Role of Tim-4 in regulating type 1 diabetes

描述（由申请人提供）：1型糖尿病（T1 D）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，T1 D的研究主要集中在自身反应性T细胞的生物学上。然而，许多研究已经指出患有T1 D的个体中抗原呈递细胞（APC）的缺陷。我们最近发现，Tim-4，树突状细胞（DC）上表达的分子之一，在T1 D的发展中起着关键作用。Tim-4的表达相对有限，因为它主要表达在活化的DC和组织炎症中的CD 11b+巨噬细胞的一些亚群上。此外，我们的观察表明Tim-4是CD 8 + DC交叉呈递所必需的。我们的初步数据表明，通过施用抗Tim-4抗体在体内阻断Tim-4导致T1 D逆转早发性糖尿病， NOD小鼠。Tim-4已被证明是一种磷脂酰丝氨酸受体，并在清除某些组织小生境中的凋亡小体中起关键作用，但我们观察到TIM-4也共刺激和扩增效应T细胞并解除Foxp 3+调节性T细胞的武装。基于初步数据，我们假设Tim-4阻断通过不同的机制在多个水平调节T1 D的发展，包括阻断交叉呈递，抑制细胞的运输，以及阻断T1 D的表达。 抗原负载的DC和调节致糖尿病效应细胞与调节性T细胞之间的平衡。为了解决这一假设，我们提出了以下具体目标：1。确定Tim-4调节免疫和自身免疫反应发展的机制。 2.在NOD模型中确定Tim-4阻断预防甚至逆转（新发）糖尿病的有效性和机制。通过一组包括抗体、TIM-4融合蛋白和TIM-4-/-小鼠在内的新型试剂，我们提出了一种多方面、跨学科的方法，包括功能、遗传和分子方法，以确定APC上表达的Tim-4调节致糖尿病T细胞反应的发展和逆转T1 D发展的机制。由于我们的初步研究指出抗TIM-4抗体治疗对逆转T1 D发展的显著作用，我们预期的发现可能与人类1型糖尿病具有直接的翻译相关性。

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.