ROLE OF MMPS IN ALLOGRAFT REJECTION AND ACCEPTANCE

Cleveland Clinic Foundation, Cleveland OH

Investigators

Abstract

Acute rejection of allografts remains a significant problem in clinical transplantation, compromising the function and survival of organs transplanted for the treatment of end-stage renal and heart disease. Acute rejection is mediated by the coordinated infiltration and effector functions of T cells with specificity for alloanfigens resulting in the destruction of the graft tissue. The T cell effector mechanisms that are critical for mediating this tissue destruction and acute rejection of organ allografts have are not completely understood. In order to mediate acute rejection of a transplanted allograft, T cells must be able to digest the basement membrane and the extracellular matrix (ECM) maintaining the architecture of the graft tissue. One possible mechanism is through the activity of matrix metalloproteinases (MMPs), a family of ECM degrading enzymes. Although these enzymes are known to be essential for morphogenesis and other physiological processes, virtually nothing is known about their role in allograft rejection. Based on our preliminary studies we propose the hypothesis that production of MW-9 is essential for CD4+ T cells to mediate acute rejection of allografts and that the delayed rejection of skin and heart allografts observed in MMP- 9-/- recipients is mediated by CDB+ T cells. Using histological, cellular immunological, and molecular approaches, this hypothesis will be tested by performing experiments proposed in three specific aims. In Specific Aim 1 we will directly test CD4+ T cell production of MMP-9 during acute rejection of allogeneic cardiac and skin grafts.. In Specific Aim 2, we will test the priming and effector functions of alloantigen- specific CDB+ T cells during rejection of allogeneic cardiac grafts by MMP-9-/- recipients and investigate the production of other ECM degrading enzymes by these T cells. In Specific Aim 3 we will test mechanisms regulating CD4+ T cell production of MMP-9 in gallium nitrate and m anti-CD4 mAb treated recipients of allogeneic cardiac grafts. The overall goal of these studies is to test the role of MMP-9 and other MMPs in the destruction of allograft tissue during acute rejection. The understanding of the role of these enzymes in acute rejection should elucidate an important mechanism of acute allograft rejection and should facilitate the development of therapeutic reagents to inhibit this activity and promote the survival of transplanted organs while decreasing the dependence on the generalized and debilitating immunosu ressants currently in use.