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Aharon A, Avni B, Louzoun D, Elias S, Stepensky P, Ram R, Zuckerman T, Meza-Romero R, Vandenbark AA, Grisariu S, Benedek G. MIF functional polymorphisms are associated with acute GVHD progression and steroid-refractoriness. Front Immunol 2025; 16:1504976. [PMID: 40421032 PMCID: PMC12105047 DOI: 10.3389/fimmu.2025.1504976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 04/09/2025] [Indexed: 05/28/2025] Open
Abstract
Introduction Approximately 50% of allogeneic hematopoietic stem cell transplantation (HSCT) Q6 recipients develop graft versus host disease (GVHD). Glucocorticoids (GC) are the first line of treatment for both acute and chronic GVHD. Failure to respond to GC [steroid-refractory (SR)] encompasses a very poor outcome with high mortality. Macrophage migration inhibitory factor (MIF) is released during transplantation and triggers enhanced and prolonged immune reactions. Persistently elevated levels of MIF have been shown to override both endogenous and exogenous antiinflammatory effects of GC. Methods Two functional polymorphisms in the MIF gene, a -794 CATT5-8 microsatellite repeat and a -173 G/C single-nucleotide polymorphism, were analyzed in 86 patients who underwent allogeneic HSCT. We also measured MIF serum levels at different time points before and after HSCT. Results Frequencies of MIF high-expression -794 CATT7 containing genotypes were increased in patients with grade III-IV acute GVHD (aGVHD) (36.8%) compared with patients that did not develop aGVHD (5.8%) and patients with grade II aGVHD (0%), (p=0.0019, 0.0080 respectively). We also demonstrated that the frequencies of the MIF-794 CATT7 and -173 C containing genotypes, were significantly associated with steroid-refractory aGVHD (46.6%, 60% respectively) compared to steroid-responsive aGVHD (0%, 5.3% respectively), (p=0.0011, P=0.0007 respectively). We further showed that MIF circulating levels preceded onset of severe aGVHD. Discussion Our findings suggest that genetically controlled high expression MIF genotypes are associated with aGVHD worsening and could serve as a biomarker enhancing identification and treatment of steroid-refractory disease.
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Affiliation(s)
- Aviran Aharon
- Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel
| | - Batia Avni
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Daniel Louzoun
- Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel
| | - Shlomo Elias
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Polina Stepensky
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Ron Ram
- Bone Marrow Transplantation and Cellular Therapy Unit, Tel Aviv Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tsila Zuckerman
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Roberto Meza-Romero
- Department of Neurology, Oregon Health & Science University, Portland, OR, United States
- Neuroimmunology Research, VA Portland Health Care System, Portland, OR, United States
| | - Arthur A. Vandenbark
- Department of Neurology, Oregon Health & Science University, Portland, OR, United States
- Neuroimmunology Research, VA Portland Health Care System, Portland, OR, United States
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States
| | - Sigal Grisariu
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Gil Benedek
- Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel
- Tissue Typing and Immunogenetics Unit, Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduct Target Ther 2025; 10:102. [PMID: 40097390 PMCID: PMC11914703 DOI: 10.1038/s41392-025-02168-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/26/2024] [Accepted: 01/26/2025] [Indexed: 03/19/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.
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Affiliation(s)
- Xiaofeng Dai
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
| | - Yuting Fan
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China
- Department of Gastroenterology, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, P. R. China
| | - Xing Zhao
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China.
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Peng X, Chinwe Oluchi-Amaka I, Kwak-Kim J, Yang X. A comprehensive review of the roles of T-cell immunity in preeclampsia. Front Immunol 2025; 16:1476123. [PMID: 39981257 PMCID: PMC11841438 DOI: 10.3389/fimmu.2025.1476123] [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: 08/05/2024] [Accepted: 01/22/2025] [Indexed: 02/22/2025] Open
Abstract
Preeclampsia (PE) is an obstetrical disorder that occurs after the 20th week of gestation. It is recognized as one of the "Great Obstetrical Syndromes" and principally contributes to maternal morbidity and mortality. PE has been associated with a range of immune disorders, including a preponderance of T helper (Th) 1 over Th2 cells and imbalanced levels of Th17 and T regulatory cells (Tregs). During pregnancy, T cells safeguard the placenta against immune rejection and aid embryo implantation while involved in pregnancy complications, such as PE. Promoting alloantigen-specific Treg cells is a potential preventive and therapeutic strategy for PE. However, ensuring the safety of mothers and infants is of the utmost importance since the risk-benefit ratio of reproductive and obstetric conditions differs significantly from that of immune diseases that pose a life-threatening risk. In this review, we systematically summarize the roles of T-cell immunity in the peripheral blood, reproductive tissues, and at the maternal-fetal interface of PE patients. Furthermore, the recent therapeutic approaches centered on targeting T cell immunity in PE are critically appraised.
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Affiliation(s)
- Xu Peng
- Department of Obstetrics, The First Hospital of China Medical University, Shenyang, China
| | | | - Joanne Kwak-Kim
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Clinical Immunology Laboratory, Foundational Sciences and Humanities, Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Xiuhua Yang
- Department of Obstetrics, The First Hospital of China Medical University, Shenyang, China
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Gutiérrez-Brito JA, Lomelí-Nieto JÁ, Muñoz-Valle JF, Oregon-Romero E, Corona-Angeles JA, Hernández-Bello J. Sex hormones and allergies: exploring the gender differences in immune responses. FRONTIERS IN ALLERGY 2025; 5:1483919. [PMID: 39840271 PMCID: PMC11747284 DOI: 10.3389/falgy.2024.1483919] [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: 08/20/2024] [Accepted: 11/22/2024] [Indexed: 01/23/2025] Open
Abstract
Allergies are closely associated with sex-related hormonal variations that influence immune function, leading to distinct symptom profiles. Similar sex-based differences are observed in other immune disorders, such as autoimmune diseases. In allergies, women exhibit a higher prevalence of atopic conditions, such as allergic asthma and eczema, in comparison to men. However, age-related changes play a significant role because men have a higher incidence of allergies until puberty, and then comes a switch ratio of prevalence and severity in women. Investigations into the mechanisms of how the hormones influence the development of these diseases are crucial to understanding the molecular, cellular, and pathological aspects. Sex hormones control the reproductive system and have several immuno-modulatory effects affecting immune cells, including T and B cell development, antibody production, lymphoid organ size, and lymphocyte death. Moreover, studies have suggested that female sex hormones amplify memory immune responses, which may lead to an excessive immune response impacting the pathogenesis, airway hyperresponsiveness, inflammation of airways, and mucus production of allergic diseases. The evidence suggests that estrogens enhance immune humoral responses, autoimmunity, mast cell reactivity, and delayed IV allergic reactions, while androgens, progesterone, and glucocorticoids suppress them. This review explores the relationship between sex hormones and allergies, including epidemiological data, experimental findings, and insights from animal models. We discuss the general properties of these hormones, their effects on allergic processes, and clinical observations and therapeutic results. Finally, we describe hypersensitivity reactions to these hormones.
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Affiliation(s)
| | | | | | | | | | - Jorge Hernández-Bello
- Research Institute of Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico
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Niu J, Zhang L, Cui L, Liu M. Regulatory T cells in CIDP and the inhibitory effect of rapamycin on them. Hum Immunol 2025; 86:111224. [PMID: 39729692 DOI: 10.1016/j.humimm.2024.111224] [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: 05/17/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 12/29/2024]
Abstract
We aim to investigate the proportion and function of regulatory T (Treg) cells, as well as mTORC activity in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients. Peripheral blood mononuclear cells (PBMCs) from 15 CIDP and healthy controls (HC) were collected. Treg and responsive T (Tresp) cells were isolated. The inhibition rate of Treg cells was analyzed with and without rapamycin. The percentage of CD4 + CD25highFoxP3+ Tregs was higher in CIDP than in HCs (median 3.06 % vs 1.98 %, P = 0.014). The suppressive function of CIDP Tregs was normal compared with that of HCs. The activity of mTORC1 and mTORC2 revealed by pAKT and p4EBP1 in Treg cells was not significantly different between CIDP and HC. The percentage of Treg cells showed no difference in the presence or absence of rapamycin, while the suppressive function of CIDP and HC Tregs was dramatically diminished in the presence of rapamycin. The percentage of P-akt in Tregs was also reduced in the presence of rapamycin. In conclusion, the percentage and suppressive function of Tregs were not impaired in CIDP patients. The presence of rapamycin had no effect on the percentage of Treg cells but could reduce the suppressive function of CIDP and HC Tregs, possibly by reducing P-Akt.
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Affiliation(s)
- Jingwen Niu
- From the Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
| | - Lei Zhang
- From the Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
| | - Liying Cui
- From the Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
| | - Mingsheng Liu
- From the Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China.
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Besedovsky H, Del Rey A. A Glucocorticoid-Mediated Immunoregulatory Circuit Integrated at Brain Levels: Our Early Studies and a Present View. Neuroimmunomodulation 2024; 31:230-245. [PMID: 39504948 DOI: 10.1159/000542401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/29/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND It was known since the 1940s that pharmacological administration of glucocorticoids can inhibit inflammatory and immune processes, and these hormones are still today among the most widely used therapeutic tools to treat diseases with immune components. However, it became clear later that endogenous glucocorticoids can either support or restrain immune processes. SUMMARY Early studies showed that (a) endogenous levels of glucocorticoids can modulate immune cell activity; (b) the immune response itself can stimulate the hypothalamus-pituitary-adrenal (HPA) axis to release glucocorticoids to levels that can exert immunoregulatory effects; (c) immune products, later identified as cytokines, mediate this effect. On these bases, the existence of a glucocorticoid-mediated immunoregulatory circuit was proposed. It was also shown that increased levels of endogenous glucocorticoids exert protective effects during infections and other diseases with immune components. However, it was found in animal models and in humans that these effects can be blunted in several immune-linked diseases by defects at several levels, for example, by glucocorticoid resistance or by adrenal insufficiency. Evidence was later provided that the glucocorticoid-mediated immunoregulatory circuit can also be activated by cytokines produced not only as consequence of immune stimulation but also following psycho/sensorial and physical stimuli. Thus, this circuit can be integrated at brain levels and, besides stimulating the HPA axis, cytokines can also affect synaptic plasticity, most likely via a tripartite synapse, with astrocytes as neuro-immune cells acting as the third component. KEY MESSAGES It is now well established that the glucocorticoid-mediated immunoregulatory circuit plays a central role in maintaining health. However, several variables can condition the efficacy of the effect of endogenous glucocorticoids. Furthermore, since cytokines and other immune products have many other neuroendocrine and metabolic effects, other neuroendocrine-immune circuits could simultaneously operate or become predominant during different pathologies. The consideration of these aspects might help to implement strategies to eventually decrease therapeutic doses of exogenous glucocorticoids.
