The Role of Complement Inhibition in Expanded Criteria Kidney Transplantation

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 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.