Memory CD4 helper T cells and antibody production following renal transplantation

项目摘要/摘要 尽管在免疫抑制和移植前常规PRA筛查方面取得了进展，但急性和 慢性抗体介导的排斥反应(AMR)破坏了移植器官的长期存活。成功之路 在移植患者中针对AMR的治疗由于对机制的不完全了解而受到限制 潜在的DSA和自身抗体的产生和功能。关于体液反应的先前研究如下 由于缺乏可靠的检测同种异体和自身反应性B细胞的方法，以及 缺乏与AMR生理相关的动物模型。致病性同种异体抗体和自身抗体的产生 需要B细胞和激活的辅助CD4T细胞之间的相互作用。许多人的T细胞谱系 包括能抵抗免疫抑制或共刺激阻断的同种异体反应性T细胞。 在上一个资助周期中，我们证明了记忆性CD4T细胞能够诱导更好的供者特异性 同种异体抗体(DSA)与主要效应者CD4T细胞的反应比较。我们在生理上已经发展了 和临床相关的急性和慢性AMR小鼠模型，以探讨异体和慢性AMR的作用机制 肾移植后自身抗体的产生。我们的初步数据显示，供体反应性记忆 CD4T细胞在肾移植受者中诱导强大的DSA和自身抗体反应，导致急性 AMR.与DSA不同的是，抗CD20抗体治疗不能阻止自身抗体的产生 并与慢性移植物组织损伤有关。该项目的目标是确定所需的辅助信号 用于产生致病性同种异体抗体和自身抗体，并利用这一信息抑制致敏的AMR 肾移植受者。我们假设同种异体抗体和自身抗体的分子需求 肾移植后产生的抗体的特异性和致病性是 取决于辅助性CD4T细胞的功能表型和移植后的强度 发炎。我们将从三个具体目标来检验这一假设： 目标1.确定生产和维护供体MHC第I类和MHC的帮手需求 肾移植受者中II类特异性DSA和IV型胶原和纤维连接蛋白特异性自身抗体。 目的2.检测BAFF/APRIL细胞因子网络在致病同种异体白血病发生中的作用。 肾移植受者的自身抗体。 目的3.检测移植后炎症对同种异体抗体和自身抗体产生的影响 在肾移植后。

Project Summary / Abstract Despite advances in immunosuppression and routine PRA screening prior to transplantation, acute and chronic antibody-mediated rejection (AMR) undermine long-term survival of transplanted organs. The success of therapies targeting AMR in transplant patients is limited by the incomplete understanding of the mechanisms underlying DSA and autoantibody generation and functions. Previous studies of humoral responses following transplantation were impeded by the lack of reliable assays to detect allo- and autoreactive B cells and by the paucity of physiologically relevant animal models of AMR. Production of pathogenic allo- and autoantibodies requires interactions between B cells and activated helper CD4 T cells. The T cell repertoire of many humans includes alloreactive memory T cells that are resistant to immunosuppression or costimulatory blockade. During the previous funding cycle, we demonstrated that memory CD4 T cells induce superior donor-specific alloantibody (DSA) responses compared to primary effector CD4 T cells. We have developed physiologically and clinically relevant mouse models of acute and chronic AMR to investigate the mechanisms of allo- and autoantibody generation after kidney transplantation. Our preliminary data show that donor-reactive memory CD4 T cells induce robust DSA and autoantibody responses in renal allograft recipients resulting in acute AMR. In contrast to de novo DSA, autoantibody generation is not prevented by anti-CD20 antibody treatment and is associated with chronic graft tissue injury. The goal of this project is to determine helper signals required for generation of pathogenic allo- and autoantibodies and to use this information to inhibit AMR in sensitized renal allograft recipients. We hypothesize that the molecular requirements for allo- and autoantibody production following renal transplantation and the specificity and pathogenicity of resulting antibody are determined by the functional phenotype of helper CD4 T cells and by the intensity of post-transplant inflammation. We will test this hypothesis in three Specific Aims: Aim 1. To determine helper requirements for the production and maintenance of donor MHC class I- and MHC class II-specific DSA and collagen IV- and fibronectin-specific autoantibodies in renal transplant recipients. Aim 2. To test the role of BAFF/APRIL cytokine network during the generation of pathogenic allo- and autoantibodies in renal allograft recipients. Aim 3. To test the effects of post-transplant inflammation on the generation of allo- and autoantibodies following renal transplantation.