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者，有新的强有力的证据表明补体在形成适应性免疫反应中具有作用。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模型中得到了广泛的研究。然而，它作为供体前治疗以提高扩大标准供体移植器官质量的潜在治疗用途尚未被研究。C1INH是一种丝氨酸蛋白酶抑制剂，调节补体和接触(激肽释放酶-激动素)系统的激活，C1INH的缺失会导致遗传性血管水肿。我们建议在肾移植中建立一个非人类灵长类动物(NHP)的翻译前临床模型，以评估通过经典和替代途径抑制补体抑制对脑死亡(BD)供者进行供者预治疗的效果，并了解补体抑制是否a)防止移植延迟功能(DGF)；b)改善先天性和获得性免疫系统的激活；c)防止肾移植中的纤维化进展；d)调节T细胞反应，从指导起始阶段到驱动谱系承诺和分化。最后，我们还将研究 肾移植扩展标准模型中阻断补体对供受者的相加治疗作用。

 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.