Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1 (original) (raw)
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Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes
Journal of Translational Medicine, 2016
Background: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment. Methods: The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 10 6 /kg b.w. of autologous expanded CD3 + CD4 + CD25 high CD127 − Tregs. Results: The disease progressed and all patients were insulin-dependent 2 years after inclusion. The β-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62L + CD45RA + to memory CD62L + CD45RA − Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes. Conclusions: The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM.
Study of Regulatory T-cells in Type 1 Diabetes
Al-Azhar International Medical Journal, 2021
Background: T1D is a common autoimmune disease, globally, diabetes affects over four hundred million individuals, with Type 1 (insulindependent) diabetes (T1D) accounting for up to 10 percent of cases. Aim of the work: to shed light on and evaluate the frequency of Treg cells in patients with type 1 diabetes. Patients and methods: This study is a cross-sectional study that was conducted in the period 9/2019 to 3/2020 at diabetes and Internal medicine clinics of Al-Azhar and Ain Shams University Hospitals. 60 adult males and females aged between 19-40 years old who were diagnosed with type 1 DM (Group I) were offered participation in the study, later we subdivided them regarding the percentage of HBA1C to two groups:-(Ia) controlled DM, (Ib) uncontrolled DM. Results: There is a considerable decrease of Tregs in patients with T1D in comparison with those in healthy subjects. There was a highly significant difference between patients with type 1 DM and healthy subjects regarding Tregs percentage, being higher in healthy subjects. There was a highly significant difference between patients with T1D and healthy subjects regarding FOXP3 percentage, being higher in healthy subjects while its level in diabetic subjects. Conclusion: There is a considerable decrease of Tregs in patients with T1D in comparison with those in healthy subjects, there is no correlation between Treg percentage and the patients' age, there is no relation between the frequency of Tregs and the control of blood sugar in type 1 diabetic patients.
Antigen-Specific Regulatory T Cells and Low Dose of IL-2 in Treatment of Type 1 Diabetes
Frontiers in Immunology, 2016
Regulatory T cells (Tregs) play an important role in preventing effector T-cell (Teff) targeting of self-antigens that can lead to tissue destruction in autoimmune settings, including type 1 diabetes (T1D). Autoimmunity is caused in part by an imbalance between Teff and Tregs. Early attempts to treat with immunosuppressive agents have led to serious side effects, thus requiring a more targeted approach. Low-dose IL-2 (LD IL-2) can provide immunoregulation with few side effects by preferentially acting on Tregs to drive tolerance. The concept of LD IL-2 as a therapeutic approach is supported by data in mouse models where autoimmunity is cured and further strengthened by success in human clinical studies in hepatitis C virus-induced vasculitis, chronic graft-versus-host disease, and Alopecia areata. Treatment will require identification of a safe therapeutic window, which is a difficult task given that patients are reported to have deficient or defective IL-2 production or signaling and have experienced mild activation of NK cells and eosinophils with LD IL-2 therapy. In T1D, an LD IL-2 clinical trial concluded that Tregs can be safely expanded in humans; however, the study was not designed to address efficacy. Antigen-specific therapies have also aimed at regulation of the autoimmune response but have been filled with disappointment despite an extensive list of diverse islet antigens tested in humans. This approach could be enhanced through the addition of LD IL-2 to the antigenic treatment regimen to improve the frequency and function of antigen-specific Tregs, without global immunosuppression. Here, we will discuss the use of LD IL-2 and islet antigen to enhance antigen-specific Tregs in T1D and focus on what is known about their immunological impact, their safety, and potential efficacy, and need for better methods to identify therapeutic effectiveness.
Expansion of Human Regulatory T-Cells From Patients With Type 1 Diabetes
Diabetes, 2008
CD4 ϩ CD127 lo/Ϫ and CD4 ϩ CD127 lo/Ϫ CD25 ϩ Tcells could be expanded and used as Tregs. However, expansion of CD4 ϩ CD127 lo/Ϫ cells required the addition of rapamycin to maintain lineage purity. In contrast, expansion of CD4 ϩ CD127 lo/Ϫ CD25 ϩ T-cells, especially the CD45RA ϩ subset, resulted in high yield, functional Tregs that maintained higher FOXP3 expression in the absence of rapamycin. Tregs from type 1 diabetic patients and control subjects expanded similarly and were equally capable of suppressing T-cell proliferation. Regulatory cytokines were produced by Tregs after culture; however, a portion of FOXP3 ϩ cells were capable of producing interferon (IFN)-␥ after reactivation. IFN-␥ production was observed from both CD45RO ϩ and CD45RA ϩ Treg populations.
