemans CA, Coffer PJ. IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.03.578580. [PMID: 38370633 PMCID: PMC10871214 DOI: 10.1101/2024.02.03.578580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
The cytokine interferon-gamma (IFNγ) plays a multifaceted role in intestinal immune responses ranging from anti-to pro-inflammatory depending on the setting. Here, using a 3D co-culture system based on human intestinal epithelial organoids, we explore the capacity of IFNγ-exposure to reprogram intestinal epithelia and thereby directly modulate lymphocyte responses. IFNγ treatment of organoids led to transcriptional reprogramming, marked by a switch to a pro-inflammatory gene expression profile, including transcriptional upregulation of the chemokines CXCL9, CXCL10, and CXCL11. Proteomic analysis of organoid-conditioned medium post-treatment confirmed chemokine secretion. Furthermore, IFNγ-treatment of organoids led to enhanced T cell migration in a CXCL11-dependent manner without affecting T cell activation status. Taken together, our results suggest a specific role for CXCL11 in T cell recruitment that can be targeted to prevent T cell trafficking to the inflamed intestine.
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11
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Schenkel JM, Pauken KE. Localization, tissue biology and T cell state - implications for cancer immunotherapy. Nat Rev Immunol 2023; 23:807-823. [PMID: 37253877 PMCID: PMC11448857 DOI: 10.1038/s41577-023-00884-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2023] [Indexed: 06/01/2023]
Abstract
Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy.
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Affiliation(s)
- Jason M Schenkel
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Kristen E Pauken
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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12
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Reali E, Ferrari D. From the Skin to Distant Sites: T Cells in Psoriatic Disease. Int J Mol Sci 2023; 24:15707. [PMID: 37958689 PMCID: PMC10648543 DOI: 10.3390/ijms242115707] [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: 09/28/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Human skin has long been known as a protective organ, acting as a mechanical barrier towards the external environment. More recent is the acquisition that in addition to this fundamental role, the complex architecture of the skin hosts a variety of immune and non-immune cells playing preeminent roles in immunological processes aimed at blocking infections, tumor progression and migration, and elimination of xenobiotics. On the other hand, dysregulated or excessive immunological response into the skin leads to autoimmune reactions culminating in a variety of skin pathological manifestations. Among them is psoriasis, a multifactorial, immune-mediated disease with a strong genetic basis. Psoriasis affects 2-3% of the population; it is associated with cardiovascular comorbidities, and in up to 30% of the cases, with psoriatic arthritis. The pathogenesis of psoriasis is due to the complex interplay between the genetic background of the patient, environmental factors, and both innate and adaptive responses. Moreover, an autoimmune component and the comprehension of the mechanisms linking chronic skin inflammation with systemic and joint manifestations in psoriatic patients is still a major challenge. The understanding of these mechanisms may offer a valuable chance to find targetable molecules to treat the disease and prevent its progression to severe systemic conditions.
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Affiliation(s)
- Eva Reali
- Department of Translational Medicine, University of Ferrara, 44100 Ferrara, Italy
| | - Davide Ferrari
- Department of Life Science and Biotechnology, University of Ferrara, 44100 Ferrara, Italy
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13
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Tissue adaptation and clonal segregation of human memory T cells in barrier sites. Nat Immunol 2023; 24:309-319. [PMID: 36658238 PMCID: PMC10063339 DOI: 10.1038/s41590-022-01395-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 11/22/2022] [Indexed: 01/21/2023]
Abstract
T lymphocytes migrate to barrier sites after exposure to pathogens, providing localized immunity and long-term protection. Here, we obtained blood and tissues from human organ donors to examine T cells across major barrier sites (skin, lung, jejunum), associated lymph nodes, lymphoid organs (spleen, bone marrow), and in circulation. By integrating single-cell protein and transcriptome profiling, we demonstrate that human barrier sites contain tissue-resident memory T (TRM) cells that exhibit site-adapted profiles for residency, homing and function distinct from circulating memory T cells. Incorporating T cell receptor and transcriptome analysis, we show that circulating memory T cells are highly expanded, display extensive overlap between sites and exhibit effector and cytolytic functional profiles, while TRM clones exhibit site-specific expansions and distinct functional capacities. Together, our findings indicate that circulating T cells are more disseminated and differentiated, while TRM cells exhibit tissue-specific adaptation and clonal segregation, suggesting that strategies to promote barrier immunity require tissue targeting.
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14
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Molecular pathogenesis of Cutaneous T cell Lymphoma: Role of chemokines, cytokines, and dysregulated signaling pathways. Semin Cancer Biol 2022; 86:382-399. [PMID: 34906723 DOI: 10.1016/j.semcancer.2021.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 01/27/2023]
Abstract
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative neoplasms that exhibit a wide spectrum of immune-phenotypical, clinical, and histopathological features. The biology of CTCL is complex and remains elusive. In recent years, the application of next-generation sequencing (NGS) has evolved our understanding of the pathogenetic mechanisms, including genetic aberrations and epigenetic abnormalities that shape the mutational landscape of CTCL and represent one of the important pro-tumorigenic principles in CTCL initiation and progression. Still, identification of the major pathophysiological pathways including genetic and epigenetic components that mediate malignant clonal T cell expansion has not been achieved. This is of prime importance given the role of malignant T cell clones in fostering T helper 2 (Th2)-bias tumor microenvironment and fueling progressive immune dysregulation and tumor cell growth in CTCL patients, manifested by the secretion of Th2-associated cytokines and chemokines. Alterations in malignant cytokine and chemokine expression patterns orchestrate the inflammatory milieu and influence the migration dynamics of malignant clonal T cells. Here, we highlight recent insights about the molecular mechanisms of CTCL pathogenesis, emphasizing the role of cytokines, chemokines, and associated downstream signaling networks in driving immune defects, malignant transformation, and disease progression. In-depth characterization of the CTCL immunophenotype and tumoral microenvironment offers a facile opportunity to expand the therapeutic armamentarium of CTCL, an intractable malignant skin disease with poor prognosis and in dire need of curative treatment approaches.
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15
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Sakakibara M, Sumida H, Yanagida K, Miyasato S, Nakamura M, Sato S. Bitter taste receptor T2R38 is expressed on skin-infiltrating lymphocytes and regulates lymphocyte migration. Sci Rep 2022; 12:11790. [PMID: 35821061 PMCID: PMC9276799 DOI: 10.1038/s41598-022-15999-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 07/04/2022] [Indexed: 12/23/2022] Open
Abstract
Bitter taste receptors (T2Rs) are G protein-coupled receptors involved in the perception of bitter taste on the tongue. In humans, T2Rs have been found in several sites outside the oral cavity. Although T2R38 has been reported to be expressed on peripheral lymphocytes, it is poorly understood whether T2R38 plays immunological roles in inflammatory skin diseases such as atopic dermatitis (AD). Then, we first confirmed that T2R38 gene expression was higher in lesional skin of AD subjects than healthy controls. Furthermore, skin T2R38 expression levels were correlated with serum thymus and activation-regulated chemokine and IgE levels in AD patients. In lesional skin of AD, section staining revealed that CD3+ T cells in the dermis were T2R38 positive. In addition, flow cytometry analysis showed T2R38 expression in skin T cells. Migration assays using T2R38-transduced Jurkat T cell leukemia cells revealed that T2R38 agonists exerted a dose-dependent migration inhibitory effect. Moreover, skin tissue extracts, as well as supernatants of cultured HaCaT keratinocytes, caused T2R38-dependent migration inhibition, indicating that there should be an endogenous ligand for T2R38 in the skin epidermis. These findings implicate T2R38 as a migratory inhibitory receptor on the skin-infiltrating lymphocytes and as a therapeutic target for allergic/inflammatory skin diseases.
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Affiliation(s)
- Moe Sakakibara
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hayakazu Sumida
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Keisuke Yanagida
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
| | - Sosuke Miyasato
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
| | - Motonao Nakamura
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
| | - Shinichi Sato
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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16
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Ogino R, Yokooji T, Hayashida M, Suda S, Yamakawa S, Hayashida K. Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. Int J Mol Sci 2022; 23:ijms23147614. [PMID: 35886961 PMCID: PMC9322118 DOI: 10.3390/ijms23147614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 02/04/2023] Open
Abstract
Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.
