The Role of Complement Inhibition in Expanded Criteria Kidney Transplantation

 描述（由申请人提供）：补体系统是先天免疫的重要效应子，并且有新的有力证据表明补体在形成适应性免疫应答中具有作用。在移植的背景下，补体激活在肾移植受者中的整体作用已经在肾缺血-再灌注损伤和抗体介导的排斥反应的模型中被广泛研究。然而，其作为供体预处理以改善来自扩展标准供体的移植器官的质量的潜在治疗用途尚未被研究。C1抑制剂（C1 INH）是一种丝氨酸蛋白酶抑制剂，可调节补体和激肽释放酶-激肽接触系统的激活，C1 INH缺乏可导致遗传性血管性水肿。我们在此提出了一种肾移植中的临床前非人灵长类动物（NHP）转化模型，以通过抑制经典和替代途径的补体抑制来评估供体预处理对脑死亡（BD）供体的影响，并了解补体抑制是否a）预防移植物功能延迟（DGF）; B）改善先天性和适应性免疫系统的激活; d）调节T细胞应答，从指导起始阶段到驱动谱系定型和分化。最后，我们还将研究 在肾移植的扩展标准模型中阻断补体在供体和受体中的附加治疗作用。

 DESCRIPTION (provided by applicant): The complement system is an important effector of innate immunity and there is new strong evidence suggesting complement has a role in shaping the adaptive immune response. In the context of transplantation, the integral role of complement activation in kidney transplant recipients has been extensively studied in models of renal ischemia-reperfusion injury and antibody-mediated rejection. However, its potential therapeutic use as a donor pre-treatment to improve the quality of organs for transplantation from expanded criteria donors has not been studied. C1 inhibitor (C1INH) is a serpin protease inhibitor that regulates both complement and contact (kallikrein-kinin) system activation and its deficiency of C1INH results hereditary angioedema. We propose here a translational pre-clinical non-human primate (NHP) model in kidney transplantation to evaluate the effect of donor pre-treatment in brain death (BD) donors by inhibiting complement inhibition via the classical and alternative pathways and to understand whether complement inhibition a) prevents delayed graft function (DGF); b) ameliorates activation of innate and adaptive immune systems; c) prevents fibrosis progression in kidney transplantation; and d) regulates T cell responses, from directing the initiation phase to driving lineage commitment and differentiation. Finally, we will also study the additive therapeutic effect of blocking complement in both donors and recipients in an expanded criteria model of kidney transplantation.