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降低了 T 细胞介导的急性排斥反应和移植物损失的发生率。相比之下，在临床移植中越来越多地观察到急性抗体介导的排斥反应（AMR）的发生，防止AMR期间移植物丢失的治疗已成为移植中的一个重要问题。抗体介导的肾移植物损伤和丢失机制的潜在机制仍知之甚少。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。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学策略的设计。该项目的长期目标是更清楚地了解 AMR 期间肾同种异体移植急性和慢性损伤的炎症机制。该项目由三名已建立的互动研究人员组成，他们将利用新型肾移植和 AMR 小鼠模型。该计划的总体目标是描述导致肾同种异体移植物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。该项目的具体目标是： 1) 测试辅助 T 细胞信号和先天免疫信号如何影响同种异体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）检测抗供体I类、II类MHC抗体和自身抗体对急性和慢性同种异体移植肾损伤的影响； 3) 测试先天免疫激活在抗体介导的急性同种异体移植损伤过程中的作用； 4) 测试先天免疫激活在抗体介导的慢性同种异体移植物损伤的发生和进展过程中的作用。我们预计这一综合计划的结果将：1）为肾移植中同种异体 MHC 分子和自身抗原的抗体产生机制提供新的见解； 2）为同种异体肾急性和慢性损伤的机制提供新的见解； 3) 确定新的靶点来抑制导致移植肾早期和晚期丧失的 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.