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Affiliation(s)
- Ryohei Ogino
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (R.O.); (T.Y.)
| | - Tomoharu Yokooji
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (R.O.); (T.Y.)
| | - Maiko Hayashida
- Department of Psychiatry, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan;
| | - Shota Suda
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
| | - Sho Yamakawa
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
| | - Kenji Hayashida
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
- Correspondence: ; Tel.: +81-853-20-2210
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17
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Davila ML, Xu M, Huang C, Gaddes ER, Winter L, Cantorna MT, Wang Y, Xiong N. CCL27 is a crucial regulator of immune homeostasis of the skin and mucosal tissues. iScience 2022; 25:104426. [PMID: 35663027 PMCID: PMC9157018 DOI: 10.1016/j.isci.2022.104426] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/30/2022] [Accepted: 05/12/2022] [Indexed: 11/24/2022] Open
Abstract
Abundant immune cells reside in barrier tissues. Understanding the regulation of these cells can yield insights on their roles in tissue homeostasis and inflammation. Here, we report that the chemokine CCL27 is critical for establishment of resident lymphocytes and immune homeostasis in barrier tissues. CCL27 expression is associated with normal skin and hair follicle development independent of commensal bacterial stimulation, indicative of a homeostatic role for the chemokine. Accordingly, in the skin of CCL27-knockout mice, there is a reduced presence and dysregulated localization of T cells that express CCR10, the cognate receptor to CCL27. Besides, CCL27-knockout mice have overreactive skin inflammatory responses in an imiquimod-induced model of psoriasis. Beyond the skin, CCL27-knockout mice have increased infiltration of CCR10+ T cells into lungs and reproductive tracts, the latter of which also exhibit spontaneous inflammation. Our findings demonstrate that CCL27 is critical for immune homeostasis across barrier tissues.
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Affiliation(s)
- Micha L Davila
- Immunology and Infectious Disease Graduate Program, The Pennsylvania State University, University Park, PA 16802, USA.,Department of Microbiology, Immunology and Molecular Genetics, Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, Mail Code 7758, San Antonio, TX 78229, USA
| | - Ming Xu
- Department of Microbiology, Immunology and Molecular Genetics, Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, Mail Code 7758, San Antonio, TX 78229, USA
| | - Chengyu Huang
- Department of Microbiology, Immunology and Molecular Genetics, Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, Mail Code 7758, San Antonio, TX 78229, USA
| | - Erin R Gaddes
- Department of Biomedical Engineering, 526 CBEB, The Pennsylvania State University, University Park, PA 16802, USA
| | - Levi Winter
- Pathobiology Graduate Program, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Margherita T Cantorna
- Pathobiology Graduate Program, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Yong Wang
- Department of Biomedical Engineering, 526 CBEB, The Pennsylvania State University, University Park, PA 16802, USA
| | - Na Xiong
- Department of Microbiology, Immunology and Molecular Genetics, Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, Mail Code 7758, San Antonio, TX 78229, USA.,Department of Medicine-Division of Dermatology and Cutaneous Surgery University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
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18
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Song Q, Nasri U, Nakamura R, Martin PJ, Zeng D. Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity. Front Immunol 2022; 13:907673. [PMID: 35677056 PMCID: PMC9168269 DOI: 10.3389/fimmu.2022.907673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/26/2022] [Indexed: 11/30/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma) due to the graft-versus-leukemia (GVL) activity mediated by alloreactive T cells that can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells can cause a serious side effect, known as graft-versus-host disease (GVHD). GVHD and GVL occur in distinct organ and tissues, with GVHD occurring in target organs (e.g., the gut, liver, lung, skin, etc.) and GVL in lympho-hematopoietic tissues where hematological cancer cells primarily reside. Currently used immunosuppressive drugs for the treatment of GVHD inhibit donor T cell activation and expansion, resulting in a decrease in both GVHD and GVL activity that is associated with cancer relapse. To prevent GVHD, it is important to allow full activation and expansion of alloreactive T cells in the lympho-hematopoietic tissues, as well as prevent donor T cells from migrating into the GVHD target tissues, and tolerize infiltrating T cells via protective mechanisms, such as PD-L1 interacting with PD-1, in the target tissues. In this review, we will summarize major approaches that prevent donor T cell migration into GVHD target tissues and approaches that augment tolerization of the infiltrating T cells in the GVHD target tissues while preserving strong GVL activity in the lympho-hematopoietic tissues.
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Affiliation(s)
- Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States
| | - Ryotaro Nakamura
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States
| | - Paul J Martin
- Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, United States
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States
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19
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Kortekaas Krohn I, Aerts JL, Breckpot K, Goyvaerts C, Knol E, Van Wijk F, Gutermuth J. T-cell subsets in the skin and their role in inflammatory skin disorders. Allergy 2022; 77:827-842. [PMID: 34559894 DOI: 10.1111/all.15104] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/11/2021] [Indexed: 12/20/2022]
Abstract
T lymphocytes (T cells) are major players of the adaptive immune response. Naive T cells are primed in the presence of cytokines, leading to polarization into distinct T-cell subsets with specific functions. These subsets are classified based on their T-cell receptor profile, expression of transcription factors, surface cytokine and chemokine receptors, and their cytokine production, which together determine their specific function. This review provides an overview of the various T-cell subsets and their function in several inflammatory skin disorders ranging from allergic inflammation to skin tumors. Moreover, we highlight similarities of T-cell responses across different skin disorders, demonstrating the presence of similar and opposing functions for the different T-cell subsets. Finally, we discuss the effects of currently available and promising therapeutic approaches to harness T cells in inflammatory skin diseases for which efficacy next to unwanted side effects provide new insights into the pathophysiology of skin disorders.
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Affiliation(s)
- Inge Kortekaas Krohn
- Vrije Universiteit Brussel (VUB)Skin Immunology & Immune Tolerance (SKIN) Research Group Brussels Belgium
- Vrije Universiteit Brussel (VUB)Universitair Ziekenhuis Brussel (UZ Brussel)Department of DermatologyUniversitair Ziekenhuis Brussel Brussels Belgium
| | - Joeri L. Aerts
- Vrije Universiteit Brussel (VUB)Neuro‐Aging and Viro‐Immunotherapy (NAVI) Research Group Brussels Belgium
| | - Karine Breckpot
- Vrije Universiteit Brussel (VUB)Laboratory for Molecular and Cellular Therapy (LMCT)Department of Biomedical Sciences Brussels Belgium
| | - Cleo Goyvaerts
- Vrije Universiteit Brussel (VUB)Laboratory for Molecular and Cellular Therapy (LMCT)Department of Biomedical Sciences Brussels Belgium
| | - Edward Knol
- Center for Translational Immunology University Medical Center Utrecht Utrecht The Netherlands
- Department Dermatology/Allergology University Medical Center Utrecht Utrecht The Netherlands
| | - Femke Van Wijk
- Center for Translational Immunology University Medical Center Utrecht Utrecht The Netherlands
| | - Jan Gutermuth
- Vrije Universiteit Brussel (VUB)Skin Immunology & Immune Tolerance (SKIN) Research Group Brussels Belgium
- Vrije Universiteit Brussel (VUB)Universitair Ziekenhuis Brussel (UZ Brussel)Department of DermatologyUniversitair Ziekenhuis Brussel Brussels Belgium
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20
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Karakawa M, Kishimoto M, Ohtsuki M, Komine M. Calcipotriol induces the production of CTACK/CCL27, one of the potential suppressive factors in psoriasis inflammation. J Dermatol 2021; 48:1949-1950. [PMID: 34505709 DOI: 10.1111/1346-8138.16152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/27/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Masaru Karakawa
- Department of Dermatology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Megumi Kishimoto
- Department of Dermatology, Jichi Medical University, Shimotsuke, Japan
| | - Mamitaro Ohtsuki
- Department of Dermatology, Jichi Medical University, Shimotsuke, Japan
| | - Mayumi Komine
- Department of Dermatology, Jichi Medical University, Shimotsuke, Japan
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21
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Farsakoglu Y, McDonald B, Kaech SM. Motility Matters: How CD8 + T-Cell Trafficking Influences Effector and Memory Cell Differentiation. Cold Spring Harb Perspect Biol 2021; 13:cshperspect.a038075. [PMID: 34001529 PMCID: PMC8327832 DOI: 10.1101/cshperspect.a038075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8+ T cells provide protection by actively scanning for their cognate antigen and migrating into inflamed tissues. Trafficking patterns of CD8+ T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8+ T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8+ T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8+ T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation.
