Current immunosuppression used to treat transplant patients has decreased the incidence of T cell mediated acute rejection episodes and graft loss. In contrast, the incidence of acute antibody-mediated rejection (AMR) is increasingly observed in clinical transplants and treatment to prevent graft loss during AMR has become a significant problem in transplantation. The mechanisms underlying antibody-mediated mechanisms of renal graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of animal models to study the development of donor-specific antibody response and subsequent allograft injury. This absence has also hindered the design of strategies to inhibit antibody-mediated graft acute and chronic graft pathology. The long-term goal of this program is to provide a clearer understanding of inflammatory mechanisms underlying renal allograft acute and chronic injury during AMR. This program comprises three established and interactive investigators who will utilize novel mouse models of renal transplantation and AMR. The overall goal of this program is to delineate mechanisms that lead to the production of renal allograft-reactive antibodies and mechanisms of the antibody-mediated acute and chronic injury of graft tissue.
The Specific Aims of this program are: 1) to test how helper T cell signals and innate immune signals shape alloantigen- and autoantigen-specific antibody responses in renal allograft recipients; 2) to test the impact of anti-donor clas I and class II MHC antibodies and autoantibodies on acute and chronic renal allograft injury; 3) to test the role of innate immune activation during antibody-mediated acute allograft injury; and, 4) to test the role of innate immune activation during the initiation and progression of antibody- mediated chronic allograft injury. We expect that the results of this integrated program will: 1) provide novel insights into mechanisms underlying the production of antibodies to allogeneic MHC molecules and to autoantigens in renal transplants; 2) provide novel insights into the mechanisms of acute and chronic injury to renal allografts; and, 3) identify novel targets to inhibit the incidence and intensity of AMR that leads to early and late loss of renal grafts.
The incidence of acute antibody-mediated rejection (AMR) is increasingly observed in clinical transplants and treatment to prevent graft loss during AMR has become a significant problem in transplantation. The mechanisms underlying antibody-mediated mechanisms of renal graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of animal models to study the development of donor-specific antibody response and subsequent allograft injury. The overall goal of this program is to delineate mechanisms that lead to the production of renal allograft-reactive antibodies and mechanisms of the antibody-mediated acute and chronic injury of graft tissue. We expect that the results of this integrated program will provide novel insights into mechanisms of acute and chronic injury to renal allografts and identify novel targets to inhibit the incidence and intensit of AMR that leads to early and late loss of renal grafts. Project-001: Antibody Induced Neutrophil and Macrophage Tissue Pathology in Renal Allografts Project Leader: Robert Fairchild DESCRIPTION (as provided by applicant): Antibody-mediated mechanisms leading to acute and chronic renal allograft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody (DSA) response is initiated and increases. We have developed a novel model of antibody-mediated rejection (AMR) of renal allografts in CCR5-/- recipients where the titers of DSA elicited in response to complete MHC-mismatched renal allografts are >50-fold higher than those elicited in wild-type recipients. The renal allografts are acutely rejected by this antibody response in CCR5-/- recipients between days 17 and 22 with heavy deposition of C3d, peritubular edema, and neutrophil and macrophage infiltration and activation including production of myeloperoxidase (MPO), histopathologic features of rejection that are characteristic of those observed during AMR in clinical transplants. These and our preliminary results have led us to propose the hypothesis that a key mechanism underlying acute and chronic AMR of renal allografts is the induced infiltration and activation of neutrophils and macrophages in the graft, which directly cause the acute and chronic graft tissue injury and increase the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will identify and test the role of MPO-producing cells during antibody-mediated acute rejection of renal allografts in CCR5-/- recipients. In Specific Aim 2 we will test the role of neutrophil and macrophage mediated allograft tissue damage in the generation of donor MHC- and autoantigen-specific antibodies in response to renal allografts. In Specific Aim 3 we will use a B cell depletion strategy to test the molecular mechanisms leading to the development of antibody-mediated interstitial fibrosis and tubular atrophy in the renal allografts. These studies will utilize novel models of antibody-mediated acute and chronic renal allograft injury to provide new insights into mechanisms underlying these pathologies that remain a major problem undermining the success of renal transplantation. We anticipate the results of these studies will indicate new therapeutic targets to inhibit or attenuate antibody-mediated graft injury.
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