Acute allograft rejection remains a significant problem in transplantation, undermining the function and survival of grafts transplanted to treat end-stage organ disease. Acute rejection is mediated by the coordinated infiltration and effector functions of alloantigen-primed T cells resulting in destruction of the graft tissue. Factors directing T cells into organ allografts remain poorly defined. Our studies have demonstrated the temporal induction of chemoattractant cytokines, chemokines, in skin and heart allografts during the progression of acute rejection. At the time of acute rejection in these models as well as in biopsies from clinical heart transplants, high levels of several chemokines are present, including the IFN-gamma induced chemokine Mig a potent T cell chemoattractant. Administration of Mig-specific antibodies inhibits T cells infiltration into skin allografts and promotes long-term graft survival supporting the use of this strategy in transplantation. Our preliminary studies using a heart allograft model have indicated that recipient treatment with Mig-specific antibodies delays both T cell infiltration and acute rejection of the grafts, however, the grafts are eventually rejected. This delayed rejection is not mediated through Mig directed recruitment of T cells into the allograft. In this application we will test the induction and role of chemokine receptors that direct alloantigen-primed T cell infiltration into cardiac allografts and the role of the T cell chemoattractant Mig during acute rejection of vascularized heart allografts using a murine model.
In Specific Aim 1 we will test the temporal expression of chemokine receptors on individual and identifiable alloantigen-specific T cell populations during priming to cardiac allografts.
Specific Aim 2 will test the role of these receptors in directing the alloantigen-primed CD4+ and CD8+ T cells into allografts using receptor deficient mice as recipients.
Specific Aim 3 will test the role of Mig in directing alloantigen-primed T cells into the allografts.
Specific Aim 4 will test potential mechanisms mediating the delayed rejection of heart allografts in recipients treated with Mig-specific antibodies. Understanding the role of these receptors and Mig in acute rejection will elucidate mechanisms of T cell recruitment into allografts during acute rejection. The results should support the development of novel therapeutic reagents and strategies to inhibit T cell recruitment into allografts, improving solid organ allograft survival while decreasing the dependence on the generalized and debilitating immunosuppressive regimens currently in use.