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Affiliation(s)
- Yagmur Farsakoglu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Bryan McDonald
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA.,Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California 92093, USA
| | - Susan M Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA
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22
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Oulee A, Ma F, Teles RMB, de Andrade Silva BJ, Pellegrini M, Klechevsky E, Harman AN, Rhodes JW, Modlin RL. Identification of Genes Encoding Antimicrobial Proteins in Langerhans Cells. Front Immunol 2021; 12:695373. [PMID: 34512625 PMCID: PMC8426439 DOI: 10.3389/fimmu.2021.695373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/06/2021] [Indexed: 12/03/2022] Open
Abstract
Langerhans cells (LCs) reside in the epidermis where they are poised to mount an antimicrobial response against microbial pathogens invading from the outside environment. To elucidate potential pathways by which LCs contribute to host defense, we mined published LC transcriptomes deposited in GEO and the scientific literature for genes that participate in antimicrobial responses. Overall, we identified 31 genes in LCs that encode proteins that contribute to antimicrobial activity, ten of which were cross-validated in at least two separate experiments. Seven of these ten antimicrobial genes encode chemokines, CCL1, CCL17, CCL19, CCL2, CCL22, CXCL14 and CXCL2, which mediate both antimicrobial and inflammatory responses. Of these, CCL22 was detected in seven of nine transcriptomes and by PCR in cultured LCs. Overall, the antimicrobial genes identified in LCs encode proteins with broad antibacterial activity, including against Staphylococcus aureus, which is the leading cause of skin infections. Thus, this study illustrates that LCs, consistent with their anatomical location, are programmed to mount an antimicrobial response against invading pathogens in skin.
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Affiliation(s)
- Aislyn Oulee
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Feiyang Ma
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States
| | - Rosane M B Teles
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Bruno J de Andrade Silva
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States
| | - Eynav Klechevsky
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
| | - Andrew N Harman
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.,School of Medical Sciences, Faculty of Medicine and Health Sydney, The University of Sydney, Westmead, NSW, Australia
| | - Jake W Rhodes
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.,School of Medical Sciences, Faculty of Medicine and Health Sydney, The University of Sydney, Westmead, NSW, Australia
| | - Robert L Modlin
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
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23
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Bakker DS, Nierkens S, Knol EF, Giovannone B, Delemarre EM, van der Schaft J, van Wijk F, de Bruin-Weller MS, Drylewicz J, Thijs JL. Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers. J Allergy Clin Immunol 2021; 147:189-198. [DOI: 10.1016/j.jaci.2020.04.062] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/07/2020] [Accepted: 04/24/2020] [Indexed: 11/30/2022]
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24
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Goh SJR, Tuomisto JEE, Purcell AW, Mifsud NA, Illing PT. The complexity of T cell-mediated penicillin hypersensitivity reactions. Allergy 2021; 76:150-167. [PMID: 32383256 DOI: 10.1111/all.14355] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/16/2020] [Accepted: 04/30/2020] [Indexed: 12/20/2022]
Abstract
Penicillin refers to a group of beta-lactam antibiotics that are the first-line treatment for a range of infections. However, they also possess the ability to form novel antigens, or neoantigens, through haptenation of proteins and can stimulate a range of immune-mediated adverse reactions-collectively known as drug hypersensitivity reactions (DHRs). IgE-mediated reactions towards these neoantigens are well studied; however, IgE-independent reactions are less well understood. These reactions usually manifest in a delayed manner as different forms of cutaneous eruptions or liver injury consistent with priming of an immune response. Ex vivo studies have confirmed the infiltration of T cells into the site of inflammation, and the subsets of T cells involved appear dependent on the nature of the reaction. Here, we review the evidence that has led to our current understanding of these immune-mediated reactions, discussing the nature of the lesional T cells, the characterization of drug-responsive T cells isolated from patient blood, and the potential mechanisms by which penicillins enter the antigen processing and presentation pathway to stimulate these deleterious responses. Thus, we highlight the need for a more comprehensive understanding of the underlying genetic and molecular basis of penicillin-induced DHRs.
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Affiliation(s)
- Shawn J. R. Goh
- Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia
| | - Johanna E. E. Tuomisto
- Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia
| | - Anthony W. Purcell
- Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia
| | - Nicole A. Mifsud
- Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia
| | - Patricia T. Illing
- Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia
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25
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Martínez-Rodríguez M, Monteagudo C. CCL27 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1302:113-132. [PMID: 34286445 DOI: 10.1007/978-3-030-62658-7_9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chemokines are a group of small proteins which play an important role in leukocyte migration and invasion. They are also involved in the cellular proliferation and migration of tumor cells.Chemokine CCL27 (cutaneous T cell-attracting chemokine, CTACK) is mainly expressed by keratinocytes of the normal epidermis. It is well known that this chemokine plays an important role in several inflammatory diseases of the skin, such as atopic dermatitis, contact dermatitis, and psoriasis. Moreover, several studies have shown an association between CCL27 expression and a variety of neoplasms including skin cancer.In this chapter, we address the role of chemokine CCL27 in the tumor microenvironment in the most relevant cancers of the skin and other anatomical locations. We also make a brief comment on future perspectives and the potential relation of CCL27 with different immunotherapeutic modalities.
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Affiliation(s)
| | - Carlos Monteagudo
- Department of Pathology, University Clinic Hospital-INCLIVA, University of Valencia, Valencia, Spain.
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26
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Hu C, Liu W, Xu N, Huang A, Zhang Z, Fan M, Ruan G, Wang Y, Xi T, Xing Y. Silk fibroin hydrogel as mucosal vaccine carrier: induction of gastric CD4+TRM cells mediated by inflammatory response induces optimal immune protection against Helicobacter felis. Emerg Microbes Infect 2020; 9:2289-2302. [PMID: 33000989 PMCID: PMC7594714 DOI: 10.1080/22221751.2020.1830719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tissue-resident memory T (TRM) cells, located in the epithelium of most peripheral tissues, constitute the first-line defense against pathogen infections. Our previous study reported that gastric subserous layer (GSL) vaccination induced a “pool” of protective tissue-resident memory CD4+T (CD4+TRM) cells in the gastric epithelium. However, the mechanistic details how CD4+TRM cells form in the gastric epithelium are unknown. Here, our results suggested that the vaccine containing CCF in combination with Silk fibroin hydrogel (SF) broadened the distribution of gastric intraepithelial CD4+TRM cells. It was revealed that the gastric intraepithelial TRM cells were even more important than circulating memory T cells against infection by Helicobacter felis. It was also shown that gastric-infiltrating neutrophils were involved as indispensable mediators which secreted CXCL10 to chemoattract CXCR3+CD4+T cells into the gastric epithelium. Blocking of CXCR3 or neutrophils significantly decreased the number of gastric intraepithelial CD4+TRM cells due to reduced recruitment of CD4+T cells. This study demonstrated the protective efficacy of gastric CD4+TRM cells against H. felis infection, and highlighted the influence of neutrophils on gastric intraepithelial CD4+TRM cells formation.