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Affiliation(s)
- Hugo Besedovsky
- Research Group Immunophysiology, Department Neurophysiology, Institute of Physiology and Pathophysiology, Marburg, Germany
| | - Adriana Del Rey
- Research Group Immunophysiology, Department Neurophysiology, Institute of Physiology and Pathophysiology, Marburg, Germany
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Chen Y, Deng H, Zhou R, Jiang X, Wang H, Xin S, Mo W, Wang S, Liu Y. Comprehensive mapping of immune perturbations associated with secondary hemophagocytic lymphohistiocytosis. J Leukoc Biol 2024; 116:1109-1126. [PMID: 38973235 DOI: 10.1093/jleuko/qiae138] [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: 01/08/2024] [Revised: 05/02/2024] [Accepted: 06/13/2024] [Indexed: 07/09/2024] Open
Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome characterized by immune disorders. It is imperative to elucidate the immunophenotypic panorama and the interactions among these cells in patients. Human peripheral blood mononuclear cells were collected from healthy donors and sHLH patients and tested using multicolor flow cytometry. We used FlowSOM to explore and visualize the immunophenotypic characteristics of sHLH. By demonstrating the phenotypes of immune cells, we discovered that sHLH patients had significantly higher levels of CD56+ monocytes, higher levels of myeloid-derived suppressor cells, low-density neutrophil-to-T cell ratio, and higher heterogeneous T cell activation than healthy donors. However, natural killer cell cytotoxicity and function were impaired. We then assessed the correlations among 30 immune cell types and evaluated metabolic analysis. Our findings demonstrated polymorphonuclear myeloid-derived suppressor cells, CD56+ monocytes, and neutrophil-to-T cell ratio were elevated abnormally in sHLH patients, which may indicate an association with immune overactivation and inflammatory response. We are expected to confirm that they are involved in the occurrence of the disease through further in-depth research.
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Affiliation(s)
- Yinchun Chen
- Department of Hematology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou 510180, China
- Department of Hematology, Guangzhou First People's Hospital, No. 1 Panfu Road, Guangzhou 510180, China
| | - Haimei Deng
- Department of Hematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, No. 628, Zhenyuan Road, Xinhuling Street, Shenzhen 518118, China
| | - Ruiqing Zhou
- Department of Hematology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou 510180, China
- Department of Hematology, Guangzhou First People's Hospital, No. 1 Panfu Road, Guangzhou 510180, China
| | - Xiaotao Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16 Airport Road, Guangzhou 510400, China
| | - Huijuan Wang
- Center for Medical Research on Innovation and Translation, Guangzhou First People's Hospital, No. 10 Huan Yu Second Road, Guangzhou 510180, China
| | - Songqing Xin
- Changan Hospital of Dongguan, No. 171 Changqing South Road, Dongguan 523850, China
| | - Wenjian Mo
- Department of Hematology, Guangzhou First People's Hospital, No. 1 Panfu Road, Guangzhou 510180, China
| | - Shunqing Wang
- Department of Hematology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou 510180, China
- Department of Hematology, Guangzhou First People's Hospital, No. 1 Panfu Road, Guangzhou 510180, China
| | - Yufeng Liu
- Department of Hematology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou 510180, China
- Department of Hematology, Guangzhou First People's Hospital, No. 1 Panfu Road, Guangzhou 510180, China
- Center for Medical Research on Innovation and Translation, Guangzhou First People's Hospital, No. 10 Huan Yu Second Road, Guangzhou 510180, China
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Halter S, Rosenzwajg M, Klatzmann D, Sitbon A, Monsel A. Regulatory T Cells in Acute Respiratory Distress Syndrome: Current Status and Potential for Future Immunotherapies. Anesthesiology 2024; 141:755-764. [PMID: 39037703 DOI: 10.1097/aln.0000000000005047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
This Clinical Focus Review aims to comprehensively assess current knowledge regarding the biology of Tregs and their role in COVID-19–associated and nonassociated ARDS, focusing on their involvement during the acute and resolution phases of the disease. The authors discuss the potential of Treg-based cell therapies and drugs targeting Tregs as therapeutic strategies in ARDS.
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Affiliation(s)
- Sébastien Halter
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris Sorbonne University, Paris, France; Sorbonne University-INSERM UMRS_959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; and Biotherapy (CIC-BTi), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Michelle Rosenzwajg
- Sorbonne University-INSERM UMRS_959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; Biotherapy (CIC-BTi), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - David Klatzmann
- Sorbonne University-INSERM UMRS_959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; Biotherapy (CIC-BTi), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris Sorbonne University, Paris, France; Sorbonne University, INSERM, Centre de Recherche de Saint-Antoine, UMRS-938, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris Sorbonne University, Paris, France; Sorbonne University-INSERM UMRS_959, Immunology-Immunopathology-Immunotherapy (I3), 75013 Paris, France; Biotherapy (CIC-BTi), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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Saheb Sharif-Askari F, Zakri AM, Alenazy MF, El-Wetidy MS, Khalid Salah Al-Sheakly B, Saheb Sharif-Askari N, ALKufeidy RM, Omair MA, Al-Muhsen S, Halwani R. IL-35 promotes IL-35 +IL-10 + Bregs and Conventional LAG3 + Tregs in the lung tissue of OVA-Induced Asthmatic Mice. Inflamm Res 2024; 73:1699-1709. [PMID: 39127869 DOI: 10.1007/s00011-024-01925-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 07/15/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
AIMS This study aimed to investigate the effect of interleukin-35 (IL-35) on inflamed lung tissue in a murine model of asthma. IL-35 was examined for its potential to induce regulatory lymphocytes during ovalbumin (OVA)-induced acute lung injury. METHODS Female BALB/c mice sensitized with OVA and were treated with recombinant IL-35 (rIL-35) via intranasal or intraperitoneal routes and were administered 4 h before OVA challenge. The effects of rIL-35 treatment on the lung and blood levels of regulatory B cells (Bregs) and regulatory T cells (Tregs), as well as their production of immunosuppressive cytokines, were determined using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS Treatment of OVA-sensitized asthmatic mice with rIL-35, whether administered intranasally or intraperitoneally, resulted in reduced lung inflammation and injury. This reduction was accompanied by an increase in the frequency of IL-35 producing Bregs, IL-35 and IL-10 producing Bregs, and conventional LAG3+ Tregs in the lung tissues and blood. This increase was more pronounced with intranasal rIL-35. Furthermore, there was a positive correlation between the levels of these regulatory cells and lung gene expression of IL-35 and IL-10, and an inverse correlation with both lung gene expression and plasma level of IL-17. CONCLUSIONS The results of this study suggest that IL-35, through its ability to increase Bregs and Tregs, is effective in reversing lung inflammation in the context of asthma. Since the increase was more pronounced with intranasal administration, this highlights the therapeutic potential of its local intrapulmonary application in managing asthma-related inflammation.
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Affiliation(s)
- Fatemeh Saheb Sharif-Askari
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, UAE
| | - Adel M Zakri
- Department of Plant Production, Faculty of Agriculture and Food Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Maha Fahad Alenazy
- Immunology Research Lab, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | | | - Narjes Saheb Sharif-Askari
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Roua M ALKufeidy
- Prince Naif Center for Immunology Research and Asthma Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed A Omair
- Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Saleh Al-Muhsen
- Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City , King Saud University, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Pediatrics, Faculty of Medicine, Prince Abdullah Ben Khaled Celiac Disease Chair, King Saud University, Riyadh, Saudi Arabia.
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10
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Jin S, Wan S, Xiong R, Li Y, Dong T, Guan C. The role of regulatory T cells in vitiligo and therapeutic advances: a mini-review. Inflamm Res 2024; 73:1311-1332. [PMID: 38839628 DOI: 10.1007/s00011-024-01900-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: 03/01/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8+T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8+T cells, which could be beneficial in treating vitiligo. METHODS A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo. RESULTS In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8+T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed. CONCLUSIONS A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo.
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Affiliation(s)
- Shiyu Jin
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Sheng Wan
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China
| | - Renxue Xiong
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China
| | - Yujie Li
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Tingru Dong
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Cuiping Guan
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China.
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China.
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M Yusoff NNF, Ahmad S, Wan Abdul Rahman WF, Mohamud R, C Boer J, Plebanski M, Abdullah B, Chen X, Tengku Din TADAA. CD4+ Foxp3+ Regulatory T-cells in Modulating Inflammatory Microenvironment in Chronic Rhinosinusitis with Nasal Polyps: Progress and Future Prospect. Cytokine 2024; 178:156557. [PMID: 38452440 DOI: 10.1016/j.cyto.2024.156557] [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: 11/15/2023] [Revised: 01/26/2024] [Accepted: 02/20/2024] [Indexed: 03/09/2024]
Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by the presence of nasal polyps (NP) in the paranasal mucosa. Despite the complex etiology, NP is believed to result from chronic inflammation. The long-term aftermath of the type 2 response is responsible for symptoms seen in NP patients, i.e. rhinorrhea, hyposmia, and nasal obstruction. Immune cellular tolerogenic mechanisms, particularly CD4 + Foxp3 + regulatory T cells (Tregs), are crucial to curtail inflammatory responses. Current evidence suggests impaired Treg activity is the main reason underlying the compromise of self-tolerance, contributing to the onset of CRSwNP. There is compelling evidence that tumor necrosis factor 2 (TNFR2) is preferentially expressed by Tregs, and TNFR2 is able to identify the most potent suppressive subset of Tregs. Tumor necrosis factor (TNF)-TNFR2 interaction plays a decisive role in the activation and expansion of Tregs. This review summarizes current understanding of Tregs biology, focusing on the discussion of the recent advances in the study of TNF-TNFR2 axis in the upregulation of Treg function as a negative feedback mechanism in the control of chronic inflammation. The role of dysregulation of Tregs in the immunopathogenesis of CRSwNP will be analyzed. The future perspective on the harnessing Tregs-mediated self-tolerant mechanism in the management of CRSwNP will be introduced.
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Affiliation(s)
- Nur Najwa Farahin M Yusoff
- Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Suhana Ahmad
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | | | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Jennifer C Boer
- Translational Immunology and Nanotechnology Unit, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
| | - Magdalena Plebanski
- Translational Immunology and Nanotechnology Unit, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
| | - Baharudin Abdullah
- Department of Otorhinolaryngology-Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
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12
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Petakh P, Oksenych V, Kamyshna I, Boisak I, Lyubomirskaya K, Kamyshnyi O. Exploring the complex interplay: gut microbiome, stress, and leptospirosis. Front Microbiol 2024; 15:1345684. [PMID: 38476949 PMCID: PMC10927737 DOI: 10.3389/fmicb.2024.1345684] [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: 11/28/2023] [Accepted: 01/30/2024] [Indexed: 03/14/2024] Open
Abstract
Leptospirosis, a re-emerging zoonotic disease, remains a significant global health concern, especially amid floods and disasters such as the Kakhovka Dam destruction. As is known, the stress that occurs in the conditions of military conflicts among civilian and military personnel significantly affects susceptibility to infectious diseases and possibly even influences their course. This review aims to explore how the gut microbiome and stress mediators (such as catecholamines and corticosteroids) might impact the leptospirosis disease course. The review opens new horizons for research by elucidating the connections between the gut microbiome, stress, and leptospirosis.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Iryna Boisak
- Department of Childhood Diseases, Uzhhorod National University, Uzhhorod, Ukraine
| | - Katerina Lyubomirskaya
- Department of Obstetrics and Gynecology, Zaporizhzhia State Medical and Pharmaceuticals University, Zaporizhzhia, Ukraine
| | - Oleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
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13
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Zhang J, Liu H, Chen Y, Liu H, Zhang S, Yin G, Xie Q. Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis. Front Immunol 2024; 15:1312919. [PMID: 38322264 PMCID: PMC10844451 DOI: 10.3389/fimmu.2024.1312919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune condition marked by inflammation of the joints, degradation of the articular cartilage, and bone resorption. Recent studies found the absolute and relative decreases in circulating regulatory T cells (Tregs) in RA patients. Tregs are a unique type of cells exhibiting immunosuppressive functions, known for expressing the Foxp3 gene. They are instrumental in maintaining immunological tolerance and preventing autoimmunity. Increasing the absolute number and/or enhancing the function of Tregs are effective strategies for treating RA. This article reviews the studies on the mechanisms and targeted therapies related to Tregs in RA, with a view to provide better ideas for the treatment of RA.