Altered Suppressor Function of Regulatory T Cells in Type 1 Diabetes
Iranian journal of immunology : IJI, 2015
BACKGROUND Type 1 diabetes (T1D) is a T cell mediated autoimmune disease targeting the insulin-producing β cells within pancreatic islets. Autoimmune diseases may develop as a consequence of altered balance between regulatory (Tregs) and autoreactive T cells. OBJECTIVES To evaluate Treg cells frequency and suppressive function in the peripheral blood of newly diagnosed T1D patients in comparison with healthy controls. METHODS Fifteen new cases of T1D patients and 15 age- and sex- matched healthy controls were recruited to this study. Their peripheral blood mononuclear cells (PBMCs) were isolated and CD4+CD25+FoxP3+CD127-/low Treg cells were studied by flowcytometry technique. Thereafter, Tregs were isolated by Magnetic-Activated Cell Separation (MACS) technology and by using CFSE (carboxyfluorescein succinimidyl ester) dilution assay, their suppressive activity was evaluated in the coculture of CD4+CD25- T responder cells with Treg cells. RESULTS The percentage of CD4+CD25+FoxP3+CD1...
Type 1 diabetes immunotherapy using polyclonal regulatory T cells
Science translational medicine, 2015
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...
Expansion of Human Regulatory T-Cells From Patients Wth Type 1 Diabetes
Diabetes, 2009
OBJECTIVE-Regulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells-a need forming the basis for these studies. RESEARCH DESIGN AND METHODS-Tregs from recentonset type 1 diabetic patients and healthy control subjects were isolated by fluorescence-activated cell sorting and compared for their capacity to expand in vitro in response to anti-CD3-anti-CD28-coated microbeads and IL-2. Expanded cells were examined for suppressive function, lineage markers and FOXP3, and cytokine production. RESULTS-Both CD4 ϩ CD127 lo/Ϫ and CD4 ϩ CD127 lo/Ϫ CD25 ϩ Tcells could be expanded and used as Tregs. However, expansion of CD4 ϩ CD127 lo/Ϫ cells required the addition of rapamycin to maintain lineage purity. In contrast, expansion of CD4 ϩ CD127 lo/Ϫ CD25 ϩ T-cells, especially the CD45RA ϩ subset, resulted in high yield, functional Tregs that maintained higher FOXP3 expression in the absence of rapamycin. Tregs from type 1 diabetic patients and control subjects expanded similarly and were equally capable of suppressing T-cell proliferation. Regulatory cytokines were produced by Tregs after culture; however, a portion of FOXP3 ϩ cells were capable of producing interferon (IFN)-␥ after reactivation. IFN-␥ production was observed from both CD45RO ϩ and CD45RA ϩ Treg populations. CONCLUSIONS-The results support the feasibility of isolating Tregs for in vitro expansion. Based on expansion capacity, FOXP3 stability, and functional properties, the CD4 ϩ CD127 lo/Ϫ CD25 ϩ Tcells represent a viable cell population for cellular therapy in this autoimmune disease. Diabetes 58:652-662, 2009 RESEARCH DESIGN AND METHODS Patient population. Tregs were isolated from nine adult individuals with recent-onset type 1 diabetes (six men/three women; mean age 26.0 Ϯ 9.7 years, range 17-40, with a mean disease duration of 7 months, range 20 days to 11 months) at the time of blood draw (i.e., Ͻ12 months from diagnosis) and three nondiabetic healthy control subjects (one man/two women; mean age
Therapeutic regulatory T cells (Tregs) can reverse pre established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8+ T cell accumulation in the tissue. CD8+ T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-g production by intraislet CD8+ and CD4+ T cells at the protein level with minimal effect on IFN-g mRNA. Sustained expression of IFN-g protein by effector T cells was dependent on common g-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8+ T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis.
T Regulatory Cells in Autoimmune Diabetes: Past Challenges, Future Prospects
Journal of Clinical Immunology, 2008
Introduction Accumulating evidence suggests that defective regulation is an essential underlying cause of autoimmunity. The development of type 1 diabetes in the NOD mouse strain it is a complex process that depends on a fine balance between pathogenic and regulatory pathways. Discussion We have utilized a series of transgenic and knockout mice to determine the relative importance of regulatory T cells and negative regulatory receptors on the development and progression of type 1 diabetes. Conclusion This review will focus on the origins and function of Treg in peripheral self-tolerance. We will summarize the role of Treg in preventing autoimmune diseases, with a particular focus on Type 1 Diabetes (T1D), and discuss the prospects for Treg-based therapies for autoimmune diseases.