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Affiliation(s)
- Chupeng Hu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Wei Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Ningyin Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - An Huang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Zhenxing Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Menghui Fan
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Guojing Ruan
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yue Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
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27
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Weishaupt C, Goerge T, Loser K. Activated melanoma vessels: A sticky point for successful immunotherapy. Exp Dermatol 2020; 29:1046-1054. [PMID: 32998178 DOI: 10.1111/exd.14203] [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: 06/06/2020] [Revised: 09/07/2020] [Accepted: 09/21/2020] [Indexed: 11/30/2022]
Abstract
Metastatic melanoma is a devastating disease with a marginal-albeit increasing-hope for cure. Melanoma has a high mutation rate which correlates to the expression of numerous neo-antigens and thus is associated with the potential to induce and strengthen effective antitumoral immunity. However, the incomplete and potentially insufficient response to established immunotherapies (response rates usually do not markedly exceed 60%) already points to the need of further studies to improve treatment strategies. Multiple tumor escape mechanisms that allow melanoma to evade from antitumoral immune responses have been characterized and must be overcome to achieve a better clinical efficacy of immunotherapies. Recently, promising progress has been made in targeting tumor vasculature to control and increase the infiltration of tumors with effector lymphocytes. It has been hypothesized that amplified lymphocytic infiltrates in melanoma metastases result in a switch of the tumor microenvironment from a non-inflammatory to an inflammatory state. In this view point essay, we discuss the requirements for successful homing of lymphocytes to melanoma tissue and we present a mouse melanoma xenograft model that allows the investigation of human tumor vessels in vivo. Furthermore, current clinical studies dealing with the activation of melanoma vasculature for enhanced effectiveness of immunotherapy protocols are presented and open questions for routine clinical application are addressed.
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Affiliation(s)
- Carsten Weishaupt
- Department of Dermatology, University Hospital of Muenster, Muenster, Germany
| | - Tobias Goerge
- Department of Dermatology, University Hospital of Muenster, Muenster, Germany
| | - Karin Loser
- Department of Dermatology, University Hospital of Muenster, Muenster, Germany.,Institute of Immunology, University of Oldenburg, Oldenburg, Germany
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28
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Balmer ML, Ma EH, Thompson AJ, Epple R, Unterstab G, Lötscher J, Dehio P, Schürch CM, Warncke JD, Perrin G, Woischnig AK, Grählert J, Löliger J, Assmann N, Bantug GR, Schären OP, Khanna N, Egli A, Bubendorf L, Rentsch K, Hapfelmeier S, Jones RG, Hess C. Memory CD8 + T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection. Cell Metab 2020; 32:457-467.e5. [PMID: 32738204 DOI: 10.1016/j.cmet.2020.07.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 04/21/2020] [Accepted: 07/12/2020] [Indexed: 12/31/2022]
Abstract
Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type.
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Affiliation(s)
- Maria L Balmer
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
| | - Eric H Ma
- Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Physiology, McGill University, Montreal, QC, Canada
| | - Andrew J Thompson
- Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Raja Epple
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Gunhild Unterstab
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Jonas Lötscher
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Philippe Dehio
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Christian M Schürch
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA
| | - Jan D Warncke
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Gaëlle Perrin
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Anne-Kathrin Woischnig
- Department of Biomedicine, Laboratory of Infection Biology, University of Basel and University Hospital Basel, 4031 Basel, Switzerland
| | - Jasmin Grählert
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Jordan Löliger
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Nadine Assmann
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Glenn R Bantug
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Olivier P Schären
- Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland
| | - Nina Khanna
- Department of Biomedicine, Laboratory of Infection Biology, University of Basel and University Hospital Basel, 4031 Basel, Switzerland
| | - Adrian Egli
- Clinical Microbiology, University Hospital Basel, 4031 Basel, Switzerland; Applied Microbiology Research, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Lukas Bubendorf
- Institute for Pathology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | - Katharina Rentsch
- Department of Laboratory Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | | | - Russell G Jones
- Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Physiology, McGill University, Montreal, QC, Canada
| | - Christoph Hess
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
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29
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Marino AP, Dos Santos LI, Henriques PM, Roffe E, Vasconcelos-Santos DV, Sher A, Jankovic D, Gomes MS, Amaral LR, Campi-Azevedo AC, Teixeira-Carvalho A, Martins-Filho OA, Gazzinelli RT, Antonelli LR. Circulating inflammatory mediators as biomarkers of ocular toxoplasmosis in acute and in chronic infection. J Leukoc Biol 2020; 108:1253-1264. [PMID: 32421913 DOI: 10.1002/jlb.4ma0420-702r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 04/06/2020] [Accepted: 04/27/2020] [Indexed: 11/08/2022] Open
Abstract
Toxoplasmosis is highly endemic worldwide. In Brazil, depending on the geographical region and socioeconomic status, 40-70% of individuals become seropositive at some point in their lives. A significant proportion of Toxoplasma gondii-chronically infected individuals who are otherwise immunocompetent develop recurrent ocular lesions. The inflammatory/immune mechanisms involved in development of ocular lesion are still unknown and, despite previous investigation, there are no reliable immune biomarkers to predict/follow disease outcome. To better understand the impact of the immune response on parasite control and immunopathology of ocular toxoplasmosis, and to provide insights on putative biomarkers for disease monitoring, we assessed the production of a large panel of circulating immune mediators in a longitudinal study of patients with postnatally acquired toxoplasmosis stratified by the presence of ocular involvement, both at the early acute stage and 6 months later during chronic infection, correlating them with presence of ocular involvement. We found that T. gondii-infected patients, especially during the acute stage of the disease, display high levels of chemokines, cytokines, and growth factors involved in the activation, proliferation, and migration of inflammatory cells to injured tissues. In particular, major increases were found in the IFN-induced chemokines CXCL9 and CXCL10 in T. gondii-infected patients regardless of disease stage or clinical manifestations. Moreover, a specific subgroup of circulating cytokines and chemokines including GM-CSF, CCL25, CCL11, CXCL12, CXCL13, and CCL2 was identified as potential biomarkers that accurately distinguish different stages of infection and predict the occurrence of ocular toxoplasmosis. In addition to serving as predictors of disease development, these host inflammatory molecules may offer promise as candidate targets for therapeutic intervention.
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Affiliation(s)
- Ana Pmp Marino
- Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - Luara I Dos Santos
- Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil.,Faculdade de Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Priscilla M Henriques
- Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - Ester Roffe
- Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil.,Laboratory of Molecular Immunology, Molecular Signaling Section, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Daniel V Vasconcelos-Santos
- Department of Ophthalmology and Otorinolaryngology, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Alan Sher
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Dragana Jankovic
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Matheus S Gomes
- Rede Multidisciplinar de Pesquisa, Ciência e Tecnologia, Universidade Federal de Uberlândia, Patos de Minas, Minas Gerais, Brasil.,Laboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Patos de Minas, Minas Gerais, Brasil
| | - Laurence R Amaral
- Rede Multidisciplinar de Pesquisa, Ciência e Tecnologia, Universidade Federal de Uberlândia, Patos de Minas, Minas Gerais, Brasil.,Laboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Patos de Minas, Minas Gerais, Brasil
| | - Ana C Campi-Azevedo
- Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - Andréa Teixeira-Carvalho
- Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - Olindo A Martins-Filho
- Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - Ricardo T Gazzinelli
- Laboratório de Imunopatologia, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - Lis R Antonelli
- Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz-Fiocruz, Belo Horizonte, Minas Gerais, Brazil
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30
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Rigoni R, Fontana E, Dobbs K, Marrella V, Taverniti V, Maina V, Facoetti A, D'Amico G, Al-Herz W, Cruz-Munoz ME, Schuetz C, Gennery AR, Garabedian EK, Giliani S, Draper D, Dbaibo G, Geha RS, Meyts I, Tousseyn T, Neven B, Moshous D, Fischer A, Schulz A, Finocchi A, Kuhns DB, Fink DL, Lionakis MS, Swamydas M, Guglielmetti S, Alejo J, Myles IA, Pittaluga S, Notarangelo LD, Villa A, Cassani B. Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome. J Allergy Clin Immunol 2020; 146:1165-1179.e11. [PMID: 32311393 PMCID: PMC7649331 DOI: 10.1016/j.jaci.2020.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 03/11/2020] [Accepted: 04/06/2020] [Indexed: 12/30/2022]
Abstract
Background Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS). Objective The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified. Methods We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2R229Q/R229Q (Rag2R229Q) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt. Results We show that memory/activated T cells from patients with OS and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad Th1/Th2/Th17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2R229Q mice results in increased frequency of Ccr4+ splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by Th1 effector T cells. Conclusions These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
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Affiliation(s)
- Rosita Rigoni
- Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy
| | - Elena Fontana
- Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy
| | - Kerry Dobbs
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md
| | - Veronica Marrella
- Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy
| | - Valentina Taverniti
- Department of Food, Environmental, and Nutritional Sciences, University of Milan Milan, Italy
| | - Virginia Maina
- Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy
| | - Amanda Facoetti
- Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy; Humanitas University, Rozzano, Milan, Italy
| | - Giovanna D'Amico
- Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano-Bicocca, Monza, Italy
| | - Waleed Al-Herz
- Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, Kuwait
| | | | - Catharina Schuetz
- Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Andrew R Gennery
- Great North Children's Hospital, Clinical Resource Building, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Silvia Giliani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Cytogenetic and Medical Genetics Unit, "A. Nocivelli" Institute for Molecular Medicine, Spedali Civili Hospital, Brescia, Italy
| | - Deborah Draper
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md
| | - Ghassan Dbaibo
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Raif S Geha
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Isabelle Meyts
- Department of Pediatrics, Universitair Ziekenhuis Leuven, University Hospitals Leuven, Leuven, Belgium; Laboratory for Inborn Errors of Immunity, Department of Immunology, Microbiology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Thomas Tousseyn
- Lab for Translational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Benedicte Neven
- Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France; Pediatric Immuno-Hematology Unit, Necker Children Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Despina Moshous
- Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France; Pediatric Immuno-Hematology Unit, Necker Children Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alain Fischer
- Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France; Pediatric Immuno-Hematology Unit, Necker Children Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ansgar Schulz
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Andrea Finocchi
- Department of Pediatrics, Children's Hospital Bambino Gesù, Rome, Italy
| | - Douglas B Kuhns
- Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Md
| | - Danielle L Fink
- Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Md
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Muthulekha Swamydas
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Simone Guglielmetti
- Department of Food, Environmental, and Nutritional Sciences, University of Milan Milan, Italy
| | - Julie Alejo
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Md
| | - Ian A Myles
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Md
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
| | - Anna Villa
- Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells, and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Barbara Cassani
- Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy.
