CXCR3 Chemokines in Type I Diabetes

描述(申请人提供)：我们的目标是从机制上了解IP-10(干扰素诱导蛋白10 kDa，CXCL10)及其受体CXCR3在1型糖尿病(T1D)和同种异体胰岛移植排斥反应中的作用。基于这一认识，我们希望分析IP-10阻断在诱导和自发自身免疫性糖尿病(RIP-LCMV和NOD小鼠)和胰岛移植实验模型中的治疗潜力。我们相信，这一重点分析将揭开新的干预途径，以防止产生胰岛素的β细胞被破坏，并恢复对胰岛的长期耐受。令人鼓舞的初步数据表明，在系统性IP-10阻断后，病毒诱导的RIPLCMV小鼠T1D得到了显著改善。重要的是，这种临床有益的效果是在没有任何可检测到的副作用的情况下获得的。一个有趣的观察是，IP-10的阻断似乎主要影响侵略性T淋巴细胞向胰岛的迁移/吸引，而不是整体免疫反应性的降低。因此，我们假设IP-10是一个独特的免疫学靶点，因为它的阻断将选择性地影响朗格汉斯胰岛中淋巴细胞的聚集。事实上，体内注射针对其他趋化因子的抗体并没有产生同样深远的影响。 目的1：IP-10在T1D发病机制中的重要作用--治疗阻断和机制 分析。 目的2：IP-10在同种异体胰岛移植排斥反应中的作用--治疗阻断及机制分析。

DESCRIPTION (provided by applicant): Our goal is to mechanistically understand the role of IP-10 (interferon-induced protein of 10kDa, CXCL10) and its receptor CXCR3 in the pathogenesis of type 1 diabetes (T1D) and islet allograft rejection. Based on this insight we wish to analyze the therapeutic potential of IP-10 blockade in experimental models of induced and spontaneous autoimmune diabetes (RIP-LCMV and NOD mice) and islet transplantation. We believe that this focused analysis will unravel novel interventive avenues to prevent destruction of insulin producing beta-cells and restore long-term tolerance to islets. Encouraging preliminary data demonstrate a profound amelioration of virally induced T1D in RIPLCMV mice after systemic IP-10 blockade. Importantly, this clinically beneficial effect was obtained without any detectable side effects. An intriguing observation is that IP-10 blockade appears to predominantly affect migration/attraction of aggressive T lymphocytes into the islets rather than overall reduction of immune responsiveness. Thus, we hypothesize that IP-10 is a unique immunological target in that its blockade will selectively affect lymphocyte accumulation in the islets of Langerhans. Indeed, in vivo administration of antibodies against other chemokines did not have a similarly profound effect. Aim 1: Importance of IP-10 in the pathogenesis of T1D - therapeutic blockade and mechanistic analyses. Aim 2: Importance of IP-10 during islet allograft rejection - therapeutic blockade and mechanistic analyses.