Mechanisms and Therapies of B7x and B7-H3 in T1D

 描述（由申请人提供）：B7家族及其受体CD 28家族产生的T1 D T细胞共刺激和共抑制中B7 x和B7-H3的机制和疗法在调节T淋巴细胞活化和耐受中具有关键作用。因此，这些途径是非常有吸引力的治疗靶点。除了B7-1/B7-2/CD 28/CTLA-4的长期存在的途径之外，我们和其他人在过去几年中发现了B7/CD 28家族的几个额外成员，包括B7 h/ICOS、PD-L1（B7-H1）/PD-L2（B7-DC）/PD-1、B7-H3/受体、B7 x（B7-H4或B7 S1）/受体和HHLA 2/TMIGD 2/受体。1型糖尿病（T1 D）是一种自身免疫性疾病，其特征在于淋巴细胞浸润到胰岛中，然后由于T细胞破坏产生胰岛素的β细胞而破坏葡萄糖稳态。T1 D的发病率稳步上升。关于B7 x和B7-H3在外周非淋巴器官（如T1 D发生的胰腺）中调节T细胞功能的作用知之甚少。基于我们最近发表的工作和我们令人兴奋的初步数据，我们假设B7 x和B7-H3是T1 D中效应T细胞的共抑制剂，是新的治疗靶点。该假设将通过追求三个具体目标来测试：1）具体目标1：剖析B7 x抑制T1 D发展的机制; 2）具体目标2：确定B7-H3在T1 D中的生理作用;和3）具体目标3：评估治疗效果通过靶向B7 x和B7-H3途径治疗T1 D。我们已经开发了许多新工具，并组建了一支具有互补技能的多学科团队，这为我们提供了应对挑战和实现目标的独特机会。

 DESCRIPTION (provided by applicant): Mechanisms and therapies of B7x and B7-H3 in T1D T cell co-stimulation and co-inhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. Therefore these pathways are very attractive therapeutic targets. In addition to the long-standing pathway of B7-1/B7-2/CD28/CTLA-4, we and others have discovered several additional members of the B7/CD28 families over the last several years, including B7h/ICOS, PD- L1(B7-H1)/PD-L2(B7-DC)/PD-1, B7-H3/receptor(s), B7x(B7-H4 or B7S1)/receptor(s), and HHLA2/TMIGD2/receptors. Type 1 diabetes (T1D) is an autoimmune disease characterized by infiltration of lymphocytes into the islets of the pancreas and then breakdown of glucose homeostasis as a result of destruction of insulin-producing β cells by T cells. The incidence of T1D has risen steadily. Little is known about the roles of B7x and B7-H3 in the regulation of T cell function in peripheral non-lymphoid organs such as the pancreas where T1D occurs. Based on our recently published work and our exciting preliminary data, we have hypothesized in this proposal that B7x and B7-H3 are coinhibitors of effector T cells in T1D and are new therapeutic targets. This hypothesis will be tested by pursuing three specific aims: 1) Specific Aim 1: Dissect the mechanisms by which B7x inhibits T1D development; 2) Specific Aim 2: Determine the physiologic roles of B7-H3 in T1D; and 3) Specific Aim 3: Assess the therapeutic efficacy in T1D by targeting the B7x and B7-H3 pathways. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and achieve our goals.