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31
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Zhang X, Lu WS, Qin XM. Cytokines/Chemokines: Novel Biomarkers Associated with Severe Cutaneous Adverse Reactions. J Interferon Cytokine Res 2020; 40:172-181. [PMID: 32195616 DOI: 10.1089/jir.2019.0012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Although the incidence of severe cutaneous adverse reactions (SCARs) is very low, if it is not diagnosed and treated in time, it can not only cause skin and mucous membrane involvement, but can also cause multiple organ failure and even death. The diagnostic criteria and treatment guidelines for severe drug eruptions have not been unified. Many medical centers have used human leukocyte antigen alleles to diagnose SCARs. Some prospective studies have shown that susceptibility gene testing can prevent SCARs as early as possible, but the widespread implementation of its technology is limited by being ethnically specific. With the unique advantages of cytokine detection technology, cytokines are increasingly important for the diagnosis and treatment of SCARs. Related cytokines/chemokines involved in the pathogenesis, adjuvant diagnosis, and treatment of SCARs are discussed.
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Affiliation(s)
- Xiang Zhang
- Department of Dermatology, The Second Affiliated Hospital, WanNan Medical College, Wuhu, China
| | - Wen-Shen Lu
- Department of Dermatology, Affiliated Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Xiao-Ming Qin
- Department of Dermatology, The Second Affiliated Hospital, WanNan Medical College, Wuhu, China
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32
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Insights Into the Molecular and Cellular Underpinnings of Cutaneous T Cell Lymphoma. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2020; 93:111-121. [PMID: 32226341 PMCID: PMC7087059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cutaneous T cell lymphoma (CTCL) is a rare malignancy of skin-homing T lymphocytes. Advances in whole exome sequencing have identified a vast number of both single nucleotide variants (SNVs) and genomic copy number alterations (GCNAs) as driver mutations present in CTCL cells. These alterations cluster within several key pathways - T cell/NF-κB/JAK-STAT activation, cell cycle dysregulation/apoptosis, and DNA structural dysregulation affecting gene expression - allowing the maintenance of a population of proliferating, activated malignant T lymphocytes. While much of the clinical spectrum, genetic alterations, and oncogenic behavior of CTCL have been elucidated, little is known about the etiology that underlies CTCL malignant transformation and progression. Herein, we review the epidemiology, clinical presentation, and pathophysiology of CTCL to provide a perspective on CTCL pathogenesis. We outline a series of alterations by which mature, activated T lymphocytes are endowed with apoptosis resistance and cutaneous persistence. Subsequent genomic alterations including the loss of chromosomal structural controls further promote proliferation and constitutive T cell activation. CTCL cells are both malignant cells and highly functional T cells that can have major cutaneous and immunologic effects on the patient, including the suppression of cell-mediated immunity that facilitates malignant cell expansion. A deeper understanding of the molecular and cellular underpinnings of CTCL can help guide clinical management as well as inform prognosis and therapeutic discovery.
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33
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Lauritano D, Martinelli M, Baj A, Beltramini G, Candotto V, Ruggiero F, Palmieri A. Drug-induced gingival hyperplasia: An in vitro study using amlodipine and human gingival fibroblasts. Int J Immunopathol Pharmacol 2020; 33:2058738419827746. [PMID: 31663449 PMCID: PMC6822186 DOI: 10.1177/2058738419827746] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast’s function in gingival overgrowth. To determine whether amlodipine alters the inflammatory responses, we investigated its effects on gingival fibroblast gene expression as compared with untreated cells. Fragments of gingival tissue of healthy volunteers (11 years old boy, 68 years old woman, and 20 years old men) were collected during operation. Gene expression of 29 genes was investigated in gingival fibroblast cell culture treated with amlodipine, compared with untreated cells. Among the studied genes, only 15 (CCL1, CCL2D, CCL5, CCL8, CXCL5, CXCL10, CCR1, CCR10, IL1A, IL1B, IL5, IL7, IL8, SPP1, and TNFSF10) were significantly deregulated. In particular, the most evident overexpressed genes in treated cells were CCR10 and IL1A. These results seem to indicate a possible role of amlodipine in the inflammatory response of treated human gingival fibroblasts.
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Affiliation(s)
- Dorina Lauritano
- Department of Medicine and Surgery, Centre of Neuroscience of Milan, University of Milano-Bicocca, Milan, Italy
| | - Marcella Martinelli
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Alessandro Baj
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.,Maxillofacial and Dental Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giada Beltramini
- Maxillofacial and Dental Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Valentina Candotto
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Francesco Ruggiero
- Military Policlinic of Rome, Medical Department, Cardiological Unit, Rome, Italy
| | - Annalisa Palmieri
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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34
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Kim D, Kobayashi T, Voisin B, Jo JH, Sakamoto K, Jin SP, Kelly M, Pasieka HB, Naff JL, Meyerle JH, Ikpeama ID, Fahle GA, Davis FP, Rosenzweig SD, Alejo JC, Pittaluga S, Kong HH, Freeman AF, Nagao K. Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report. Nat Med 2020; 26:236-243. [PMID: 31959990 PMCID: PMC7105105 DOI: 10.1038/s41591-019-0733-7] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022]
Abstract
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.
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Affiliation(s)
- Doyoung Kim
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tetsuro Kobayashi
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA
| | - Benjamin Voisin
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA
| | - Jay-Hyun Jo
- Cutaneous Microbiome and Inflammation Section, Dermatology Branch, NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Keiko Sakamoto
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA
| | - Seon-Pil Jin
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA
| | - Michael Kelly
- Cancer Research Technology Program, Single-Cell Analysis Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Helena B Pasieka
- Department of Dermatology, MedStar Washington Hospital Center & Georgetown University Hospital, Washington, DC, USA
| | - Jessica L Naff
- Department of Dermatology, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Jon H Meyerle
- Department of Dermatology, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Ijeoma D Ikpeama
- Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA
| | - Gary A Fahle
- Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA
| | - Fred P Davis
- Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD, USA
| | - Sergio D Rosenzweig
- Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA
| | - Julie C Alejo
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Heidi H Kong
- Cutaneous Microbiome and Inflammation Section, Dermatology Branch, NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA
| | - Keisuke Nagao
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.
