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      Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients

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          Abstract

          Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.

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          Most cited references137

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          EASL Clinical Practice Guidelines: Autoimmune hepatitis.

          (2015)
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            Type 1 diabetes immunotherapy using polyclonal regulatory T cells.

            Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing β cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo-expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 × 10(8) to 26 × 10(8) cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype long-term. There were no infusion reactions or cell therapy-related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy.
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              Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer

              Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a critical role in the maintenance of immune homeostasis and prevention of autoimmunity. Recent advances in single cell analyses have revealed a range of Treg cell activation and differentiation states in different human pathologies. Here we review recent progress in the understanding of human Treg cell heterogeneity and function. We discuss these findings within the context of concepts in Treg cell development and function derived from preclinical models and insight from approaches targeting Treg cells in clinical settings. Distinguishing functional Treg cells from other T cells and understanding the context-dependent function(s) of different Treg subsets will be crucial to the development of strategies toward the selective therapeutic manipulation of Treg cells in autoimmunity and cancer.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                07 October 2020
                2020
                : 11
                : 575572
                Affiliations
                Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                Author notes

                Edited by: Urs Christen, Goethe University Frankfurt, Germany

                Reviewed by: Matthias Hardtke-Wolenski, Essen University Hospital, Germany; Pascal Lapierre, University of Montreal Hospital Centre (CRCHUM), Canada; Yun Ma, King's College London, United Kingdom

                *Correspondence: Wei Yan yanwei@ 123456tjh.tjmu.edu.cn

                This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.575572
                7575771
                33117375
                9639bc4d-e55d-4893-87f1-95a0b8c60f54
                Copyright © 2020 Wang, Feng, Yan and Tian.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 June 2020
                : 07 September 2020
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 137, Pages: 12, Words: 10418
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Categories
                Immunology
                Review

                Immunology
                autoimmune hepatitis,regulatory t cell,mouse model,cytochrome p450 2d6,treatment
                Immunology
                autoimmune hepatitis, regulatory t cell, mouse model, cytochrome p450 2d6, treatment

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