Antibody-Mediated Rejection of Renal Allografts

 描述(由申请人提供)：目前用于治疗移植患者的免疫抑制已经减少了T细胞介导的急性排斥反应和移植物丢失的发生率。相比之下，急性抗体介导的排斥反应(AMR)在临床移植中的发生率越来越高，在AMR期间防止移植物丢失的治疗已成为移植中的一个重要问题。抗体介导的肾移植损伤和丢失的机制仍然知之甚少。由于缺乏研究供者特异性抗体反应的发展和随后的同种异体移植损伤的动物模型，阻碍了对这些机制的研究。这种缺失也阻碍了抑制抗体介导的移植物急性和慢性移植物病理的策略的设计。该计划的长期目标是更清楚地了解AMR期间移植肾急性和慢性损伤的炎症机制。这一计划包括三名已建立的和互动的研究人员，他们将利用肾移植和AMR的新小鼠模型。该计划的总体目标是描述导致肾移植反应性抗体产生的机制，以及抗体介导的移植组织急性和慢性损伤的机制。该计划的具体目的是：1)测试辅助性T细胞信号和先天免疫信号如何形成肾移植受者的同种异体抗原和自身抗原特异性抗体反应；2)测试抗供体I类和II类MHC抗体和自身抗体对急、慢性移植肾损伤的影响；3)测试先天免疫激活在抗体介导的急性移植肾损伤中的作用；以及4)测试先天免疫激活在抗体介导的慢性移植肾损伤的发生和发展中的作用。我们期望这一综合计划的结果将：1)为肾移植中产生针对同种异体MHC分子和自身抗原的抗体的潜在机制提供新的见解；2)为移植肾的急性和慢性损伤机制提供新的见解；以及3)确定新的靶点以抑制导致移植肾早期和晚期丢失的AMR的发生率和强度。

 DESCRIPTION (provided by applicant): 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.