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35
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Aldon Y, Kratochvil S, Shattock RJ, McKay PF. Chemokine-Adjuvanted Plasmid DNA Induces Homing of Antigen-Specific and Non-Antigen-Specific B and T Cells to the Intestinal and Genital Mucosae. THE JOURNAL OF IMMUNOLOGY 2020; 204:903-913. [PMID: 31915263 PMCID: PMC6994839 DOI: 10.4049/jimmunol.1901184] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 11/29/2019] [Indexed: 01/19/2023]
Abstract
Plasmid DNA is a promising vaccine platform that together with electroporation can elicit significant systemic Ab responses; however, immunity at mucosal sites remains low. In this study, we sought to program T and B cells to home to the gastrointestinal and vaginal mucosae using genetic chemokine adjuvants and assessed their impact on immune homeostasis in various distinct immune compartments. BALB/c mice were immunized i.m. with plasmid DNA encoding a model Ag HIV-1 Env gp140 and selected chemokines/cytokine and boosted intravaginally with gp140 recombinant protein. Isolated splenocytes, intestinal lymphocytes, and genital lymphocytes as well as serum and intestinal luminal contents were assessed for Ag-specific reactivity. In addition, flow cytometric analysis was performed to determine the impact on immune homeostasis at these sites. Different molecular chemokine/cytokine adjuvants effected significant alterations to the recruitment of B and T cells to the spleen, vaginal and intestinal mucosae, for example CCL25 enhanced splenic and vaginal Ag-specific T cell responses whereas CCL28 increased the levels of specific T cells only in the vaginal mucosa. The levels of Ab could be modulated in the systemic circulation, as well as the vaginal vault and intestinal lumen, with CCL20 playing a central role. Our data demonstrate that the CCL20, CCL25, and CCL28 genetic chemokine adjuvants enhance the vaccine Ag-specific humoral and cellular responses and induce homing to the intestinal and female genital mucosae.
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Affiliation(s)
- Yoann Aldon
- Department of Medicine, Imperial College London, London W2 1PG, United Kingdom
| | - Sven Kratochvil
- Department of Medicine, Imperial College London, London W2 1PG, United Kingdom
| | - Robin J Shattock
- Department of Medicine, Imperial College London, London W2 1PG, United Kingdom
| | - Paul F McKay
- Department of Medicine, Imperial College London, London W2 1PG, United Kingdom
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36
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Abstract
The skin is the outermost organ of the body and is exposed to many kinds of external pathogens. To manage this, the skin contains multiple types of immune cells. To achieve sufficient induction of cutaneous adaptive immune responses, the antigen presentation/recognition in the skin is an essential process. Recent studies have expanded our knowledge of how T cells survey their cognate antigens in the skin. In addition, the formation of a lymphoid cluster, named inducible skin-associated lymphoid tissue (iSALT), has been reported during skin inflammation. Although iSALT may not be classified as a typical tertiary lymphoid organ, it provides specific antigen presentation sites in the skin. In this article, we provide an overview of the antigen presentation mechanism in the skin, with a focus on the development of iSALT and its function.
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Affiliation(s)
- Gyohei Egawa
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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37
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Brys AK, Rodriguez-Homs LG, Suwanpradid J, Atwater AR, MacLeod AS. Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity. J Invest Dermatol 2020; 140:21-28. [PMID: 31101475 PMCID: PMC6854274 DOI: 10.1016/j.jid.2019.03.1133] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/07/2019] [Accepted: 03/07/2019] [Indexed: 12/30/2022]
Abstract
The role of the innate immune system in allergic contact dermatitis (ACD) has traditionally been confined to the initial antigen sensitization phase. However, more recent findings have shown the role of innate immunity in additional aspects of ACD, including the effector phase of the classic type IV hypersensitivity reaction. As a result, the precise immunologic mechanisms mediating ACD are more complex than previously believed. The aim of this review is to provide insight into recent advances in understanding the role of the innate immune system in the pathogenesis of ACD, including novel mechanistic roles for macrophages, innate lymphoid cells, natural killer cells, innate γδ T cells, and other signaling molecules. These insights provide new opportunities for therapeutic intervention in ACD.
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Affiliation(s)
- Adam K Brys
- Duke University Medical Center, Department of Dermatology, Duke University Medical Center, DUMC 3135, Durham, North Carolina, USA
| | - Larissa G Rodriguez-Homs
- Duke University Medical Center, Department of Dermatology, Duke University Medical Center, DUMC 3135, Durham, North Carolina, USA
| | - Jutamas Suwanpradid
- Duke University Medical Center, Department of Dermatology, Duke University Medical Center, DUMC 3135, Durham, North Carolina, USA
| | - Amber Reck Atwater
- Duke University Medical Center, Department of Dermatology, Duke University Medical Center, DUMC 3135, Durham, North Carolina, USA
| | - Amanda S MacLeod
- Duke University Medical Center, Department of Dermatology, Duke University Medical Center, DUMC 3135, Durham, North Carolina, USA.
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38
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Knipfer L, Schulz-Kuhnt A, Kindermann M, Greif V, Symowski C, Voehringer D, Neurath MF, Atreya I, Wirtz S. A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2-mediated inflammation. J Exp Med 2019; 216:2763-2777. [PMID: 31537642 PMCID: PMC6888976 DOI: 10.1084/jem.20182111] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 06/17/2019] [Accepted: 09/03/2019] [Indexed: 01/03/2023] Open
Abstract
Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2-mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor-dependent mechanism by which ILC2s are regulated during type 2 responses.
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Affiliation(s)
- Lisa Knipfer
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Anja Schulz-Kuhnt
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Markus Kindermann
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Vicky Greif
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Cornelia Symowski
- Department of Infection Biology, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - David Voehringer
- Department of Infection Biology, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
| | - Stefan Wirtz
- Department of Medicine 1, University Hospital Center, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
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39
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Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS. Blood Adv 2019; 2:2242-2252. [PMID: 30194138 DOI: 10.1182/bloodadvances.2018018754] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 07/23/2018] [Indexed: 12/23/2022] Open
Abstract
Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.
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40
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Menzies FM, Oldham RS, Waddell C, Nelson SM, Nibbs RJB. A Comprehensive Profile of Chemokine Gene Expression in the Tissues of the Female Reproductive Tract in Mice. Immunol Invest 2019; 49:264-286. [PMID: 31429329 DOI: 10.1080/08820139.2019.1655573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Homeostatic leukocyte trafficking into and within the female reproductive tract (FRT) contributes to fertility and reproductive health. It is unclear how this process is regulated in the anatomically distinct reproductive tissues, or whether the genes involved are affected by cyclical changes in reproductive hormones. In tissues such as skin and intestine, mouse studies have defined evolutionarily conserved molecular mechanisms for tissue-specific homing, interstitial positioning, and leukocyte egress. Chemokine family members are invariably involved, with the chemokine expression profile of a tissue regulating leukocyte content. Reproductive tissues (ovary, vagina, cervix, uterine horn) of 8 week old virgin female C57BL/6 mice (n = 20) were collected, and expression of mRNA for leukocyte markers and chemokines conducted by qPCR. Lymphocytic and myeloid cell populations within the uterus, cervix, bone marrow and PALN from virgin C57BL/6 mice were determined by flow cytometric analysis. Variation in leukocyte content between reproductive tissues is evident, with the uterus and cervix containing complex mixtures of lymphocytes and myeloid cells. Twenty-six chemokine genes are expressed in the FRT, many by several component tissues, some preferentially by one. Most striking are Xcl1 and Ccl28, which are restricted to the uterus. Ccl20 and genes encoding CXCR2 ligands are primarily transcribed in cervix and vagina. Ovary shows the lowest expression of most chemokine genes, with the notable exception of Ccl21 and Ccl27. We also identify eight chemokines in the vagina whose expression fluctuates substantially across the oestrous cycle. These data reveal complex chemokine networks within the FRT, and provide a framework for future studies of homeostatic leukocyte trafficking into and within these tissues.Abbreviations: BM: bone marrow; DC: dendritic cell; DN: double negative; FRT: female reproductive tract; FSC: forward scatter; NK: natural killer; PALN: para-aortic lymph node; SSC: side scatter; Tregs: regulatory T cells.