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Affiliation(s)
- Jiaqian Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjiang Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuehong Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Shengxiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Geng Yin
- Department of General Practice, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qibing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
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14
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Martinez GJ, Appleton M, Kipp ZA, Loria AS, Min B, Hinds TD. Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries. Physiol Rev 2024; 104:473-532. [PMID: 37732829 PMCID: PMC11281820 DOI: 10.1152/physrev.00021.2023] [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: 05/22/2023] [Revised: 08/07/2023] [Accepted: 09/10/2023] [Indexed: 09/22/2023] Open
Abstract
The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.
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Affiliation(s)
- Genesee J Martinez
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Malik Appleton
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Zachary A Kipp
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Analia S Loria
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Booki Min
- Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
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15
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Klein M, Plante S, Boulay MÈ, Boulet LP, Chakir J. Discrepancy in the suppressive function of regulatory T cells in allergic asthmatic vs. allergic rhinitis subjects upon low-dose allergen challenges. FRONTIERS IN ALLERGY 2023; 4:1296601. [PMID: 38106504 PMCID: PMC10722309 DOI: 10.3389/falgy.2023.1296601] [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: 09/18/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Background Regulatory T cells (Tregs) contribute to the maintenance of immunological tolerance. There is evidence of impaired function of these cells in people with asthma and allergy. In this study, we evaluated and compared the function of Tregs in allergic asthmatic and allergic non-asthmatic patients, both before and after low-dose allergen challenges. Methods Three groups of subjects were recruited for a baseline evaluation: healthy controls without allergy or asthma, allergic asthmatic subjects, and allergic non-asthmatic subjects. All of them were subjected to expiratory flow measurements, sputum induction, and blood sampling. In addition, both groups of allergic subjects underwent low-dose allergen challenges. Tregs were isolated from whole blood using CD4+CD25high and CD127low staining. The suppression function was measured by flow cytometry. The levels of IL-10, IFN-γ, IgG4, IgA, and TGF-β were measured using ELISA, and sputum Foxp3 was evaluated using qRT-PCR. Results The suppressive function of Tregs in healthy controls was significantly higher than in allergic asthmatic or allergic non-asthmatic subjects. Repeated exposure to low doses of allergen increased the suppressor function of Tregs in allergic non-asthmatic subjects but decreased it in allergic asthmatic subjects. Foxp3 gene expression was increased in induced sputum in allergic non-asthmatic subjects, whereas it did not change in asthmatic subjects. Serum IL-10 level was decreased in allergic asthmatic subjects after allergen challenge but not in allergic non-asthmatic subjects. IFN-γ level increased upon allergen challenge in allergic non-asthmatic subjects. IgG4 level was higher in allergic non-asthmatic subjects than in allergic asthmatic subjects. Conclusions Low-dose allergen challenges stimulate the suppressor function of Tregs in non-asthmatic allergic subjects but not in allergic asthmatic subjects.
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Affiliation(s)
| | | | | | | | - Jamila Chakir
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, QC, Canada
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Bagherinia E, Falahi S, Mortazavi SH, Salari F, Rezaiemanesh A, Karaji AG. Co-treatment with Fexofenadine and Budesonide Increases FoxP3 Gene Expression in Patients with Allergic Rhinitis. Am J Rhinol Allergy 2023; 37:623-629. [PMID: 36882993 DOI: 10.1177/19458924231160596] [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] [Indexed: 03/09/2023]
Abstract
BACKGROUND T helper type 2 (Th2), Th17, and regulatory T cells (Tregs) play essential roles in the pathogenesis and control of allergic rhinitis (AR). Fexofenadine and budesonide are first-line treatments for AR. This study aimed to investigate the effect of co-treatment with fexofenadine and budesonide on the expression of Th2, Th17, and Treg-specific transcription factors (GATA-binding protein 3 [GATA-3], RAR-related orphan receptor gamma [RORγt], and forkhead box P3 [FoxP3], respectively) in AR patients. METHODS In this study, 29 AR patients were co-treated with fexofenadine and budesonide for 1 month. Blood was collected from AR patients before and after 1 month of treatment. The gene expression levels of GATA-3, RORγt, and FoxP3 transcription factors in blood samples were measured. In addition, serum immunoglobulin E (IgE) levels and eosinophil percentages in blood samples were determined. FINDINGS The expression level of FoxP3 increased significantly after treatment compared with that before treatment (P < .001). In contrast, GATA-3 and RORγt expression levels did not show any noticeable changes. In addition, the percentage of peripheral blood eosinophils significantly decreased (P < .01). Serum IgE levels decreased compared with those before treatment, but the difference was not statistically significant. Furthermore, the clinical symptoms of the patients improved compared with those before treatment. CONCLUSION Our results showed that combined treatment with fexofenadine and budesonide increased the expression level of the FoxP3 gene, decreased the percentage of peripheral blood eosinophils, and improved the clinical symptoms of AR patients. This regimen appears to improve disease symptoms, at least in part by increasing the Treg population and decreasing the eosinophil population.
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Affiliation(s)
- Elham Bagherinia
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sara Falahi
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Hamidreza Mortazavi
- Department of Pediatrics, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farhad Salari
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Gorgin Karaji
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Slavick A, Furer V, Polachek A, Tzemach R, Elkayam O, Gertel S. Circulating and Synovial Monocytes in Arthritis and Ex-Vivo Model to Evaluate Therapeutic Modulation of Synovial Monocytes. Immunol Invest 2023; 52:832-855. [PMID: 37615125 DOI: 10.1080/08820139.2023.2247438] [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] [Indexed: 08/25/2023]
Abstract
Monocytes are innate immune cells that play a dual role in protection of host against pathogens and initiation and perpetuation of inflammatory disorders including joint diseases. During inflammation, monocytes migrate from peripheral blood to tissues via chemokine receptors where they produce inflammatory factors. Monocytes are classified into three subsets, namely: classical, intermediate and non-classical, each subset has particular function. Synovium of patients with inflammatory joint diseases, such as rheumatoid arthritis and psoriatic arthritis as well as osteoarthritis, is enriched by monocytes that differ from circulatory ones by distinct subsets distribution. Several therapeutic agents used systemically or locally through intra-articular injections in arthritis management modulate monocyte subsets. This scoping review summarized the existing literature delineating the effect of common therapeutic agents used in arthritis management on circulating and synovial monocytes/macrophages. As certain agents have an inhibitory effect on monocytes, we propose to test their potential to inhibit synovial monocytes via an ex-vivo platform based on cultured synovial fluid mononuclear cells derived from patients with rheumatic diseases. Information obtained from the ex-vivo platform can be applied to explore the therapeutic potential of medications in clinical practice.
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Affiliation(s)
- Adam Slavick
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Victoria Furer
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ari Polachek
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Reut Tzemach
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ori Elkayam
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Smadar Gertel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Bayegi SN, Hamidieh AA, Behfar M, Bozorgmehr M, Saghazadeh A, Tajik N, Delbandi AA, Zavareh FT, Delavari S, Shekarabi M, Rezaei N. Disturbance in the reconstitution of distinct T-cell subsets and the incidence of GvHD following allo-HSCT in pediatric patients with non-malignant hematological disorders. Immunol Lett 2023; 261:25-36. [PMID: 37474024 DOI: 10.1016/j.imlet.2023.07.008] [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: 01/31/2023] [Revised: 07/09/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND The reconstitution of different T-cell subsets following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for efficient pathogen protection and the prevention of graft-versus-host disease (GvHD). In particular, studies have highlighted the importance of balanced ratios of regulatory T-cells (Tregs) and distinct functionally T-cells in preventing acute and chronic GvHD. METHODS We evaluated the regeneration of CD4 and CD8 T-cell subpopulations in nine pediatric patients with non-malignant disorders following allo-HSCT from a fully HLA-identical donor. RESULTS CD4 and CD8 T-cells were higher 12 months after the transplant but still lower than in healthy controls and pre-transplant. However, we found after allo-HSCT, central memory and effector memory cell subsets were the predominant phenotypes in the CD4 and CD8 T-cell populations, respectively. In patients who had developed acute GvHD, there was an increase in the frequency of TEMRA (effector memory T cells that re-express CD45RA) cells within the CD4 T-cell population. Meanwhile, in patients with chronic GvHD, we observed a decrease in Th1 cells in CD4 T-cells and effector memory cells within the CD8 T-cell population. In addition, we found decreased TEMRA cell subsets in CD4 and CD8 T-cell populations in chronic GvHD. CONCLUSION Our findings suggest a possible relationship between the influence of acute GvHD and its prevention on delayed CD4 T-cell reconstitution and, reciprocally, unbalanced regeneration of CD4 and CD8 T-cell subsets in the development of chronic GvHD.
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Affiliation(s)
- Shideh Namazi Bayegi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Behfar
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Bozorgmehr
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amene Saghazadeh
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nader Tajik
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Tofighi Zavareh
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Delavari
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mehdi Shekarabi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Chen H, Liu Z, Zha J, Zeng L, Tang R, Tang C, Cai J, Tan C, Liu H, Dong Z, Chen G. Glucocorticoid regulation of the mTORC1 pathway modulates CD4 + T cell responses during infection. Clin Transl Immunology 2023; 12:e1464. [PMID: 37649974 PMCID: PMC10463561 DOI: 10.1002/cti2.1464] [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: 05/23/2023] [Revised: 07/29/2023] [Accepted: 08/17/2023] [Indexed: 09/01/2023] Open
Abstract
Objectives Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4+ T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4+ T cells during infection. Methods We consistently measured FOXP3, inflammatory cytokines and phospho-S6 ribosomal protein levels in CD4+ T cells from patients undergoing conventional GC treatment. Using Foxp3EGFP animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4+ T cells under the influence of GCs. Results GCs dynamically altered the expression pattern of FOXP3 in CD4+ T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4+ T cells. Dynamic activation of the mTORC1 signaling modified the GC-dampened immunoregulatory capacity of CD4+ T cells by phenotypically and functionally bolstering the FOXP3+ Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC-dampened immunoregulatory capacity of CD4+ T cells. Conclusion These findings highlight a novel mTORC1-mediated mechanism underlying CD4+ T cell immunity in the context of conventional GC treatment.
