CXCR3 Chemokines in Type I Diabetes

描述（由申请人提供）：我们的目标是从机制上了解IP-10（10 kDa干扰素诱导蛋白，CXCL 10）及其受体CXCR 3在1型糖尿病（T1 D）和胰岛移植排斥反应发病机制中的作用。基于这一认识，我们希望分析IP-10阻断在诱导和自发性自身免疫性糖尿病（RIP-LCMV和NOD小鼠）和胰岛移植的实验模型中的治疗潜力。我们相信，这种集中的分析将揭示新的干预途径，以防止破坏胰岛素产生β细胞和恢复对胰岛的长期耐受性。令人鼓舞的初步数据表明，在全身IP-10阻断后，RIPLCMV小鼠中病毒诱导的T1 D得到了显著改善。重要的是，这种临床有益效果是在没有任何可检测到的副作用的情况下获得的。一个有趣的观察结果是IP-10阻断似乎主要影响侵袭性T淋巴细胞迁移/吸引到胰岛中，而不是免疫应答的总体降低。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淋巴细胞在胰岛中的积聚。事实上，体内施用针对其他趋化因子的抗体没有类似的深刻影响。 目的1：IP-10在T1 D发病机制中的重要性-治疗性阻断和机制 分析。 目的2：IP-10在胰岛移植排斥反应中的重要性-治疗性阻断和机制分析。

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.