Post-Transplant Inflammatory Response

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

Investigators

Linked publications & trials

Abstract

Abstract Acute allograft rejection is a T cell mediated immune response that continues to undermine the success of transplantation to treat end-stage organ disease. Two key factors contributing to acute and chronic allograft injury and graft loss are ischemia-reperfusion injury (IRI) and heterologous immunity by heterologous memory T cells with reactivity to graft alloantigens, but whether these factors are connected and how has not been tested. Reperfusion of ischemic tissues is an inherent component of transplantation and quickly induces an acute inflammatory response that directs the infiltration and activation of many types of leukocytes into the tissue. Clinically, the presence of donor-reactive memory T cells in the peripheral blood of kidney transplant patients prior to transplant is associated with increases in acute rejection and delayed graft function resulting in poorer graft survival. Studies performed during the last funding period indicated that heterologous memory CD8 T cells rapidly infiltrate cardiac allografts and are activated by graft allogeneic class I MHC molecules to proliferate and produce IFN-γ and other inflammatory factors mediating graft tissue injury. The infiltration and activities of these memory CD8 T cells are markedly increased in allografts subjected to longer duration of cold ischemic storage (CIS) prior to transplant and require helper signals generated by donor-reactive CD4 T cells that infiltrate the allograft. The resulting increases in the IRI and activation of these memory CD4 and CD8 T cells promotes costimulatory blockade resistant memory CD8 T cell mediated rejection of the allografts. These and our preliminary results have led us to propose the hypothesis that reperfusion of allografts subjected to prolonged CIS initiates a TLR9-dependent cycle of graft inflammation promoting pre-existing donor- reactive memory CD4 T cells to generate helper signals required for heterologous memory CD8 T cell activation to proliferate and express functions mediating acute graft injury and rejection. The hypothesis will be tested in two specific aims: first, we will test the role of TLR9 signaling in activating innate immune components that promote donor-reactive memory CD4 cells to generate help required for heterologous CD8 T cell responses to mediate graft rejection; and, second, we will test the source and role of IL-21 in heterologous memory CD8 T cell activation to express functions mediating acute graft injury. The proposed experiments in this renewal application will connect IRI with pre-existing donor-reactive memory CD4 and CD8 T cell activation in allografts and provide novel insights into mechanisms underlying an important and poorly understood clinical problem. We anticipate these studies will identify new targets for development of therapeutic strategies to inhibit innate immune enhancement of pre-existing/heterologous donor-reactive memory T cells in grafts and the acute graft injury mediated by these activated memory T cells.