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Affiliation(s)
- Huihui Chen
- Department of Ophthalmologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Clinical Immunology Research Center of Central South UniversityChangshaChina
| | - Zhiwen Liu
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jie Zha
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Li Zeng
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Runyan Tang
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Chengyuan Tang
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Juan Cai
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Chongqing Tan
- Department of Pharmacythe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Hong Liu
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zheng Dong
- Department of Cellular Biology and AnatomyMedical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical CenterAugustaGAUSA
| | - Guochun Chen
- Clinical Immunology Research Center of Central South UniversityChangshaChina
- Department of Nephrologythe Second Xiangya Hospital of Central South UniversityChangshaChina
- Hunan Key Laboratory of Kidney Disease and Blood Purificationthe Second Xiangya Hospital of Central South UniversityChangshaChina
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Chen Z, Huang Y, Wang B, Peng H, Wang X, Wu H, Chen W, Wang M. T cells: an emerging cast of roles in bipolar disorder. Transl Psychiatry 2023; 13:153. [PMID: 37156764 PMCID: PMC10167236 DOI: 10.1038/s41398-023-02445-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/10/2023] Open
Abstract
Bipolar disorder (BD) is a distinctly heterogeneous and multifactorial disorder with a high individual and social burden. Immune pathway dysregulation is an important pathophysiological feature of BD. Recent studies have suggested a potential role for T lymphocytes in the pathogenesis of BD. Therefore, greater insight into T lymphocytes' functioning in patients with BD is essential. In this narrative review, we describe the presence of an imbalance in the ratio and altered function of T lymphocyte subsets in BD patients, mainly in T helper (Th) 1, Th2, Th17 cells and regulatory T cells, and alterations in hormones, intracellular signaling, and microbiomes may be potential causes. Abnormal T cell presence explains the elevated rates of comorbid inflammatory illnesses in the BD population. We also update the findings on T cell-targeting drugs as potentially immunomodulatory therapeutic agents for BD disease in addition to classical mood stabilizers (lithium, valproic acid). In conclusion, an imbalance in T lymphocyte subpopulation ratios and altered function may be involved in the development of BD, and maintaining T cell immune homeostasis may provide an overall therapeutic benefit.
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Affiliation(s)
- Zhenni Chen
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yiran Huang
- School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Bingqi Wang
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Huanqie Peng
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Xiaofan Wang
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Hongzheng Wu
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Wanxin Chen
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Min Wang
- Department of Laboratory Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
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21
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Bayegi SN, Hamidieh AA, Behfar M, Saghazadeh A, Bozorgmehr M, Karamlou Y, Shekarabi M, Tajik N, Delbandi AA, Zavareh FT, Delavari S, Rezaei N. T helper 17 and regulatory T-cell profile and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in pediatric patients with beta-thalassemia. Transpl Immunol 2023; 77:101803. [PMID: 36842567 DOI: 10.1016/j.trim.2023.101803] [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: 11/30/2022] [Revised: 01/29/2023] [Accepted: 02/21/2023] [Indexed: 02/28/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hereditary hemoglobin disorders, such as beta-thalassemia; However, this procedure is not without constraints, mainly engendering complications such as acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and susceptibility to infections. The clinical outcomes of allo-HSCT are highly dependant on the quality and quantity of T-cell subsets reconstitution. Following the allo-HSCT of six pediatric patients afflicted with beta-thalassemia, their mononuclear cells were isolated, and then cultured with a combination of phorbol myristate acetate (PMA)/ionomycin and Brefeldin A. The content of CD4 T-cell subsets, including T helper 17 (Th17) cells and regulatory T cells (Tregs), were determined by specific conjugated-monoclonal antibodies three and six months post-HSCT. An increased frequency of total CD4 T-cells, Tregs and Th17 cells was observed at day 90 and 180 after allo-HSCT, albeit the numbers were still lower than that of our healthy controls. In patients who developed cGvHD, a lower Th17/Treg ratio was observed, owing it to a decreased proportion of Th17 cells. In conclusion, creating balance between Th17 and Treg subsets may prevent acute and chronic GvHD in patients after allo-HSCT.
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Affiliation(s)
- Shideh Namazi Bayegi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Behfar
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amene Saghazadeh
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahmood Bozorgmehr
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yalda Karamlou
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Shekarabi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nader Tajik
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Tofighi Zavareh
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Delavari
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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22
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Panagoulias I, Charokopos N, Thomas I, Spantidea PI, de Lastic AL, Rodi M, Anastasopoulou S, Aggeletopoulou I, Lazaris C, Karkoulias K, Leonidou L, Georgopoulos NA, Markou KB, Mouzaki A. Shifting gears: Study of immune system parameters of male habitual marathon runners. Front Immunol 2023; 13:1009065. [PMID: 36713459 PMCID: PMC9880332 DOI: 10.3389/fimmu.2022.1009065] [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: 08/01/2022] [Accepted: 12/27/2022] [Indexed: 01/15/2023] Open
Abstract
Aim Marathon is a running event in which athletes must cover a distance of 42.195 km. In addition to participating in marathons, marathoners have incorporated extensive running into their lifestyle. In the present study, we investigated the effect of long-term strenuous exercise in the form of marathon running on the immune system. Methods & Results We collected peripheral blood samples from 37 male marathoners before/after a race and 37 age/sex/body mass index (BMI)-matched healthy sedentary controls. Hematological and biochemical tests revealed race-induced leukocytosis attributable to neutrophilia and significant increases in plasma lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and cortisol concentrations. Phenotypic analysis of lymphocytes revealed race-induced significant decrease in the number of lymphocytes, memory helper T (Th) cells, naive, memory and activated cytotoxic T (Tc) cells, natural killer (NK), NKT, and B1 cells, and a significant increase in the number of activated Th and regulatory Th cells (Tregs). Compared with controls, marathoners maintained significantly lower levels of memory and activated Th cells and higher levels of activated Tc and B1 cells. Measurement of plasma cytokine levels revealed a pro-inflammatory cytokine polarization that increased after the race. Examination of gene expression of cytokines and Th-cell signature transcription factors in peripheral blood mononuclear cells revealed a significant decrease in tumor necrosis factor α (TNF-α) and interleukin (IL)-17, and a significant increase in IL-6, IL-10 and forkhead box P3 (FoxP3) after the race. Compared with controls, marathoners maintained significantly higher levels of TNF-α. Assessment of the suppressive capacity of Tregs in co-cultures of isolated effector Th cells and Tregs showed significantly increased suppressive capacity of marathoners' Tregs after the race. Conclusions Compared with controls, marathoners live with permanent changes in certain immune parameters. Marathoners exhibit a stable pro-inflammatory cytokine polarization that increases after the race and is counterbalanced by increased numbers of Tregs overexpressing FoxP3 and having increased suppressive capacity.
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Affiliation(s)
- Ioannis Panagoulias
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Nikolaos Charokopos
- Department of Respiratory Medicine, General Hospital of Pyrgos “Andreas Papandreou”, Pyrgos, Greece
| | - Iason Thomas
- Allergy Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Panagiota I. Spantidea
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Anne-Lise de Lastic
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Maria Rodi
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Spyridoula Anastasopoulou
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Ioanna Aggeletopoulou
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Charalampos Lazaris
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Kiriakos Karkoulias
- Division of Respiratory Medicine, Department of Internal Medicine, Patras University Hospital, Patras, Greece
| | - Lydia Leonidou
- Division of Infectious Diseases, Department of Internal Medicine, Patras University Hospital, Patras, Greece
| | - Neoklis A. Georgopoulos
- Division of Endocrinology, Department of Internal Medicine, Patras University Hospital, Patras, Greece
| | - Kostas B. Markou
- Division of Endocrinology, Department of Internal Medicine, Patras University Hospital, Patras, Greece
| | - Athanasia Mouzaki
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece,*Correspondence: Athanasia Mouzaki,
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23
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Perna-Barrull D, Gomez-Muñoz L, Rodriguez-Fernandez S, Gieras A, Ampudia-Carrasco RM, Almenara-Fuentes L, Risueño RM, Querol S, Tolosa E, Vives-Pi M. Impact of Betamethasone Pretreatment on Engrafment of Cord Blood-Derived Hematopoietic Stem Cells. Arch Immunol Ther Exp (Warsz) 2023; 71:1. [PMID: 36528821 PMCID: PMC9760591 DOI: 10.1007/s00005-022-00666-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/28/2022] [Indexed: 12/23/2022]
Abstract
Hematopoietic stem cell (HSC) transplantation is crucial to cure hematologic malignancies. Umbilical cord blood (UCB) is a source of stem cells, but 90% of UCB units are discarded due to low cellularity. Improving the engraftment capacities of CD34+ stem cells would allow the use of UCB that were so far rejected. Betamethasone induces long-term transcriptomic and epigenomic changes in immune cells through glucocorticoid receptor. We hypothesize that discarded UCB could be used owing to improvements induced by betamethasone. Isolated CD34+ HSC from UCB were exposed to the synthetic glucocorticoids betamethasone and fluticasone for 20 h, and cell phenotype was determined before transplantation. NSG mice were sub-lethally irradiated (1 Gy or 2 Gy) 6 h before intravenously transferring 2-5 × 105 CD34+ HSC. The peripheral blood engraftment levels and the leukocyte subsets were followed up for 20 weeks using flow cytometry. At end point, the engraftment and leukocyte subsets were determined in the spleen and bone marrow. We demonstrated that betamethasone has surprising effects in recovering immune system homeostasis. Betamethasone and fluticasone increase CXCR4 and decrease HLA class II and CD54 expression in CD34+ HSCs. Both glucocorticoids-exposed cells showed a similar engraftment in 2 Gy-irradiated NSG mice. Interestingly, betamethasone-exposed cells showed enhanced engraftment in 1 Gy-irradiated NSG mice, with a trend to increase regulatory T cell percentage when compared to control. Betamethasone induces alterations in CD34+ HSCs and improve the engraftment, leading to a faster immune system recovery, which will contribute to engrafted cells survival.
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Affiliation(s)
- David Perna-Barrull
- grid.7080.f0000 0001 2296 0625Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | - Laia Gomez-Muñoz
- grid.7080.f0000 0001 2296 0625Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | - Silvia Rodriguez-Fernandez
- grid.7080.f0000 0001 2296 0625Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | - Anna Gieras
- grid.13648.380000 0001 2180 3484Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rosa M. Ampudia-Carrasco
- grid.7080.f0000 0001 2296 0625Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | | | - Ruth M. Risueño
- grid.429289.cJosep Carreras Leukaemia Research Institute, Campus IGTP-ICO, Badalona, Spain
| | - Sergi Querol
- grid.438280.5Cell Therapy Services and Cord Blood Bank, Catalan Blood and Tissue Bank, Barcelona, Spain
| | - Eva Tolosa
- grid.13648.380000 0001 2180 3484Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marta Vives-Pi
- grid.7080.f0000 0001 2296 0625Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
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Maślanka T. Effect of IL-27, Teriflunomide and Retinoic Acid and Their Combinations on CD4 + T Regulatory T Cells-An In Vitro Study. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238471. [PMID: 36500570 PMCID: PMC9739213 DOI: 10.3390/molecules27238471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/22/2022] [Accepted: 11/28/2022] [Indexed: 12/11/2022]
Abstract
The principal goal of the study was to verify the concept of pharmacological induction of Foxp3+CD25+CD4+ T regulatory (Treg) cells which will additionally be characterized by a highly suppressive phenotype, i.e., by extensive CD25 and CD39 expression and IL-10 and TGF-β production. Stimulated and unstimulated murine lymphocytes were exposed to IL-27, teriflunomide (TER), and all trans retinoic acid (ATRA) alone and to their combinations. The study demonstrated that: (a) IL-27 alone induced CD39 expression on Treg cells and the generation of Tr1 cells; (b) TER alone induced Foxp3-expressing CD4+ T cells and up-regulated density of CD25 on these cells; TER also induced the ability of Treg cells to TGF-β production; (c) ATRA alone induced CD39 expression on Treg cells. The experiments revealed a strong superadditive effect between IL-27 and ATRA with respect to increasing CD39 expression on Treg cells. Moreover, IL-27 and ATRA in combination, but not alone, induced the ability of Treg cells to IL-10 production. However, the combination of IL-27, TER, and ATRA did not induce the generation of Treg cell subset with all described above features. This was due to the fact that TER abolished all listed above desired effects induced by IL-27 alone, ATRA alone, and their combination. IL-27 alone, ATRA alone, and their combination affected TER-induced effects to a lesser extent. Therefore, it can be concluded that in the aspect of pharmacological induction of Treg cells with a highly suppressive phenotype, the triple combination treatment with TER, IL-27, and ATRA does not provide any benefits over TER alone or dual combination including IL-27 and ATRA.