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Affiliation(s)
- Fiona M Menzies
- School of Health & Life Science, University of the West of Scotland, Paisley, UK.,Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Rachel S Oldham
- Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.,Institute of Infection, Immunity & Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Carolann Waddell
- Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Scott M Nelson
- Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Robert J B Nibbs
- Institute of Infection, Immunity & Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
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41
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Wang Y, Zhang C. The Roles of Liver-Resident Lymphocytes in Liver Diseases. Front Immunol 2019; 10:1582. [PMID: 31379818 PMCID: PMC6648801 DOI: 10.3389/fimmu.2019.01582] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/25/2019] [Indexed: 12/18/2022] Open
Abstract
Tissue-resident lymphocytes usually reside in barrier sites and are involved in innate and adaptive immunity. In recent years, many studies have shown that multiple types of lymphocytes are resident in the liver, including memory CD8+ T (TRM) cells; "unconventional" T cells, such as invariant natural killer T (iNKT) cells, mucosal associated invariant T (MAIT) cells, and γδT cells; innate lymphoid cells (ILCs) such as natural killer (NK) cells and other ILCs. Although diverse types of tissue-resident lymphocytes share similar phenotypes, functional properties, and transcriptional regulation, the unique microenvironment of the liver can reshape their phenotypic and functional characteristics. Liver-resident lymphocytes serve as sentinels and perform immunosurveillance in response to infection and non-infectious insults, and are involved in the maintenance of liver homeostasis. Under the pathological conditions, distinct liver-resident lymphocytes exert protective or pathological effects in the process of various liver diseases. In this review, we highlight the unique properties of liver-resident lymphocytes, and discuss their functional characteristics in different liver diseases.
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Affiliation(s)
- Yanan Wang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Cai Zhang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
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42
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Inflammatory chemokine profiles and their correlations with effector CD4 T cell and regulatory cell subpopulations in cutaneous lupus erythematosus. Cytokine 2019; 119:95-112. [DOI: 10.1016/j.cyto.2019.03.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/08/2019] [Accepted: 03/14/2019] [Indexed: 11/23/2022]
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43
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Richmond JM, Strassner JP, Essien KI, Harris JE. T-cell positioning by chemokines in autoimmune skin diseases. Immunol Rev 2019; 289:186-204. [PMID: 30977191 PMCID: PMC6553463 DOI: 10.1111/imr.12762] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 03/18/2019] [Accepted: 03/21/2019] [Indexed: 12/12/2022]
Abstract
Autoimmune skin diseases are complex processes in which autoreactive cells must navigate through the skin tissue to find their targets. Regulatory T cells in the skin help to mitigate autoimmune inflammation and may in fact be responsible for the patchy nature of these conditions. In this review, we will discuss chemokines that are important for global recruitment of T cell populations to the skin during disease, as well as signals that fine-tune their localization and function. We will describe prototypical disease responses and chemokine families that mediate these responses. Lastly, we will include an overview of chemokine-targeting drugs that have been tested as new treatment strategies for autoimmune skin diseases.
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Affiliation(s)
- Jillian M Richmond
- Department of Dermatology, UMass Medical School, Worcester, Massachusetts
| | - James P Strassner
- Department of Dermatology, UMass Medical School, Worcester, Massachusetts
| | - Kingsley I Essien
- Department of Dermatology, UMass Medical School, Worcester, Massachusetts
| | - John E Harris
- Department of Dermatology, UMass Medical School, Worcester, Massachusetts
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44
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Farnsworth RH, Karnezis T, Maciburko SJ, Mueller SN, Stacker SA. The Interplay Between Lymphatic Vessels and Chemokines. Front Immunol 2019; 10:518. [PMID: 31105685 PMCID: PMC6499173 DOI: 10.3389/fimmu.2019.00518] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/26/2019] [Indexed: 12/21/2022] Open
Abstract
Chemokines are a family of small protein cytokines that act as chemoattractants to migrating cells, in particular those of the immune system. They are categorized functionally as either homeostatic, constitutively produced by tissues for basal levels of cell migration, or inflammatory, where they are generated in association with a pathological inflammatory response. While the extravasation of leukocytes via blood vessels is a key step in cells entering the tissues, the lymphatic vessels also serve as a conduit for cells that are recruited and localized through chemoattractant gradients. Furthermore, the growth and remodeling of lymphatic vessels in pathologies is influenced by chemokines and their receptors expressed by lymphatic endothelial cells (LECs) in and around the pathological tissue. In this review we summarize the diverse role played by specific chemokines and their receptors in shaping the interaction of lymphatic vessels, immune cells, and other pathological cell types in physiology and disease.
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Affiliation(s)
- Rae H Farnsworth
- Tumor Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
| | - Tara Karnezis
- Lymphatic and Regenerative Medicine Laboratory, O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Simon J Maciburko
- Lymphatic and Regenerative Medicine Laboratory, O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Melbourne, VIC, Australia
| | - Steven A Stacker
- Tumor Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.,Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
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45
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Kataru RP, Baik JE, Park HJ, Wiser I, Rehal S, Shin JY, Mehrara BJ. Regulation of Immune Function by the Lymphatic System in Lymphedema. Front Immunol 2019; 10:470. [PMID: 30936872 PMCID: PMC6431610 DOI: 10.3389/fimmu.2019.00470] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 02/21/2019] [Indexed: 12/13/2022] Open
Abstract
The lymphatic vasculature has traditionally been thought to play a passive role in the regulation of immune responses by transporting antigen presenting cells and soluble antigens to regional lymph nodes. However, more recent studies have shown that lymphatic endothelial cells regulate immune responses more directly by modulating entry of immune cells into lymphatic capillaries, presenting antigens on major histocompatibility complex proteins, and modulating antigen presenting cells. Secondary lymphedema is a disease that develops when the lymphatic system is injured during surgical treatment of cancers or is damaged by infections. We have used mouse models of lymphedema in order to understand the effects of chronic lymphatic injury on immune responses and have shown that lymphedema results in a mixed T helper cell and T regulatory cell (Treg) inflammatory response. Prolonged T helper 2 biased immune responses in lymphedema regulate the pathology of this disease by promoting tissue fibrosis, inhibiting formation of collateral lymphatics, decreasing lymphatic vessel pumping capacity, and increasing lymphatic leakiness. Treg infiltration following lymphatic injury results from proliferation of natural Tregs and suppresses innate and adaptive immune responses. These studies have broad clinical relevance since understanding how lymphatic injury in lymphedema can modulate immune responses may provide a template with which we can study more subtle forms of lymphatic injury that may occur in physiologic conditions such as aging, obesity, metabolic tumors, and in the tumor microenvironment.
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Affiliation(s)
- Raghu P Kataru
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jung Eun Baik
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Hyeung Ju Park
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Itay Wiser
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Sonia Rehal
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jin Yeon Shin
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Babak J Mehrara
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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Wolf RM, Jaffe AE, Steele KE, Schweitzer MA, Magnuson TH, Wolfe A, Wong GW. Cytokine, Chemokine, and Cytokine Receptor Changes Are Associated With Metabolic Improvements After Bariatric Surgery. J Clin Endocrinol Metab 2019; 104:947-956. [PMID: 30544212 PMCID: PMC6364507 DOI: 10.1210/jc.2018-02245] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
Abstract
Context Altered cytokine levels and chronic low-grade inflammation contribute to metabolic dysfunction in obesity. The extent of cytokine changes and their impact on metabolic improvements after bariatric surgery have not been fully explored. Objective To compare 76 circulating cytokines, chemokines, and secreted cytokine receptors in subjects with obesity and lean subjects and determine how these cytokines are altered by bariatric surgery. Design, Setting, and Participants A total of 37 patients with obesity and 37 lean patients in a cross-sectional study at an academic medical center. We also investigated cytokine changes in 25 patients with obesity after bariatric surgery. Intervention Bariatric surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy). Main Outcome Measures Quantification of 76 circulating cytokines, chemokines, and secreted cytokine receptors. Results A total of 13 cytokines were significantly higher, and 4 lower, in patients with obesity relative to lean controls. Soluble vascular endothelial growth factor receptor 2 (sVEGFR2), soluble TNF receptor (sTNFR) 1, and sTNFR2 were positively correlated, and soluble receptor for advanced glycation end-products was inversely correlated, with weight and body mass index. sTNFR2 was positively correlated with fasting glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c. After bariatric surgery, adiponectin increased, and leptin decreased. Elevated sVEGFR2 levels in patients with obesity were decreased (P = 0.01), whereas reduced chemokine (C-X-C motif) ligand (CXCL) 12 levels in patients with obesity increased (P = 0.03) after surgery. Patients with higher soluble interleukin receptor (sIL) 1R2 and sIL-6R levels before surgery had greater weight loss after surgery (P < 0.05). Conclusions We demonstrate that chemokine (C-C motif) ligand (CCL) 14, sVEGFR2, and platelet-derived growth factor BB are elevated in obesity, and CXCL12, CCL11, and CCL27 are lower in obesity. We found clinically concordant directionality between lean and patients with obesity and before vs after surgery for six cytokines, suggesting that bariatric surgery shifted the cytokine profiles of patients with obesity toward that of lean controls.
