Acute rejection remains a significant problem in clinical transplantation, undermining the survival of organs transplanted for treatment of end-stage organ disease. Acute rejection is mediated by the coordinated infiltration and effector functions of alloantigen-specific T cells resulting in graft tissue destruction. Factors directing T cells and other leukocytes into allografts remain poorly defined. During the previous cycle of this grant we demonstrated the early (e.g. 9-24 hours post-transplant) infiltration of neutrophils into cardiac iso- and allo-grafts. However, neutrophil infiltration into allografts is increased 3-4 fold compared to isografts and is associated with detectable areas of parenchymal tissue necrosis indicating the ability of the recipient to react to the presence of allogeneic tissue as early as 12-24 hours post-transplant. Subsequent studies indicated that the increased neutrophil infiltration into allografts is mediated by CD8 T cells expressing a memory phenotype. Antagonism of early neutrophil infiltration into cardiac allografts decreases the efficiency of alloantigen-primed effector T cell infiltration into the allografts with a 10-15 day prolongation of allograft survival. When this antagonism is combined with a low dose of costimulatory blockade to delay donor-specific effector T cell activation, the cardiac allografts survive longer than 130 days with little-no cellular infiltration into the grafts. The studies proposed in this Continuation Renewal will test the hypothesis that initial neutrophil infiltration into cardiac iso- and allo-grafts is mediated by an organized and interdependent program of cytokine and chemokine production, that donor-reactive memory CD8 T cells amplify this early neutrophil infiltration into the allograft and induce neutrophil activation in the allograft, and that this neutrophil activation results in changes, or """"""""marking"""""""", of the allograft tissue that promotes the recruitment of donor antigen-primed effector T cells into the allograft. This hypothesis will be tested in three Specific Aims: 1) To test the induction and role of early innate immune components that direct neutrophil infiltration into cardiac iso- and allo-grafts;2) To test the phenotype, specificity and function of CD8 T cells that amplify neutrophil infiltration and activation in allografts;and, 3) To test neutrophil activation functions that direct donor antigen-primed effector T cell infiltration into cardiac allografts. The results of these studies will elucidate poorly understood inflammatory events that occur almost immediately after reperfusion of cardiac allografts. Solid organ transplantation includes a period where the organ is removed from an oxygen supply and underlies an intense inflammatory response induced during revascularization of the organ. Although this inflammation enhances the recipient immune response to the graft and promotes rejection, the key components of this initial inflammation in the graft and their interaction with the recipient immune system are poorly understood. The results of the proposed studies will reveal novel cellular and molecular interactions that increase the intensity of early inflammation in transplanted organs and will provide novel targets to attenuate this inflammation and promote better function and survival of solid organs transplanted for the treatment of end-stage organ disease.
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