Acute Humoral Rejection of Renal Allografts

描述（由申请人提供）：目前的免疫抑制降低了同种异体肾移植急性细胞排斥反应的发生率。然而，肾移植患者急性体液性排斥反应（AHR）的发生率越来越高，并且特别难以治疗。抗体介导的引起肾移植损伤和损失的机制仍然知之甚少。由于缺乏动物模型来研究供体特异性抗体反应的发展和随后的同种异体移植物损伤，对这些机制的研究受到阻碍。缺乏合适的模型也阻碍了抑制抗体介导的移植物急性和慢性病理的策略设计。这个新项目的长期目标是为AHR期间同种异体肾移植损伤的炎症机制提供更清晰的认识。该项目由三名已建立的互动研究人员组成，他们将利用肾移植小鼠模型来研究T细胞致敏如何影响同种异体移植物反应性抗体的产生，并确定抗体介导的移植物损伤导致急性排斥反应或同种异体肾移植物间质纤维化的机制。项目1将研究移植物反应性抗体诱导的中性粒细胞浸润和活化对不同MHC差异的同种异体肾移植急性移植物损伤和间质纤维化的影响。项目2将研究其他先天介质，血小板和补体，在抗体与移植物内皮结合时介导同种异体肾移植损伤的作用。项目3将确定供体抗原特异性记忆T辅助细胞对供体反应性抗体反应产生的影响，重点关注诱导抗体的特异性和亲和力的变化。这些相互交织的项目的结果将为从抗体结合到移植物内皮的下游发生的一系列致病事件提供新的见解。重要的是，这些研究将测试新的策略，以防止产生供体反应性抗体和抗体介导的肾移植急性损伤以及间质纤维化的发展。

DESCRIPTION (provided by applicant): Current Immunosuppression has decreased the incidence of acute cellular rejection of renal allografts. However, the incidence of acute humoral rejection (AHR) in renal transplant patients is increasingly observed and is particularly difficult to treat. Antibody mediated mechanisms causing 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 absence of appropriate models has also hindered the design of strategies to inhibit antibody-mediated graft acute and chronic graft pathology. The long-term goal of this new program is to provide a clearer understanding of inflammatory mechanisms underlying renal allograft injury during AHR. This program comprises three established and interactive investigators who will utilize mouse models of kidney transplantation to address how T cell sensitization impacts allograft reactive antibody production and to identify mechanisms of antibody mediated graft injury leading to either acute rejection or to the development of interstitial fibrosis in the renal allograft. Project 1 will study the impact of graft-reactive antibody induced neutrophil infiltration and activation on acute graft injury and the development of interstitial fibrosis in renal allografts with varying MHC disparities. Project 2 will investigate the role of other innate mediators, platelets and complement, in mediating renal allograft injury in response to antibody binding to the graft endothelium. Project 3 will determine the impact of donor-antigen specific memory T helper cells on the generation of the donor-reactive antibody response, focusing on changes in the specificities and affinities of the antibodies induced. The results of these intertwined projects will provide novel insights into the series of pathogenic events occurring down-stream from antibody binding to the graft endothelium. Importantly, these studies will test novel strategies to prevent generation of donor-reactive antibody and antibody mediated acute injury in renal allografts as well as the development of interstitial fibrosis. RELEVANCE: The use of current immunosuppression has decreased the incidence of T lymphocyte mediated rejection of renal transplants but rejection mediated by antibodies that bind to the graft continues to be a problem in causing graft loss. This project will utilize mouse models to investigate mechanisms of kidney graft injury and rejection induced by graft-reactive antibody and will test novel strategies to prevent this injury. PROJECT 1: Title: - Antibody Induced Neutrophil Tissue Pathology in Renal Allografts Project Leader: Fairchild, R PROJECT 1 DESCRIPTION (provided by applicant): Antibody mediated mechanisms leading to graft 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 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-mediated rejection of renal allografts in CCR5-/- recipients where the titers of donor specific antibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and graft rejection was characteristic of acute humoral rejection 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 infiltration. These and our preliminary results have led us to propose the hypothesis that a key mechanisms 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 tissue pathology inflated by specific antibodies in the rejection of renal allografts of varying MHC disparities in the CCR5-/- recipients. In Specific Aim 2 we will test the role of this neutrophil mediated tissue damage on the repertoire of antibodies 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 interstitial fibrosis, pathologies that impact the immediate function and long-term outcome of renal allograft survival. These studies will provide novel insights into mechanisms underlying the pathologies induced following donor-reactive antibody binding to the allograft endothelium. RELEVANCE: Rejection of renal transplants mediated by antibodies that bind to the graft continues to be a problem in causing graft dysfunction and loss. This project will utilize a novel mouse model to investigate graft-reactive antibody induced mechanisms that mediate the acute or chronic kidney graft injury that causes the loss of kidney transplants