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Affiliation(s)
- Risa M Wolf
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrew E Jaffe
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Kimberley E Steele
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael A Schweitzer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Thomas H Magnuson
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrew Wolfe
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - G William Wong
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Oreskovic Z, Nechvatalova K, Krejci J, Kummer V, Faldyna M. Aspects of intradermal immunization with different adjuvants: The role of dendritic cells and Th1/Th2 response. PLoS One 2019; 14:e0211896. [PMID: 30742635 PMCID: PMC6370205 DOI: 10.1371/journal.pone.0211896] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
Intradermal (i.d.) application of vaccine is promising way how to induce specific immune response against particular pathogens. Adjuvants, substances added into vaccination dose with the aim to increase immunogenicity, play important role in activation of dendritic cells with subsequent activation of lymphocytes. They can, however, induce unwanted local reactions. The aim of the study was to determine the effect of i.d. administration of model antigen keyhole limped hemocyanine alone or with different adjuvants-aluminium hydroxide and oil-based adjuvants-on local histopathological reaction as well as dendritic cell activation at the site of administration and local cytokine and chemokine response. This was assessed at 4 and 24 hours after application. Selection of the adjuvants was based on the fact, that they differently enhance antibody or cell-mediated immunity. The results showed activation of dendritic cells and both Th1 and Th2 response stimulated by oil-based adjuvants. It was associated with higher expression of set of genes, incl. chemokine receptor CCR7 or Th1-associated chemokine CXCL10 and cytokine IFNγ. Application of the antigen with aluminium hydroxide induced higher expression of Th2-associated IL4 or IL13. On the other hand, both complete and incomplete Freund´s adjuvants provoked strong local reaction associated with influx of neutrophils. This was accompanied with high expression of proinflammatory IL1 or neutrophil chemoattractant CXCL8. Surprisingly, similarly strong local reaction was detected also after application of aluminium hydroxide-based adjuvant. The best balanced local reaction with sufficient activation of immune cells was detected after application of oil-based adjuvants Montanide and Emulsigen.
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Affiliation(s)
- Zrinka Oreskovic
- Department of Immunology, Veterinary Research Institute, Brno, Czech Republic
- Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | | | - Josef Krejci
- Department of Immunology, Veterinary Research Institute, Brno, Czech Republic
| | - Vladimir Kummer
- Department of Immunology, Veterinary Research Institute, Brno, Czech Republic
| | - Martin Faldyna
- Department of Immunology, Veterinary Research Institute, Brno, Czech Republic
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Valiki FH, Mohammadi MM, Ajami A, Khalatbari A, Haghi FM. Evaluation of Lymphocyte Migration to Induced Paederus Dermatitis: An Experimental Study in Rats. Indian J Dermatol 2019; 64:431-435. [PMID: 31896838 PMCID: PMC6862375 DOI: 10.4103/ijd.ijd_447_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Background: Paederus dermatitis (PD) is a blistering disorder that is caused by a small insect of the genus Paederus, especially Paederus fuscipes. This study aimed to investigate the reaction of the adaptive immune system regarding the recruitment of CD3, CCR4, and CCR10 markers, which are specifically expressed on the surface of T lymphocytes. Materials and Methods: In this experimental study, 24 female rats were divided into two groups: the test and the negative control. In the test group, PD was induced by making insects in contact with shaved rat skin. Biopsies were obtained 24, 72, and 120 h after induction. In the negative control group, physiological saline was applied. Specimens were evaluated by immunohistochemical staining method. Antibodies against CD3, CCR4, and CCR10 were used. Distribution and staining intensities of CD3, CCR4, and CCR10 markers were estimated by the H-score index and findings were analyzed using the Kruskal–Wallis and Wilcoxon statistical tests. Results: Based on the results of immunohistochemistry, the expression of CD3, CCR4, and CCR10 in the test group at 24, 72, and 120 h compared to the control group showed significant increase (P = 0.0006, P = 0.001, and P < 0.0001), respectively. The peak of expression of all markers was at 72 h after exposure. Hematoxylin and eosin staining also confirmed the fact that the majority of the lymphocyte infiltration occurred at 72 h postexposure. Conclusion: The expression of CD3, CCR4, and CCR10 on cells present in PD lesions could indicate that T-lymphocytes are recruited to the site of inflammation by chemokine–chemokine receptor interactions and hence provide evidence for the response by the adaptive immune system following a PD.
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Affiliation(s)
| | - Mohammad Mahdi Mohammadi
- Department of Immunology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Abolghasem Ajami
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Mazandaran, Iran
| | - Alireza Khalatbari
- Department of Anatomy, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Farzad Motevalli Haghi
- Department of Medical Entomology and Vector Control, Faculty of Public Health, Mazandaran University of Medical Sciences, Sari, Iran
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Querfeld C, Zain J, Rosen ST. Primary Cutaneous T-Cell Lymphomas: Mycosis Fungoides and Sezary Syndrome. Cancer Treat Res 2019; 176:225-248. [PMID: 30596221 DOI: 10.1007/978-3-319-99716-2_11] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Mycosis fungoides and Sézary syndrome are the most common subtypes of all primary cutaneous lymphomas and represent complex diseases that require a multidisciplinary assessment by dermatologists, oncologists, and pathologists. Staging and work-up are critical to guarantee an optimal treatment plan that includes skin-directed and/or systemic regimens depending on the clinical stage, tumor burden, drug-related side effect profile, and patient comorbidities. However, there is no cure and patients frequently relapse, requiring repeated treatment courses for disease control. The study of the tumor microenvironment and molecular mechanisms of these rare neoplasms may assist in the development of new immune therapies providing promising treatment approaches tailored for patients with relapse/refractory disease.
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Affiliation(s)
- Christiane Querfeld
- Division of Dermatology, City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
- Department of Hematology/Hematopoietic Cell Transplantation, Duarte, USA.
- Department of Pathology, Duarte, USA.
- Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USA.
| | - Jasmine Zain
- Department of Hematology/Hematopoietic Cell Transplantation, Duarte, USA
- Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USA
| | - Steven T Rosen
- Department of Hematology/Hematopoietic Cell Transplantation, Duarte, USA
- Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USA
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50
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Jacquelot N, Duong CPM, Belz GT, Zitvogel L. Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers. Front Immunol 2018; 9:2480. [PMID: 30420855 PMCID: PMC6215820 DOI: 10.3389/fimmu.2018.02480] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 10/08/2018] [Indexed: 12/19/2022] Open
Abstract
The tumor microenvironment is highly heterogeneous. It is composed of a diverse array of immune cells that are recruited continuously into lesions. They are guided into the tumor through interactions between chemokines and their receptors. A variety of chemokine receptors are expressed on the surface of both tumor and immune cells rendering them sensitive to multiple stimuli that can subsequently influence their migration and function. These features significantly impact tumor fate and are critical in melanoma control and progression. Indeed, particular chemokine receptors expressed on tumor and immune cells are strongly associated with patient prognosis. Thus, potential targeting of chemokine receptors is highly attractive as a means to quench or eliminate unconstrained tumor cell growth.
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Affiliation(s)
- Nicolas Jacquelot
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Connie P M Duong
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,INSERM U1015, Villejuif, France
| | - Gabrielle T Belz
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Laurence Zitvogel
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,INSERM U1015, Villejuif, France.,Faculty of Medicine, Paris Sud/Paris XI University, LeKremlin-Bicêtre, France.,Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France
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