Reversal of Type I Diabetes in NOD Mice

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): The primary mediators of beta cell destruction in Type 1 diabetes (T1D) are CD4+ and CD8+ T cells. Currently, there is a need for strategies that effectively suppress established beta cell-specific T cell reactivity in diabetics in order to reverse T1D, and rescue residual beta cell mass. The current proposal investigates the use of CD4 and CD8 co-receptor blockade to suppress ongoing beta cell autoimmunity in diabetic NOD mice. For this purpose, the nondepleting anti-CD4 and -CD8 monoclonal antibodies YTS177.9 and YTS105, respectively, will be employed. Preliminary data demonstrate that application of a short course of YTS177.9 and YTS105 results in reversal of hyperglycemia and long-term remission in recent onset diabetic NOD mice. As expected, both YTS177.9 and YTS105 have direct effects on beta cell-specific CD4+ and CD8+ T cell reactivity. Surprisingly, YTS105 also mediates protection via a mechanism involving CD11c+CD8a+ dendritic cells that indirectly affects CD4+ and CD8+ T cell pathogenicity. Herein, we propose to further investigate the novel and robust effects of YTS177.9 and YTS105 in suppressing established beta cell autoimmunity in diabetic NOD mice. Specific Aim 1 will focus on defining at the cellular level mechanisms by which YTS177.9 and YTS105 directly and indirectly influence beta cell-specific T cell reactivity. Specific Aim 2 will identify the key events driving diabetes remission in recent onset diabetic mice. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to block autoimmunity associated with type 1 diabetes and reverse clinical disease. Our approach makes use of two sets of antibodies that selectively bind to T lymphocytes and alter their function. Preliminary results indicate that this is a highly effective approach to induce remission in recent onset diabetic NOD mice. Accordingly, experiments will be carried out to assess the mechanisms of protection and the therapeutic value of these antibodies.