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Affiliation(s)
- Tomasz Maślanka
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Street 13, 10-719 Olsztyn, Poland
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25
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de Candia P, Procaccini C, Russo C, Lepore MT, Matarese G. Regulatory T cells as metabolic sensors. Immunity 2022; 55:1981-1992. [PMID: 36351373 DOI: 10.1016/j.immuni.2022.10.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/15/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022]
Abstract
Compelling experimental evidence links immunity and metabolism. In this perspective, we propose forkhead-box-P3 (FoxP3)+CD4+CD25+ regulatory T (Treg) cells as key metabolic sensors controlling the immunological state in response to their intrinsic capacity to perceive nutritional changes. Treg cell high anabolic state in vivo, residency in metabolically crucial districts, and recirculation between lymphoid and non-lymphoid sites enable them to recognize the metabolic cues and adapt their intracellular metabolism and anti-inflammatory function at the paracrine and systemic levels. As privileged regulators at the interface between neuroendocrine and immune systems, the role of Treg cells in maintaining metabolic homeostasis makes these cells promising targets of therapeutic strategies aimed at restoring organismal homeostasis not only in autoimmune but also metabolic disorders.
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Affiliation(s)
- Paola de Candia
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", 80131 Naples, Italy.
| | - Claudio Procaccini
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Naples, Italy; Unità di Neuroimmunologia, IRCCS-Fondazione Santa Lucia, 00143 Rome, Italy.
| | - Claudia Russo
- Unità di Neuroimmunologia, IRCCS-Fondazione Santa Lucia, 00143 Rome, Italy
| | - Maria Teresa Lepore
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Naples, Italy
| | - Giuseppe Matarese
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", 80131 Naples, Italy; Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Naples, Italy.
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26
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Bilvayeh S, Mortazavi SH, Salari F, Gorginkaraji A. Glucocorticoids Decreased GATA-3 Expression but Increased FOXP3 Expression in Allergic Rhinitis Patients. TURKISH JOURNAL OF IMMUNOLOGY 2022. [DOI: 10.4274/tji.galenos.2022.35220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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27
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Dai H, Zheng R, Wang L, Wan J, Tong Y, Zhao W, Zhang W. ICS/LABA Combined With Subcutaneous Immunotherapy Modulates the Th17/Treg Imbalance in Asthmatic Children. Front Immunol 2022; 13:779072. [PMID: 35355985 PMCID: PMC8960042 DOI: 10.3389/fimmu.2022.779072] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
Rationale The imbalance of T helper (Th17) cell and regulatory T (Treg) cell are involved in allergic asthma pathogenesis. We hypothesized that ICS/LABA could modulate the Th17/Treg imbalance and that subcutaneous immunotherapy (SCIT) could coordinate with ICS/LABA to rebalance the dysfunction of Th17/Treg. Methods Thirty house dust mites (HDM) allergic asthmatic children and fifteen healthy control subjects were enrolled in this study. Fifteen asthmatic children were treated by ICS/LABA powder inhalation, while the other fifteen asthmatic children were treated by ICS/LABA powder inhalation combined with HDM-SCIT. Asthmatic subjects were followed up for 6 months, but 2 asthmatics treated with ICS/LABA were lost to follow-up. Flow cytometry was used to determine the proportions of Th17 and Treg in CD4+ T cells from peripheral blood mononuclear cells (PBMCs). Serum levels of IL-17A and IL-10 were assessed by ELISA. Result ICS/LABA treatment significantly reduced the percentage of Th17 cells (1.252 ± 0.134% vs. 2.567 ± 0.386%), serum IL-17A (49.42 ± 2.643 pg/ml vs. 66.75 ± 3.442 pg/ml) and Th17/Treg ratio (0.194 ± 0.025 vs. 0.439 ± 0.072) compared to baseline (P<0.01). The ICS/LABA+HDM-SCIT treatment group showed similar reduction in the percentage of Th17 cells (1.11 ± 0.114% vs. 2.654 ± 0.276%), serum IL-17A (49.23 ± 2.131 pg/ml vs. 66.41 ± 2.616 pg/ml) and the Th17/Treg ratio (0.133 ± 0.015 vs. 0.4193 ± 0.050) (P<0.01). ICS/LABA+HDM-SCIT treatment group demonstrated elevated Treg percentages (8.483 ± 0.408% vs. 6.549 ± 0.299%) and serum IL-10 levels (127.4 ± 4.423 pg/ml vs. 93.15 ± 4.046 pg/ml), resulting in a lower Th17/Treg ratio than the ICS/LABA group. Conclusion ICS/LABA treatment regulates Th17/Treg imbalance mainly by mitigating Th17-induced inflammation in asthma patients. The addition of SCIT further enhanced such effect by upregulating Treg cells.
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Affiliation(s)
- Huan Dai
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rongying Zheng
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Like Wang
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jinyi Wan
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu Tong
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Zhao
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Weixi Zhang
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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28
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Muscari I, Fierabracci A, Adorisio S, Moretti M, Cannarile L, Thi Minh Hong V, Ayroldi E, Delfino DV. Glucocorticoids and natural killer cells: A suppressive relationship. Biochem Pharmacol 2022; 198:114930. [PMID: 35149054 DOI: 10.1016/j.bcp.2022.114930] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 11/02/2022]
Abstract
Glucocorticoids exert their pharmacological actions by mimicking and amplifying the function of the endogenous glucocorticoid system's canonical physiological stress response. They affect the immune system at the levels of inflammation and adaptive and innate immunity. These effects are the basis for therapeutic use of glucocorticoids. Innate immunity is the body's first line of defense against disease conditions. It is relatively nonspecific and, among its mediators, natural killer (NK) cells link innate and acquired immunity. NK cell numbers are altered in patients with auto immune diseases, and research suggests that interactions between glucocorticoids and natural killer cells are critical for successful glucocorticoid therapy. The aim of this review is to summarize these interactions while highlighting the latest and most important developments in this field. Production and release in the blood of endogenous glucocorticoids are strictly regulated by the hypothalamus-pituitary adrenal axis. A self-regulatory mechanism prevents excessive plasma levels of these hormones. However, exogenous stimuli such as stress, inflammation, infections, cancer, and autoimmune disease can trigger the hypothalamus-pituitary-adrenal axis response and lead to excessive systemic release of glucocorticoids. Thus, stress stimuli, such as sleep deprivation, intense exercise, depression, viral infections, and cancer, can result in release of glucocorticoids and associated immunosuppressant effects. Among these effects are decreases in the numbers and activities of NK cells in inflammatory and autoimmune diseases (e.g., giant cell arteritis, polymyalgia rheumatica, and familial hypogammaglobulinemia).
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Affiliation(s)
- Isabella Muscari
- Section of Onco-hematology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandra Fierabracci
- Infectivology and Clinical Trials Research Department, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Sabrina Adorisio
- Foligno Nursing School, Department of Medicine and Surgery, University of Perugia, Foligno, PG, Italy
| | - Marina Moretti
- Section of Onco-hematology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Lorenza Cannarile
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Emira Ayroldi
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Domenico V Delfino
- Foligno Nursing School, Department of Medicine and Surgery, University of Perugia, Foligno, PG, Italy; Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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29
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Beurel E, Medina-Rodriguez EM, Jope RS. Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells. Pharmacol Rev 2022; 74:373-386. [PMID: 35302045 PMCID: PMC8973514 DOI: 10.1124/pharmrev.120.000256] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.
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Affiliation(s)
- Eléonore Beurel
- Department of Psychiatry and Behavioral Sciences (E.B., E.M.M.-R., R.S.J.) and Department of Biochemistry and Molecular Biology Miller School of Medicine (E.B., R.S.J.), University of Miami, Miami, Florida and Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida (E.M.M.-R., R.S.J.)
| | - Eva M Medina-Rodriguez
- Department of Psychiatry and Behavioral Sciences (E.B., E.M.M.-R., R.S.J.) and Department of Biochemistry and Molecular Biology Miller School of Medicine (E.B., R.S.J.), University of Miami, Miami, Florida and Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida (E.M.M.-R., R.S.J.)
| | - Richard S Jope
- Department of Psychiatry and Behavioral Sciences (E.B., E.M.M.-R., R.S.J.) and Department of Biochemistry and Molecular Biology Miller School of Medicine (E.B., R.S.J.), University of Miami, Miami, Florida and Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida (E.M.M.-R., R.S.J.)
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30
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Lei C, Jiang J, Zhang Y, Xiong G. Role and Function of Regulatory T Cell in Chronic Rhinosinusitis with Nasal Polyposis. J Immunol Res 2022; 2022:1144563. [PMID: 35378904 PMCID: PMC8976649 DOI: 10.1155/2022/1144563] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/28/2022] [Accepted: 03/14/2022] [Indexed: 11/21/2022] Open
Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis characterized by high edema in the stroma, albumin deposition, and formation of pseudocysts. The pathogenesis of CRSwNP is not yet fully understood. Regulatory T (Treg) cells are a subset of CD4+ T cells that play a suppressive immunoregulatory role in the process of CRSwNP. Recent studies have found that there was a significant reduction in Treg cells in polyp tissues, which leads to the onset of CRSwNP. An imbalance between Th17 and Treg cells can also aggravate inflammation toward the Th2 type. This review focuses on our understanding of the function and role of Treg cells and their regulatory factors and clinical significance in CRSwNP. We also summarize the current drug treatments for CRSwNP with Tregs as the potential therapeutic target, which will provide new ideas for the treatment of CRSwNP in the future.
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Affiliation(s)
- Chenyang Lei
- Department of Otorhinolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Juan Jiang
- Department of Otorhinolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Yanyan Zhang
- Department of Otorhinolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Gaoyun Xiong
- Department of Otorhinolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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31
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Cremoni M, Massa F, Sicard A. Overcoming barriers to widespread use of CAR-Treg therapy in organ transplant recipients. HLA 2022; 99:565-572. [PMID: 35233971 DOI: 10.1111/tan.14591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 11/30/2022]
Abstract
Preventing allograft rejection has been the main challenge of transplantation medicine since the discovery of immune responses against foreign HLA molecules in the mid-20th century. Prevention of rejection currently relies on immunosuppressive drugs, which lack antigen specificity and therefore increase the risk for infections and cancers. Adoptive cell therapy with donor-reactive regulatory T cells (Tregs) has progressively emerged as a promising approach to reduce the need for pan-immunosuppressive drugs and minimize morbidity and mortality in solid-organ transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate Tregs specific for donor HLA molecules and overcome the limitations of Tregs enrichment protocols based on repetitive stimulations with alloantigens. While this novel approach opens new possibilities to make Tregs therapy more feasible, it also creates additional challenges. It is essential to determine which source of therapeutic Tregs, CAR constructs, target alloantigens, safety strategies, patients and immunosuppressive regimens are optimal for the success of CAR Treg therapy. Here, we discuss unmet needs and strategies to bring donor-specific CAR Treg therapy to the clinic and make it as accessible as possible.
