Memory CD4 helper T cells and antibody production following renal transplantation

项目总结/摘要 尽管在移植前免疫抑制和常规PRA筛查方面取得了进展， 慢性抗体介导的排斥（AMR）破坏移植器官的长期存活。成功 针对移植患者的AMR治疗受到机制不完全理解的限制， 基础DSA和自身抗体的产生和功能。先前的体液反应研究， 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， 缺乏AMR的生理学相关动物模型。致病性同种抗体和自身抗体的产生 需要B细胞和活化的辅助性CD 4 T细胞之间的相互作用。许多人的T细胞库 包括对免疫抑制或共刺激阻断具有抗性的同种异体反应性记忆T细胞。 在之前的资助周期中，我们证明了记忆性CD 4 T细胞诱导上级供体特异性免疫应答。 与初级效应CD 4 T细胞相比，同种抗体（DSA）应答。我们已经在生理上 和临床相关的急性和慢性AMR小鼠模型，以研究同种异体和 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 CD 4 T细胞在肾移植受者中诱导强烈的DSA和自身抗体应答，导致急性肾移植。 AMR。与从头DSA相反，抗CD 20抗体治疗不能阻止自身抗体的产生 并且与慢性移植组织损伤有关。这个项目的目标是确定所需的辅助信号 用于产生致病性同种抗体和自身抗体，并使用该信息来抑制致敏细胞中的AMR。 肾移植受者我们假设同种抗体和自身抗体的分子要求 肾移植后抗体的产生以及产生的抗体的特异性和致病性， 由辅助性CD 4 T细胞的功能表型和移植后免疫反应的强度确定。 炎症我们将在三个具体目标中检验这一假设： 目标1.为了确定辅助需求的生产和维持供体MHC I类和MHC 肾移植受者中II类特异性DSA和IV型胶原和纤连蛋白特异性自身抗体 目标2.为了检测BAFF/APRIL细胞因子网络在致病性同种异体和非致病性同种异体造血干细胞生成过程中的作用， 肾移植受者的自身抗体 目标3：检测移植后炎症对同种抗体和自身抗体产生的影响 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.