Acute rejection of allografts remains a significant problem in clinical transplantation, undermining the function and survival of organs transplanted for the treatment of end-stage organ disease. Acute rejection is mediated by the coordinated infiltration and effector functions of T cells with specificity for alloantigens resulting in the destruction of the graft tissue. The factors directing T cells and other leukocytes into solid organ allografts remain poorly defined. In studies performed during the initial funding period of this grant we demonstrated the temporal induction of chemoattractant cytokines, chemokines, in skin allografts during the progression of acute rejection. Administration of antibodies to one of these chemokines, Mig, inhibited T cell infiltration into skin allografts and promoted long-term graft survival supporting the use of this strategy in transplantation. Our preliminary studies using a heart allograft model have indicated that an early program of inflammatory events regulates the production of T cell chemoattractants and T cell infiltration into the allografts. Antagonism of specific components of this early inflammation delays subsequent infiltration of alloantigen-pnmed T cells into these grafts and significantly extends allograft survival. In this competitive renewal application we will test the induction and inter-dependent relationships between specific components of the inflammatory response that leads to the production of the T cell chemoattractants such as Mig using a mouse model of vascularized heart allograft rejection.
In Specific Aim 1 we will test the induction and role of TNFa and IL-1 on the induction of early chemokines anad later T cell chemoattractants in heart allografts.
In Specific Aim 2 we will test the role of neutrophils and neutrophil and macrophage chemoattractants in the production of the T cell chemoattractants. Experiments in Specific Aim 3 will test the synergy between the adhesion molecule ICAM-1 and chemokines in directing leukocyte infiltration into heart allografts and the progression of inflammation during acute allograft rejection. The understanding of the role of each of these early inflammatory events in acute rejection should further elucidate important mechanisms of acute allograft rejection. Furthermore, the results should support the development of novel therapeutic reagents and strategies to inhibit these early inflammatory events and promote the survival of transplanted organs while decreasing the dependence on the generalized and debilitating immunosuppressive regimens currently in use.
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