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Affiliation(s)
- Marion Cremoni
- Department of Nephrology, Dialysis, Transplantation, Nice University Hospital, Nice, France.,Clinical Research Unit, University Côte d'Azur (UR2CA), Nice, France
| | - Filippo Massa
- Department of Nephrology, Dialysis, Transplantation, Nice University Hospital, Nice, France.,Laboratory of Molecular Physio Medicine (LP2M), University Côte d'Azur, Nice, France
| | - Antoine Sicard
- Department of Nephrology, Dialysis, Transplantation, Nice University Hospital, Nice, France.,Laboratory of Molecular Physio Medicine (LP2M), University Côte d'Azur, Nice, France
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32
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Kalfeist L, Galland L, Ledys F, Ghiringhelli F, Limagne E, Ladoire S. Impact of Glucocorticoid Use in Oncology in the Immunotherapy Era. Cells 2022; 11:770. [PMID: 35269392 PMCID: PMC8909189 DOI: 10.3390/cells11050770] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/18/2022] [Accepted: 02/18/2022] [Indexed: 12/11/2022] Open
Abstract
Thanks to their anti-inflammatory, anti-oedema, and anti-allergy properties, glucocorticoids are among the most widely prescribed drugs in patients with cancer. The indications for glucocorticoid use are very wide and varied in the context of cancer and include the symptomatic management of cancer-related symptoms (compression, pain, oedema, altered general state) but also prevention or treatment of common side effects of anti-cancer therapies (nausea, allergies, etc.) or immune-related adverse events (irAE). In this review, we first give an overview of the different clinical situations where glucocorticoids are used in oncology. Next, we describe the current state of knowledge regarding the effects of these molecules on immune response, in particular anti-tumour response, and we summarize available data evaluating how these effects may interfere with the efficacy of immunotherapy using immune checkpoint inhibitors.
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Affiliation(s)
- Laura Kalfeist
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
| | - Loïck Galland
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
- Department of Medical Oncology, Georges-François Leclerc Center, 21000 Dijon, France
| | - Fanny Ledys
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
| | - François Ghiringhelli
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
- Department of Medical Oncology, Georges-François Leclerc Center, 21000 Dijon, France
- School of Medicine, University of Burgundy Franche-Comté, 21000 Dijon, France
| | - Emeric Limagne
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
| | - Sylvain Ladoire
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
- Department of Medical Oncology, Georges-François Leclerc Center, 21000 Dijon, France
- School of Medicine, University of Burgundy Franche-Comté, 21000 Dijon, France
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33
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Liu C, Cao M, Yang N, Reid-Adam J, Tversky J, Zhan J, Li XM. Time-dependent dual beneficial modulation of interferon-γ, interleukin 5, and Treg cytokines in asthma patient peripheral blood mononuclear cells by ganoderic acid B. Phytother Res 2022; 36:1231-1240. [PMID: 35112740 DOI: 10.1002/ptr.7266] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/20/2021] [Accepted: 08/14/2021] [Indexed: 11/09/2022]
Abstract
Th2 cytokines play a dominant role in the pathogenesis of allergic asthma. Interferon gamma (IFN-γ), a Th1 cytokine, links to therapeutic mechanisms of allergic asthma. Interleukin (IL)-10, a regulatory cytokine, is involved in the induction of immune tolerance. We previously demonstrated that Anti-Asthma Simplified Herbal Medicine Intervention (ASHMI) suppressed Th2 and increased IFN-γ in patients with asthma and in animal models, but its bioactive compound is unknown. Ganoderic acid beta (GAB) was isolated from Ganoderma lucidum (one herb in ASHMI). Human peripheral blood mononuclear cells (PBMCs) from adult patients with asthma were cultured with GAB or dexamethasone (Dex) in the presence of environmental allergens. The cytokine levels of IL-10, IFN-γ, IL-5, transcription factors T-bet, Foxp-3, and GATA3 were measured. Following 3-day culture, GAB, but not Dex, significantly increased IL-10 and IFN-γ levels by allergic patients' PBMCs. Following 6-day treatment, GAB inhibited IL-5 production, but IL-10 and IFN-γ remained high. Dex suppressed production of all three cytokines. GAB suppressed GATA3 and maintained Foxp-3 and T-bet gene expression, while Dex significantly suppressed GATA3 and T-bet expression. GAB simultaneously increased IL-10, IFN-γ associated with induction of T-bet and Foxp3, while suppressing IL-5, which was associated with suppression of GATA3, demonstrating unique beneficial cytokine modulatory effect, which distinguishes from Dex's overall suppression.
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Affiliation(s)
- Changda Liu
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Mingzhuo Cao
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Nan Yang
- General Nutraceutical Technology LLC, Elmsford, New York, USA.,Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, USA
| | - Jessica Reid-Adam
- Department of Pediatrics, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Jody Tversky
- The Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA
| | - Jixun Zhan
- Department of Biological Engineering, Utah State University, Logan, Utah, USA
| | - Xiu-Min Li
- Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, USA.,Department of Otolaryngology, New York Medical College, Valhalla, New York, USA
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34
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Meyer A, Wittekind PS, Kotschenreuther K, Schiller J, von Tresckow J, Haak TH, Kofler DM. Regulatory T cell frequencies in patients with rheumatoid arthritis are increased by conventional and biological DMARDs but not by JAK inhibitors. Ann Rheum Dis 2021; 80:e196. [PMID: 31744827 DOI: 10.1136/annrheumdis-2019-216576] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 11/05/2019] [Indexed: 11/03/2022]
Affiliation(s)
- Anja Meyer
- Department I of Internal Medicine, University of Cologne, Cologne, Germany
| | - Paula S Wittekind
- Department I of Internal Medicine, University of Cologne, Cologne, Germany
| | | | - Joanna Schiller
- Department I of Internal Medicine, University of Cologne, Cologne, Germany
| | - Julia von Tresckow
- Department I of Internal Medicine, University of Cologne, Cologne, Germany
| | - Thomas H Haak
- Department I of Internal Medicine, University of Cologne, Cologne, Germany
| | - David M Kofler
- Department I of Internal Medicine, University of Cologne, Cologne, Germany
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35
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Siomkajło M, Mizera Ł, Szymczak D, Kolačkov K, Grzegrzółka J, Bolanowski M, Daroszewski J. Effect of systemic steroid therapy in Graves' orbitopathy on regulatory T cells and Th17/Treg ratio. J Endocrinol Invest 2021; 44:2475-2484. [PMID: 33866536 DOI: 10.1007/s40618-021-01565-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/29/2021] [Indexed: 12/16/2022]
Abstract
PURPOSE Glucocorticoids are a mainstay treatment for Graves' orbitopathy, yet their exact mechanisms of action remain unclear. We aimed to determine whether the therapeutic effects of systemic steroid therapy in Graves' orbitopathy are mediated by changes in regulatory T lymphocytes (Tregs) and T helper 17 lymphocytes (Th17). METHODS We assessed Treg and Th17 levels in the peripheral blood of 32 patients with active, moderate-to-severe Graves' orbitopathy who received 12 weekly pulses of methylprednisolone, and determined their association with disease severity, disease activity, and treatment outcomes. The acute orbitopathy phase was confirmed based on clinical evaluation and magnetic resonance imaging, and assessed using the clinical activity score (CAS). The severity of the disease was classified according to ETA/EUGOGO guidelines, and quantified based on the total eye score. Treatment response was determined based on specific criteria (e.g., changes in CAS score, diplopia grade, visual acuity, etc.). Treg and Th17 cells were identified using flow cytometry. RESULTS Methylprednisolone treatment improved the activity of the disease and altered the Th17/Treg balance (i.e., the percentage of Tregs decreased while the number of Th17 cells remained unchanged). There was no association between the Treg/Th17 ratio and the activity and severity of the disease or the treatment response. CONCLUSIONS Therapeutic effects of steroid therapy in Graves' orbitopathy are not mediated by Treg and Th17 alterations in the peripheral blood. The decrease in peripheral Treg percentage is likely a consequence of the non-specific effects of steroids and does not impact clinical outcome.
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Affiliation(s)
- M Siomkajło
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, 50-367, Wroclaw, Poland.
| | - Ł Mizera
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, 50-367, Wroclaw, Poland
| | - D Szymczak
- Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, L. Pasteur 4, 50-367, Wroclaw, Poland
| | - K Kolačkov
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, 50-367, Wroclaw, Poland
| | - J Grzegrzółka
- Department of Human Morphology and Embryology, Wroclaw Medical University, T. Chalubinskiego 6a, 50-368, Wroclaw, Poland
| | - M Bolanowski
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, 50-367, Wroclaw, Poland
| | - J Daroszewski
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, 50-367, Wroclaw, Poland
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36
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Shimba A, Ejima A, Ikuta K. Pleiotropic Effects of Glucocorticoids on the Immune System in Circadian Rhythm and Stress. Front Immunol 2021; 12:706951. [PMID: 34691020 PMCID: PMC8531522 DOI: 10.3389/fimmu.2021.706951] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 09/22/2021] [Indexed: 12/16/2022] Open
Abstract
Glucocorticoids (GCs) are a class of steroid hormones secreted from the adrenal cortex. Their production is controlled by circadian rhythm and stress, the latter of which includes physical restraint, hunger, and inflammation. Importantly, GCs have various effects on immunity, metabolism, and cognition, including pleiotropic effects on the immune system. In general, GCs have strong anti-inflammatory and immunosuppressive effects. Indeed, they suppress inflammatory cytokine expression and cell-mediated immunity, leading to increased risks of some infections. However, recent studies have shown that endogenous GCs induced by the diurnal cycle and dietary restriction enhance immune responses against some infections by promoting the survival, redistribution, and response of T and B cells via cytokine and chemokine receptors. Furthermore, although GCs are reported to reduce expression of Th2 cytokines, GCs enhance type 2 immunity and IL-17-associated immunity in some stress conditions. Taken together, GCs have both immunoenhancing and immunosuppressive effects on the immune system.
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Affiliation(s)
- Akihiro Shimba
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Aki Ejima
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Koichi Ikuta
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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37
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Landwehr-Kenzel S, Zobel A, Schmitt-Knosalla I, Forke A, Hoffmann H, Schmueck-Henneresse M, Klopfleisch R, Volk HD, Reinke P. Cyclosporine A but Not Corticosteroids Support Efficacy of Ex Vivo Expanded, Adoptively Transferred Human Tregs in GvHD. Front Immunol 2021; 12:716629. [PMID: 34707604 PMCID: PMC8543016 DOI: 10.3389/fimmu.2021.716629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/02/2021] [Indexed: 11/13/2022] Open
Abstract
Reshaping the immune balance by adoptive transfer of regulatory T-cells (Tregs) has emerged as a promising strategy to combat undesired immune reactions, including in Graft-versus-Host Disease (GvHD), which is the most lethal non-relapse complication of allogeneic hematopoietic stem cell transplantation. Currently however, little is known about the potentially inhibitory in vivo effects of conventional immunosuppressive drugs, which are routinely used to treat GvHD, on adoptively transferred Tregs. Here we demonstrate drug-specific effects of the conventional immunosuppressive drugs Cyclosporine A, Mycophenolate mofetil and methylprednisolone on adoptively transferred Tregs in a humanized NOD/SCID/IL2Rgamma-/- GvHD mouse model. The clinical course of GvHD and postmortem organ histology, including cellular organ infiltration, showed that co-administration of Cyclosporine A and Tregs is highly beneficial as it enhanced Treg accumulation at inflammatory sites like lung and liver. Similarly, co-administration of Mycophenolate mofetil and Tregs improved clinical signs of GvHD. In contrast, co-administration of methylprednisolone and Tregs resulted in reduced Treg recruitment to inflammatory sites and the fast deterioration of some animals. Consequently, when clinical trials investigating safety and efficacy of adjunctive Treg therapy in GvHD are designed, we suggest co-administering Cyclosporine A, whereas high doses of glucocorticosteroids should be avoided.
