Reversal of Type I Diabetes in NOD Mice

描述（由申请人提供）：1型糖尿病（T1D）中β细胞破坏的主要介质是CD4+和CD8+ T细胞。目前，需要有效抑制糖尿病患者中已建立的β细胞特异性T细胞反应性的策略，以逆转T1D，并拯救残留的β细胞群。目前的提议研究了使用CD4和CD8共受体阻断剂来抑制糖尿病NOD小鼠中正在进行的β细胞自身免疫。为此，将分别使用非消耗性抗CD4和抗CD8单克隆抗体YTS 177.9和YTS 105。初步数据表明，短期应用YTS 177.9和YTS 105可逆转新近发病的糖尿病NOD小鼠的高血糖症并长期缓解。正如预期的那样，YTS177.9和YTS105两者对β细胞特异性CD4+和CD8+ T细胞反应性具有直接作用。令人惊讶的是，YTS105还通过涉及CD11c+CD8a+树突细胞的机制介导保护作用，该机制间接影响CD4+和CD8+ T细胞的致病性。在此，我们建议进一步研究YTS177.9和YTS105在抑制糖尿病NOD小鼠中建立的β细胞自身免疫中的新颖和稳健的作用。具体目标1将侧重于在细胞水平上定义YTS177.9和YTS105直接和间接影响β细胞特异性T细胞反应性的机制。具体目标2将确定在新近发作的糖尿病小鼠中驱动糖尿病缓解的关键事件。公共卫生相关性：该提案的目标是阻断与1型糖尿病相关的自身免疫并逆转临床疾病。我们的方法利用了两组抗体，它们选择性地与T淋巴细胞结合并改变其功能。初步结果表明，这是一种非常有效的方法，以诱导缓解在最近发病的糖尿病NOD小鼠。因此，将进行实验以评估这些抗体的保护机制和治疗价值。

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.