HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4+ T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells’ (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management. 1. Introduction Induction of antigen-specific tolerance is a logical strategy for immunological therapy for type 1 diabetes (T1D). T1D is an organ-specific autoimmune disease resulting from the destruction of insulin-producing pancreatic islet beta cells. In nondiabetics, islet antigen-specific T cells are deleted during thymic development, rendered anergic, or converted to regulatory T cells (Tregs) that actively suppress effector responses to islet cell antigens. In persons with T1D and in the non-obese diabetic (NOD) mouse model of T1D, these tolerance-inducing mechanisms do not function properly. In humans, defects in Tregs have been proposed as one mechanism by which individuals develop T1D, and this defect is said to be both functional and quantitative [1]. In the absence of effective regulatory suppression, CD8+ and CD4+ auto-reactive T cells respond to islet antigens presented by human leukocyte antigen (HLA) molecules. The gradual destruction of islet cells by these auto-reactive cells eventually leads to
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