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Affiliation(s)
- Sybille Landwehr-Kenzel
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Zobel
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Isabela Schmitt-Knosalla
- Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Forke
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Henrike Hoffmann
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Michael Schmueck-Henneresse
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Robert Klopfleisch
- Department of Veterinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
| | - Hans-Dieter Volk
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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38
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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39
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Agache I, Palmer E, Sanver D, Kirtland M, Shamji MH. Molecular allergology approach to allergic asthma. Mol Aspects Med 2021; 85:101027. [PMID: 34579961 DOI: 10.1016/j.mam.2021.101027] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 07/26/2021] [Accepted: 09/15/2021] [Indexed: 12/25/2022]
Abstract
Allergic asthma is a frequently encountered and well described asthma phenotype. However, its precise mechanisms are less known. The tools for targeted selection of patients for an optimal response to intervention (prevention or treatment) are also lacking. Here we explore the potential of the molecular allergology approach to achieve a better understanding of allergic asthma mechanisms, a precise diagnosis and an optimal management of these patients.
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Affiliation(s)
- Ioana Agache
- Faculty of Medicine, Transylvania University, Brasov, Romania.
| | - Elizabeth Palmer
- Imperial College, Faculty of Medicine, National Heart & Lung Institute, London, UK
| | - Didem Sanver
- Imperial College, Faculty of Medicine, National Heart & Lung Institute, London, UK; Necmettin Erbakan University, Engineering & Architecture Faculty, Department of Food Engineering, Konya, Turkey
| | - Max Kirtland
- Imperial College, Faculty of Medicine, National Heart & Lung Institute, London, UK
| | - Mohamed H Shamji
- Imperial College, Faculty of Medicine, National Heart & Lung Institute, London, UK
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40
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Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis. Dig Dis Sci 2021; 66:2493-2512. [PMID: 32833154 DOI: 10.1007/s10620-020-06562-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/12/2020] [Indexed: 12/11/2022]
Abstract
Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8+ T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.
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41
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Luo MH, Qian YQ, Huang DL, Luo JC, Su Y, Wang H, Yu SJ, Liu K, Tu GW, Luo Z. Tailoring glucocorticoids in patients with severe COVID-19: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1261. [PMID: 34532398 PMCID: PMC8421952 DOI: 10.21037/atm-21-1783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 06/10/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To discuss the pathogenesis of severe coronavirus disease 2019 (COVID-19) infection and the pharmacological effects of glucocorticoids (GCs) toward this infection. To review randomized controlled trials (RCTs) using GCs to treat patients with severe COVID-19, and investigate whether GC timing, dosage, or duration affect clinical outcomes. Finally. to discuss the use of biological markers, respiratory parameters, and radiological evidence to select patients for improved GC therapeutic precision. BACKGROUND COVID-19 has become an unprecedented global challenge. As GCs have been used as key immunomodulators to treat inflammation-related diseases, they may play key roles in limiting disease progression by modulating immune responses, cytokine production, and endothelial function in patients with severe COVID-19, who often experience excessive cytokine production and endothelial and renin-angiotensin system (RAS) dysfunction. Current clinical trials have partially proven this efficacy, but GC timing, dosage, and duration vary greatly, with no unifying consensus, thereby creating confusion. METHODS Publications through March 2021 were retrieved from the Web of Science and PubMed. Results from cited references in published articles were also included. CONCLUSIONS GCs play key roles in treating severe COVID-19 infections. Pharmacologically, GCs could modulate immune cells, reduce cytokine and chemokine, and improve endothelial functions in patients with severe COVID-19. Benefits of GCs have been observed in multiple clinical trials, but the timing, dosage and duration vary across studies. Tapering as an option is not widely accepted. However, early initiation of treatment, a tailored dosage with appropriate tapering may be of particular importance, but evidence is inconclusive and more investigations are needed. Biological markers, respiratory parameters, and radiological evidence could also help select patients for specific tailored treatments.
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Affiliation(s)
- Ming-Hao Luo
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi-Qi Qian
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dan-Lei Huang
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing-Chao Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Su
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huan Wang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shen-Ji Yu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kai Liu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guo-Wei Tu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhe Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Critical Care Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
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42
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Prenek L, Litvai T, Balázs N, Kugyelka R, Boldizsár F, Najbauer J, Németh P, Berki T. Regulatory T cells are less sensitive to glucocorticoid hormone induced apoptosis than CD4 + T cells. Apoptosis 2021; 25:715-729. [PMID: 32737651 PMCID: PMC7527366 DOI: 10.1007/s10495-020-01629-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Earlier we have reported that thymic regulatory T cells (Treg) are resistant to in vivo glucocorticoid hormone (GC)-induced apoptosis, while the most GC-sensitive DP thymocytes died through the activation of mitochondrial apoptotic pathway. Here we analyzed the apoptosis-inducing effect of high dose (10-6 M) in vitro dexamethasone (DX) treatment in mouse thymic- and splenic Tregs and CD4+ T cells. Activation of both extrinsic and intrinsic apoptotic pathways started after 2 h of DX treatment in CD4 SP thymocytes and was 3 × higher than in CD4+ splenocytes, while in Treg cells, weak activation of the extrinsic apoptotic pathway started only after 3 h. We also investigated the expression of 21 apoptosis-related molecules using a protein array and found higher level of both pro-and anti-apoptotic molecules in Tregs compared to CD4+ T cells. 4 h in vitro DX treatment induced upregulation of most apoptosis-related molecules both in Tregs and CD4+ T cells, except for the decrease of Bcl-2 expression in CD4+ T cells. We found high basal cytosolic Ca2+ levels in untreated Treg cells, which further increased after DX treatment, while the specific TCR-induced Ca2+ signal was lower in Tregs than in CD4+ T cells. Our results suggest that in the background of the relative apoptosis resistance of Treg cells to GCs might be their high basal cytosolic Ca2+ level and upregulated Bcl-2 expression. In contrast, downregulation of Bcl-2 expression in CD4+ T cells can explain their higher, DX-induced apoptosis sensitivity.
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Affiliation(s)
- Lilla Prenek
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - Tímea Litvai
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - Noémi Balázs
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - Réka Kugyelka
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - Ferenc Boldizsár
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - József Najbauer
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - Péter Németh
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary
| | - Timea Berki
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs, 7624, Hungary.
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43
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Zhao J, Jiang L, Uehara M, Banouni N, Al Dulaijan BS, Azzi J, Ichimura T, Li X, Jarolim P, Fiorina P, Tullius SG, Madsen JC, Kasinath V, Abdi R. ACTH treatment promotes murine cardiac allograft acceptance. JCI Insight 2021; 6:e143385. [PMID: 34236047 PMCID: PMC8410061 DOI: 10.1172/jci.insight.143385] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 06/02/2021] [Indexed: 12/13/2022] Open
Abstract
Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4–Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.
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Affiliation(s)
- Jing Zhao
- Transplantation Research Center.,Renal Division, and
| | - Liwei Jiang
- Transplantation Research Center.,Renal Division, and
| | - Mayuko Uehara
- Transplantation Research Center.,Renal Division, and
| | - Naima Banouni
- Transplantation Research Center.,Renal Division, and
| | | | - Jamil Azzi
- Transplantation Research Center.,Renal Division, and
| | | | - Xiaofei Li
- Transplantation Research Center.,Renal Division, and
| | - Petr Jarolim
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paolo Fiorina
- Department of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,International Center for Type 1 Diabetes, Centro di Ricerca Pediatrica Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università di Milano, Milan, Italy.,Endocrinology Division, ASST Fatebenefratelli Sacco, Milan, Italy
| | - Stefan G Tullius
- Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joren C Madsen
- Center for Transplantation Sciences, Department of Surgery, and.,Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Reza Abdi
- Transplantation Research Center.,Renal Division, and
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44
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Hansen W, Luppus S, Barthel R, Chang D, Broemstrup J, Zwarg T, Shibata J, Westendorf AM, Buer J, Scherbaum N. Heroin-assisted treatment of heroin-addicted patients normalizes regulatory T cells but does not restore CD4 + T cell proliferation. Addict Biol 2021; 26:e12998. [PMID: 33336491 DOI: 10.1111/adb.12998] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/12/2020] [Accepted: 11/19/2020] [Indexed: 01/07/2023]
Abstract
Heroin dependence may result in suppression of adaptive immune responses. Previously, we demonstrated an increase in relative numbers of inhibitory CD4+ regulatory T cells (Tregs) and impaired proliferative activity of CD4+ T cells from heroin-addicted patients in contrast to patients in opioid maintenance therapy and healthy controls. However, it remains elusive whether heroin has a direct impact on the CD4+ T cell compartment or whether observed effects result from stressful living conditions. Here, we analyzed the frequencies of Tregs and the proliferation as well as the cytokine production of stimulated CD4+ T cells from heroin-addicted patients with use of illicit heroin, patients in heroin-assisted treatment (HAT), and patients in methadone maintenance therapy (MMT). Relative numbers of CD4+ Tregs were significantly enhanced in patients with illicit heroin abuse compared with patients in HAT or MMT. Notably, CD4+ T cells from patients in HAT and from persons using illicit heroin showed significant reduced proliferation and secretion of the pro-inflammatory cytokines IFN-γ and IL-6 upon stimulation in vitro. From these results, we conclude that structured programs such as HAT and MMT dampen elevated frequencies of Tregs in heroin-addicted patients, whereas chronic heroin administration irrespective of using illicit heroin or receiving HAT has a direct impact on the proliferative activity and cytokine production of CD4+ T cells.
