CD4+ CD25+ cells in type 1 diabetic patients with other autoimmune manifestations (original) (raw)
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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.
The review of diabetic studies : RDS, 2005
Type I diabetes is increasing in incidence in developed countries [1]. Diabetes arises from a breakdown of tolerance to islet antigens, resulting in T cell-driven destruction of the islet cells and concomitant hyperglycemia. In this review, we explore whether this loss of tolerance results in part from a defect in the action of regulatory T cells. We draw on both human data and that obtained from NOD mice, the murine model of autoimmune diabetes. Although insulin-based therapies have been highly successful in treating diabetes, the complications of long-term hyperglycemia are still major causes of morbidity and mortality. Accordingly, we also discuss whether treatment with regulatory T cells is a viable method for restoring long-term tolerance to self-antigens in recently diagnosed or pre-diabetic individuals. Regulatory T cell therapy offers many potential advantages, including a specific and lasting dampening of inflammation. However, some significant hurdles would have to be over...
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...
regulatory T cells during autoimmune diabetes
Natural CD4 ϩ CD25 ϩ regulatory T (CD4 ϩ CD25 ϩ T reg) cells play a key role in the immunoregulation of autoimmunity. However, little is known about the interactions between CD4 ϩ CD25 ϩ T reg cells and autoreactive T cells. This is due, in part, to the difficulty of using cell surface markers to identify CD4 ϩ CD25 ϩ T reg cells accurately. Using a novel real-time PCR assay, mRNA copy number of FoxP3, TGF  1, and interleukin (IL)-10 was measured in single cells to characterize and quantify CD4 ϩ CD25 ϩ T reg cells in the nonobese diabetic (NOD) mouse, a murine model for type 1 diabetes (T1D). The suppressor function of CD4 ϩ CD25 ϩ CD62L hi T cells, mediated by TGF  , declined in an age-dependent manner. This loss of function coincided with a temporal decrease in the percentage of FoxP3 and TGF  1 coexpressing T cells within pancreatic lymph node and islet infiltrating CD4 ϩ CD25 ϩ CD62L hi T cells, and was detected in female NOD mice but not in NOD male mice, or NOR or C57BL/6 female mice. These results demonstrate that the majority of FoxP3-positive CD4 ϩ CD25 ϩ T reg cells in NOD mice express TGF  1 but not IL-10, and that a defect in the maintenance and/or expansion of this pool of immunoregulatory effectors is associated with the progression of T1D.
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.
Clinical and Experimental Immunology, 2008
Summary Type I diabetes (T1D) is a T cell-mediated autoimmune disease characterized by loss of tolerance to islet autoantigens, leading to the destruction of insulin-producing beta cells. Peripheral tolerance to self is maintained in health through several regulatory mechanisms, including a population of CD4+CD25hi naturally occurring regulatory T cells (Tregs), defects in which could contribute to loss of self-tolerance in patients with T1D. We have reported previously that near to T1D onset, patients demonstrate a reduced level of suppression by CD4+CD25hi Tregs of autologous CD4+CD25- responder cells. Here we demonstrate that this defective regulation is also present in subjects with long-standing T1D (> 3 years duration; P = 0·009). No difference was observed in forkhead box P3 or CD127 expression on CD4+CD25hi T cells in patients with T1D that could account for this loss of suppression. Cross-over co-culture assays demonstrate a relative resistance to CD4+CD25hi Treg-mediate...
Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1
International Journal of Molecular Sciences, 2021
The autoimmune reaction against the beta cells of the pancreatic islets in type 1 diabetes mellitus (T1DM) patients is active in prediabetes and during the development of the clinical manifestation of T1DM, but it decreases within a few years of the clinical manifestation of this disease. A key role in the pathogenesis of T1DM is played by regulatory T cell (Treg) deficiency or dysfunction. Immune interventions, such as potential therapeutic applications or the induction of the Treg-cell population in T1DM, will be important in the development of new types of treatment. The aim of this study was to evaluate innovative immune interventions as treatments for T1DM. After an evaluation of full-length papers from the PubMed database from 2010 to 2021, 20 trials were included for the final analysis. The analysis led to the following conclusions: Treg cells play an important role in the limitation of the development of T1DM, the activation or application of Tregs may be more effective in t...
Defective Suppressor Function in CD4+CD25+ T-Cells From Patients With Type 1 Diabetes
Diabetes, 2005
Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to selfantigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4 ؉ CD25 ؉ T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4 ؉ CD25 ؉ Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4 ؉ CD25 ؉ T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P ؍ 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-␥ (P ؍ 0.005) and decreased interleukin-10 production (P ؍ 0.03). These deficiencies may reflect a disturbance in the balance of the CD4 ؉ CD25 ؉ population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P ؍ 0.007) and intracellular CTLA-4 (P ؍ 0.01). These data demonstrate deficiency in function of the CD4 ؉ CD25 ؉ Treg population that may influence the pathogenesis of type 1 diabetes. Diabetes 54:92-99, 2005 RESEARCH DESIGN AND METHODS Fresh peripheral blood samples were obtained from 21 patients with recentonset type 1 diabetes (mean Ϯ SD: age 32.3 Ϯ 6.8 years) and 15 age-, sex-, and HLA-matched healthy nondiabetic control subjects with no family history of the disease (age 30.3 Ϯ 6.8 years) for use in the frequency and phenotypic analysis studies and from 11 patients with recent-onset type 1 diabetes (age From the
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.