Reversal of Type I Diabetes in NOD Mice

总结/摘要 1型糖尿病（T1 D）中β细胞破坏的主要介质是CD 4+和CD 8 + 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T1 D并挽救残余的β细胞群。目前的提案调查了CD 4的使用情况， 和CD 8共受体阻断剂以抑制糖尿病NOD小鼠中正在进行的β细胞自身免疫。为此 为了达到这一目的，非消耗性抗-CD 4和-CD 8单克隆抗体YTS 177.9和YTS 105分别将 被雇用。初步数据表明，应用YTS 177.9和YTS 105的短期结果 逆转高血糖和长期缓解近期发病糖尿病NOD小鼠。正如所料，双方 YTS177.9和YTS 105对β细胞特异性CD 4+和CD 8 + T细胞反应性具有直接作用。令人惊奇的是， YTS 105还通过涉及CD 11 c + CD 8a+树突状细胞的机制介导保护作用， CD 4+和CD 8 + T细胞致病性。在此，我们建议进一步研究新的和强大的影响， YTS177.9和YTS 105抑制糖尿病NOD小鼠中建立的β细胞自身免疫。具体目标 1将集中于在细胞水平上定义YTS177.9和YTS 105直接和间接 影响β细胞特异性T细胞反应性。具体目标2将确定驱动糖尿病的关键事件 缓解近期发病的糖尿病小鼠。

SUMMARY/ABSTRACT 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.