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（干扰素诱导的10kDa蛋白CXCL10）及其受体CXCR3在1型糖尿病（T1D）和胰岛异体移植排斥的发病机制中的作用。基于这一见解，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示新的干预途径，以防止破坏产生胰岛素的β细胞，并恢复对胰岛的长期耐受性。令人鼓舞的初步数据表明，在系统阻断IP-10后，RIPLCMV小鼠病毒诱导的T1D有了深刻的改善。重要的是，这种临床有益的效果没有任何可检测到的副作用。一个有趣的观察是，IP-10阻断似乎主要影响侵袭性T淋巴细胞向胰岛的迁移/吸引，而不是整体降低免疫反应性。因此，我们假设IP-10是一个独特的免疫靶点，它的阻断会选择性地影响朗格汉斯胰岛的淋巴细胞积累。事实上，在体内施用针对其他趋化因子的抗体并没有类似的深远影响。

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.