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.
Delayed graft function (DGF) is the most common complication affecting kidney allografts in the immediate post-transplant period. Defined as the necessity for dialysis in the first week after surgery, delayed graft function occurs in 20% to 50% of patients receiving a first deceased donor graft. DGF is usually the result of ischemic damage to the graft before or during recovery of the organs and is further aggravated by the reperfusion syndrome, a multifactorial event in which polymorphonuclear (PMN) cells play a pivotal role. Specifically, complement activation has gained special attention, since it has been found to play a central role in the pathogenesis of renal/ischemia injury. C1 inhibitor (C1INH) is a serpin protease inhibitor that regulates both complement and contact (kallikrein-kinin) system activation. Deficiency of C1INH results in hereditary angioedema. In this application we are proposing a novel utilization of C1qINH for the pre-treatment of brain death donors aiming to prevent DGF in kidney transplantation from expanded criteria donors in a non-human primate model. In addition, we are proposing to study the synergistic effect of donor and recipient treatment with complement inhibitor in the context of understanding a) the role of complement inhibition to prevent kidney fibrosis, and b) how the complement system intervenes in regulation of T cell responses, from directing the initiation phase to driving lineage commitment and differentiation, and how that role mediates the adaptive immune response. This application provides new insight into the treatment of brain death donors and their recipients and represents a promising treatment strategy for future clinical trials in expanded criteria donors aiming to expand graft and patient survival.
| Zens, Tiffany J; Danobeitia, Juan S; Chlebeck, Peter J et al. (2017) Guidelines for the management of a brain death donor in the rhesus macaque: A translational transplant model. PLoS One 12:e0182552 |