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Affiliation(s)
- Wiebke Hansen
- Institute of Medical Microbiology University Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Sina Luppus
- Institute of Medical Microbiology University Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Romy Barthel
- Institute of Medical Microbiology University Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Dae‐In Chang
- Addiction Research Group at the Department of Psychiatry and Psychotherapy LVR‐Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Julia Broemstrup
- Addiction Research Group at the Department of Psychiatry and Psychotherapy LVR‐Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Thomas Zwarg
- Addiction Research Group at the Department of Psychiatry and Psychotherapy LVR‐Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Jo Shibata
- Substitution Outpatient Clinic Health Department of the City of Cologne Cologne Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology University Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Jan Buer
- Institute of Medical Microbiology University Hospital Essen, University of Duisburg‐Essen Essen Germany
| | - Norbert Scherbaum
- Addiction Research Group at the Department of Psychiatry and Psychotherapy LVR‐Hospital Essen, University of Duisburg‐Essen Essen Germany
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45
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Nayak SP, Roy S. Immune phase transition under steroid treatment. Phys Rev E 2021; 103:062401. [PMID: 34271610 DOI: 10.1103/physreve.103.062401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/11/2021] [Indexed: 11/07/2022]
Abstract
The steroid hormone glucocorticoid (GC) is a well-known immunosuppressant that controls T-cell-mediated adaptive immune response. In this work, we have developed a minimal kinetic network model of T-cell regulation connecting relevant experimental and clinical studies to quantitatively understand the long-term effects of GC on pro-inflammatory T-cell (T_{pro}) and anti-inflammatory T-cell (T_{anti}) dynamics. Due to the antagonistic relation between these two types of T cells, their long-term steady-state population ratio helps us to characterize three classified immune regulations: (i) weak ([T_{pro}]>[T_{anti}]), (ii) strong ([T_{pro}]<[T_{anti}]), and (iii) moderate ([T_{pro}]∼[T_{anti}]), holding the characteristic bistability. In addition to the differences in their long-term steady-state outcome, each immune regulation shows distinct dynamical phases. In the presteady state, a characteristic intermediate stationary phase is observed to develop only in the moderate regulation regime. In the medicinal field, the resting time in this stationary phase is distinguished as a clinical latent period. GC dose-dependent steady-state analysis shows an optimal level of GC to drive a phase transition from the weak or autoimmune prone to the moderate regulation regime. Subsequently, the presteady state clinical latent period tends to diverge near that optimal GC level where [T_{pro}]:[T_{anti}] is highly balanced. The GC-optimized elongated stationary phase explains the rationale behind the requirement of long-term immune diagnostics, especially when long-term GC-based chemotherapeutics and other immunosuppressive drugs are administrated. Moreover, our study reveals GC sensitivity of clinical latent period, which might serve as an early warning signal in diagnosing different immune phases and determining immune phasewise steroid treatment.
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Affiliation(s)
| | - Susmita Roy
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Campus Road, Mohanpur, West Bengal 741246, India
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46
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Yamamoto Y, Negoro T, Tada R, Narushima M, Hoshi A, Negishi Y, Nakano Y. Surface Phenotype Changes and Increased Response to Oxidative Stress in CD4 +CD25 high T Cells. Biomedicines 2021; 9:616. [PMID: 34072455 PMCID: PMC8229188 DOI: 10.3390/biomedicines9060616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 11/16/2022] Open
Abstract
Conversion of CD4+CD25+FOXP3+ T regulatory cells (Tregs) from the immature (CD45RA+) to mature (CD45RO+) phenotype has been shown during development and allergic reactions. The relative frequencies of these Treg phenotypes and their responses to oxidative stress during development and allergic inflammation were analysed in samples from paediatric and adult subjects. The FOXP3lowCD45RA+ population was dominant in early childhood, while the percentage of FOXP3highCD45RO+ cells began increasing in the first year of life. These phenotypic changes were observed in subjects with and without asthma. Further, there was a significant increase in phosphorylated ERK1/2 (pERK1/2) protein in hydrogen peroxide (H2O2)-treated CD4+CD25high cells in adults with asthma compared with those without asthma. Increased pERK1/2 levels corresponded with increased Ca2+ response to T cell receptor stimulation. mRNA expression of peroxiredoxins declined in Tregs from adults with asthma. Finally, CD4+CD25high cells from paediatric subjects were more sensitive to oxidative stress than those from adults in vitro. The differential Treg sensitivity to oxidative stress observed in children and adults was likely dependent on phenotypic CD45 isoform switching. Increased sensitivity of Treg cells from adults with asthma to H2O2 resulted from a reduction of peroxiredoxin-2, -3, -4 and increased pERK1/2 via impaired Ca2+ response in these cells.
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Affiliation(s)
- Yoshiki Yamamoto
- Department of Paediatrics, Tokyo Metropolitan Ebara Hospital, Tokyo 145-0065, Japan
| | - Takaharu Negoro
- Department of Pharmacogenomics, School of Pharmacy, Showa University, Tokyo 142-8555, Japan; (T.N.); (A.H.); (Y.N.)
| | - Rui Tada
- Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan;
| | - Michiaki Narushima
- Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa 224-8503, Japan;
| | - Akane Hoshi
- Department of Pharmacogenomics, School of Pharmacy, Showa University, Tokyo 142-8555, Japan; (T.N.); (A.H.); (Y.N.)
| | - Yoichi Negishi
- Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan;
| | - Yasuko Nakano
- Department of Pharmacogenomics, School of Pharmacy, Showa University, Tokyo 142-8555, Japan; (T.N.); (A.H.); (Y.N.)
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47
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Tamura H, Kuraoka S, Hidaka Y, Nagata H, Furuie K, Nakazato H. A Case of Nephrotic Syndrome that Resolved with Influenza B Infection. Case Rep Nephrol Dial 2021; 11:103-109. [PMID: 34055920 PMCID: PMC8138236 DOI: 10.1159/000515062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/29/2021] [Indexed: 01/24/2023] Open
Abstract
It has been postulated that measles virus infection is associated with remission of idiopathic nephrotic syndrome (INS) in childhood. There are few reports on the correlation of INS remission with other infections. Previously, there have been two case reports suggesting an association between influenza B virus infection and the remission of INS. The patient was an 18-year-old Japanese woman. The onset of steroid-sensitive NS was at 9 years of age, and pathological diagnosis was minimal change nephrotic syndrome (MCNS). Until 10 months prior to visiting our hospital, the patient's NS was in remission. The patient experienced fever, cough, and malaise and she was diagnosed with type B influenza by a local physician 4 days before visiting our hospital. The patient had vomiting and diarrhea 1 day prior to visiting our hospital. Her weight was 54.7 kg (+5.0 kg) and she had pitting edema of both lower legs. Her serum albumin level was 0.9 g/dL, proteinuria level was 8.73 g/gCr, and urine sediments showed 1-4 red blood cells per high-power field. She was diagnosed with relapse of NS. The level of proteinuria decreased to 0.03 g/gCr with rest alone on day 4 of admission, and a complete remission from NS was observed at approximately 2 weeks after the onset of influenza B infection. We report a rare case wherein spontaneous remission of NS occurred within a short period of 2 weeks after influenza B infection. It is clear that some immunity is involved in the pathogenesis of INS, but there are some cases in which infection improves NS and others in which it recurs.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shohei Kuraoka
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuko Hidaka
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroko Nagata
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Keishiro Furuie
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Nakazato
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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48
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De Bruyn Carlier T, Badloe FMS, Ring J, Gutermuth J, Kortekaas Krohn I. Autoreactive T cells and their role in atopic dermatitis. J Autoimmun 2021; 120:102634. [PMID: 33892348 DOI: 10.1016/j.jaut.2021.102634] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
Atopic dermatitis (AD) is an itchy, non-contagious relapsing and chronic inflammatory skin disease that usually develops in early childhood. This pathology is associated with food allergy, allergic asthma, allergic rhinitis and anaphylaxis which may persist in adulthood. The underlying mechanisms of AD (endotypes) are just beginning to be discovered and show a complex interaction of various pathways including skin barrier function and immune deviation. Immune reactions to self-proteins (autoantigens) of the skin have been identified in patients with inflammatory skin diseases, such as chronic spontaneous urticaria, connective tissue disease, pemphigus vulgaris and bullous pemphigoid. IgE antibodies and T cells directed against epitopes of the skin were observed in adult patients with severe and chronic AD as well. This was associated with disease severity and suggests a progression from allergic inflammation to severe autoimmune processes against the skin. IgE-mediated autoimmunity and self-reactive T cells might accelerate the ongoing skin inflammation or might contribute to the relapsing course of the disease. However, to date, the exact mechanisms of IgE-mediated autoimmunity and self-reactive T cells in the pathophysiology of AD are still unclear. The aim of this review is to evaluate the development of (autoreactive) T cells and their response to (auto)antigens, as well as the role of the peripheral tolerance in autoimmunity in the pathophysiology of AD, including the unmet needs and gaps.
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Affiliation(s)
- Tina De Bruyn Carlier
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Fariza Mishaal Saiema Badloe
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Johannes Ring
- Department of Dermatology and Allergology Biederstein, Technical University Munich, München, Germany.
| | - Jan Gutermuth
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Inge Kortekaas Krohn
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
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49
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Grbac E, So T, Varshney S, Williamson N, Dimitriadis E, Menkhorst E. Prednisolone Alters Endometrial Decidual Cells and Affects Decidual-Trophoblast Interactions. Front Cell Dev Biol 2021; 9:647496. [PMID: 33898438 PMCID: PMC8063028 DOI: 10.3389/fcell.2021.647496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/18/2021] [Indexed: 12/14/2022] Open
Abstract
Poor pregnancy outcomes such as recurrent pregnancy loss (RPL) and preeclampsia are associated with impaired decidualization and abnormal trophoblast invasion. Emerging evidence suggests that use of corticosteroids, including prednisolone affects fertility by altering uterine function and may be associated with preeclampsia incidence. In this study, using primary and gestational-age appropriate tissue, we aimed to define the effect of prednisolone on human endometrial stromal fibroblast (hESF) decidualization and determine whether hESF decidualization in the presence of prednisolone would alter hESF regulation of trophoblast function. We found that prednisolone treatment reduced hESF cytokine expression (IL6, IL11, IL18, LIF, and LIFR) but had no effect on hESF expression or secretion of the classic markers of decidualization [prolactin (PRL) and IGFBP1]. Using proteomics we determined that prednisolone altered decidualized hESF protein production, enriching hESF proteins associated with acetylation and mitrochondria. Conditioned media from hESF decidualized in the presence of prednisolone significantly enhanced trophoblast outgrowth and trophoblast mRNA expression of cell motility gene PLCG1 and reduced trophoblast production of PGF. Prednisolone treatment during the menstrual cycle and 1st trimester of pregnancy might alter decidual interactions with other cells, including invasive trophoblast.
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Affiliation(s)
- Eliza Grbac
- Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia.,Gynaecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia
| | - Teresa So
- Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia.,Gynaecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia
| | - Swati Varshney
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology, Parkville, VIC, Australia
| | - Nicholas Williamson
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology, Parkville, VIC, Australia
| | - Evdokia Dimitriadis
- Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia.,Gynaecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia.,Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
| | - Ellen Menkhorst
- Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia.,Gynaecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia
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50
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Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease. Blood 2021; 136:429-440. [PMID: 32526035 DOI: 10.1182/blood.2019000953] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/24/2020] [Indexed: 12/12/2022] Open
Abstract
Acute graft-versus-host disease (GVHD) is 1 of the major life-threating complications after allogeneic cell transplantation. Although steroids remain first-line treatment, roughly one-half of patients will develop steroid-refractory GVHD (SR-GVHD), which portends an extremely poor prognosis. Many agents that have shown encouraging response rates in early phase 1/2 trials for prevention and treatment have been unsuccessful in demonstrating a survival advantage when applied in the setting of SR-GVHD. The discovery of novel treatments has been further complicated by the absence of clinically informative animal models that address what may reflect a distinct pathophysiology. Nonetheless, the combined knowledge of established bone marrow transplantation models and recent human trials in SR-GVHD patients are beginning to illuminate novel mechanisms for inhibiting T-cell signaling and promoting tissue tolerance that provide an increased understanding of the underlying biology of SR-GVHD. Here, we discuss recent findings of newly appreciated cellular and molecular mechanisms and provide novel translational opportunities for advancing the effectiveness of treatment in SR-GVHD.
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