Acute allograft rejection is a T cell mediated immune response that continues to undermine treatment of end-stage organ disease through transplantation. Two factors contributing to acute and chronic allograft injury and graft loss are heterologous immunity by endogenous memory T cells with reactivity to graft alloantigens and ischemia-reperfusion injury. The mechanisms directing endogenous memory T cells into allografts and the effector functions mediating graft injury remain poorly understood. Reperfusion of ischemic tissues is an inherent component of transplantation and induces an acute inflammatory response that includes neutrophil infiltration and activation to mediate graft injury. Since the infiltration of neutrophils and endogenous memory T cells into allografts both occur early after reperfusion, it is likely that these components interact and synergize with the effector functions expressed by each to increase graft tissue injury. Studies performed during the last funding period indicated that the increased intensity of neutrophil infiltration into allografts is mediated by the rapid infiltration of endogenous memory CD8 T cells into the graft and their activation by graft allogeneic class I MHC molecules to proliferate and produce IFN-? and other mediators promoting neutrophil infiltration and increased tissue injury. We have recently observed that the infiltration and activities of both neutrophils and endogenous memory CD8 T cells is increased when increased cold ischemic storage is imposed on the allografts and these interactions are sufficient to mediate intense graft tissue injury and potentially acute rejection of the allograft independent of de novo primary effector T cell development. These results have led us to propose the hypothesis that reperfusion of allografts subjected to increased cold ischemic storage generates an inflammatory environment within the graft that enhances the infiltration and activation of granulocytes and endogenous memory CD8 T cells with donor reactivity and promotes the synergy of their functions to exacerbate graft tissue injury and provoke graft failure. The hypothesis will be tested in two specific aims: first, we will test he impact of increased allograft ischemia in exacerbating the pathogenesis of endogenous memory CD8 T cells;and, second, we will test the impact of increased ischemic injury by granulocytes and endogenous memory CD8 T cells on the efficacy of strategies applied to prolong cardiac allograft survival. The cellular components of the early inflammation induced in allografts and the impact of these components on graft tissue injury and acute rejection remain poorly understood. Experiments in this competitive renewal application will test an important process in which granulocytes intersect with endogenous memory CD8 T cells early following allograft reperfusion to exacerbate acute graft injury. In addition to increasing understanding of early inflammatory events in allografts and their impact on acute rejection, the results should suggest new therapeutic strategies to decrease this inflammation and inhibit acute graft injury and failure.

Public Health Relevance

Acute allograft rejection is a T cell mediated immune response that continues to undermine treatment of end- stage organ disease through transplantation. The infiltration of neutrophils and endogenous memory T cells into allografts both occur early after reperfusion and the experiments proposed in this study will test the interaction and synergy of these two graft infiltrating cells to mediate increased graft tissue injury. Overall, the experiments will test the interdependent relationships of neutrophils and endogenous memory CD8 T cells in early inflammation and define their roles in directly mediating acute graft injury and the results should suggest new therapeutic strategies to decrease this inflammation and inhibit acute graft injury and failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI040459-16A1
Application #
8630592
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
1997-04-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
16
Fiscal Year
2014
Total Cost
$356,625
Indirect Cost
$131,625
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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