Role of Tim-4 in regulating type 1 diabetes

描述（申请人提供）：1型糖尿病（T1D）是一种自身免疫性疾病，其中T细胞介导胰腺中产生胰岛素的细胞的破坏。因此，对T1D的研究主要集中在自身反应性T细胞的生物学上。然而，许多研究指出T1D患者的抗原呈递细胞（APC）存在缺陷。我们最近发现树突状细胞（dc）上表达的分子Tim-4在T1D的发展中起着关键作用。Tim-4的表达相对受限，主要表达于组织炎症中活化的dc和部分CD11b+巨噬细胞亚群。此外，我们的观察结果表明，Tim-4是CD8¿+ DCs交叉呈递所必需的。我们的初步数据表明，通过抗Tim-4抗体在体内阻断Tim-4，可以逆转早发性糖尿病患者的T1D

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate destruction of insulin-producing ¿ cells in the pancreas. Consequently, research in T1D has been heavily focused on the biology of auto-reactive T cells. However, numerous studies have pointed to defects in antigen- presenting cells (APC) in individuals with T1D. We have recently discovered that Tim-4, one of the molecules expressed on dendritic cells (DCs), plays a critical role in the development of T1D. Tim-4 has relatively restricted expression in that it is largely expressed on activated DCs and some subsets of CD11b+ macrophages in tissue inflammation. In addition, our observations suggest that Tim-4 is required for cross-presentation by CD8¿+ DCs. Our preliminary data demonstrates that blocking Tim-4 in vivo by the administration of anti-Tim-4 antibody results in reversal of T1D in early onset diabetes in the NOD mice. Tim-4 is has been shown to be a phosphotidylserine receptor and has a critical role in clearing apoptotic bodies in certain tissue niches, but we have observed that TIM-4 also costimulates and expands effector T cells and disarms Foxp3+ regulatory T cells. Based on the preliminary data we hypothesize that Tim-4 blockade regulates development of T1D at multiple levels by different mechanisms, including blockade of cross-presentation, inhibiting trafficking of antigen loaded DCs and regulating the balance between the diabetogenic effector and regulatory T cells. To address this hypothesis, we propose the following specific aims: 1. To identify the mechanism by which Tim-4 regulates development of immune and autoimmune responses. 2. To determine the effectiveness and mechanism by which Tim-4 blockade prevents and even reverses (new onset) diabetes in the NOD model. With a panel of novel reagents including antibodies, TIM-4 fusion protein and TIM-4-/- mice, we are proposing a multifaceted, interdisciplinary approach consisting of functional, genetic, and molecular approaches to identify mechanisms by which Tim-4 expressed on APCs regulates the development of a diabetogenic T cell response and reverses development of T1D. As our preliminary studies point to a striking effect of anti-TIM-4 antibody treatment on reversing the development of T1D, our anticipated findings are likely to have direct translational relevance to type 1 diabetes in humans.