Antibody mediated mechanisms leading to graft injury and loss remain pooriy understood. Investigafion into these mechanisms is hampared by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody response is initiated and increases. For the most part, models studying acute humoral rejection use either transfer of graft-reactive antibodies or sensitization of recipients with donor cells which also primes donor-reactive T cell populations. We have recently reported a novel model of antibody-meidated rejection of renal allografts in CCR5-/- recipients where the titers of donorspecific anfibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and graft rejection was characterisfic of acute humoral rejecfion observed in clinical transplants. In CCR5- deficient animals, the renal allografts are rejected between days 10 and 20 with heavy deposition of C3d, peritubular edema and neutrophil infiltrafion. These and our preliminary results have led us to propose the hypothesis that a key mechanims underlying antibody-mediated rejection of renal allografts is the induced infiltration and activation of neutrophils in the grafts which directly causes graft tissue injury and increases the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims.
In Specific Aim 1 we will directly test the role of neutrophils in the graft fissue pathology inflated by specifc antibodies in the rejecfion of renal allografts of varying MHC disparities in the CCR5-/- recipients.
In Specific Aim 2 we will test the role of this neutrophil mediated fissue damage on the repertoire of anfibodies induced to renal allografts of varying MHC disparities. In the final specific aim we will use a B cell depletion strategy to test the effect of limiting donor-specific antibody interaction with the renal allograft on the development of acute tissue injury as well as on the development of interstitital fibrosis, pathologies that impact the immediate function and longterm outcome of renal allograft survival. These studies will provide novel insights into mechanisms underlying the pathologies induced following donor-reactive anfibody binding to the allograft endothelium.
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