Memory CD4 T cell driven antibody responses to renal allografts

尽管改进了免疫抑制和粗略的PRA筛查，但同种异体反应的五种抗体(allo-Ab)介导了 相当大比例的同种异体移植急性排斥反应发生，并有助于慢性 拒绝。致病同种异体抗体的产生需要B细胞和辅助性CD4T之间的相互作用 供体无花果的细胞。通常，这种帮助发生在次级淋巴内的生发中心。 并依赖于CD40/CD154共调节通路。然而，许多T细胞的功能 人类含有五种同种异体反应的记忆T细胞，它们能抵抗免疫抑制或共刺激 封锁。我们的初步数据显示，供者反应性记忆CD4T细胞诱导更高滴度的同种异体抗体 与原始的CD4T细胞相比，即使在没有常规生发中心的情况下也是如此 CD40/CD154相互作用。然而，导致观察到的高同种异体抗体效价以及 记忆对CD4T细胞的解剖位置和分子需求的帮助是未知的，需要 接受测试。本研究的目的是鉴定记忆性CD4T细胞的功能表型，为临床治疗提供帮助 同种异体反应五个B细胞，并调查这一帮助的特征和要求。我们有 建立小鼠肾移植模型以研究供者特异性同种异体抗体反应 记忆性CD4T细胞。我们推测，与幼稚细胞相比，记忆力增强的CD4T细胞 GCs的发育和B细胞的更大增殖，促进高亲和力的同种异体抗体的产生 用于供体抗原，并诱导长寿抗体分泌浆细胞和记忆B 细胞。我们进一步提出，虽然滤泡辅助记忆T细胞在诱导同种异体抗体方面更具优势 与其他谱系相比，记忆辅助的CD4T细胞可以发生在典型的生发细胞之外 并可通过其他分子途径绕过CD40/CD154相互作用的要求 例如TLR和BAFF/APRIL信令。我们将从三个具体目标来检验这一假设： 目的1.探讨供者特异性记忆诱导同种异体抗体产生的机制 CD4T细胞对肾移植的反应。目的2.鉴定记忆CD4T细胞的功能表型 能够为移植肾术后产生同种异体抗体提供帮助。目标3.确定 记忆CD4T细胞产生同种异体抗体的位置和分子需求

Despite improved immunosuppression and roufine PRA screening, alloreacfive anfibodies (alloAb) mediate a significant proportion of acute allograft rejection episodes and contribute to the development of chronic rejection. Production of pathogenic alloAb isotypes requires interactions between B cells and helper CD4 T cells specific for donor anfigens. Typically, this help occurs in germinal centers within secondary lymphoid organs and is dependent on CD40/CD154 cosfimulatory pathway. However, the T cell repertoire of many humans contains alloreacfive memory T cells that are resistant to immunosuppression or cosfimulatory blockade. Our preliminary data show that donor-reactive memory CD4 T cells induce higher titers of alloAb compared to naive CD4 T cells even in the absence of conventional germinal center formafion and CD40/CD154 interacfion. However, the mechanisms underiying the observed high alloAb titers as well as anatomical sites and molecular requirements of help by memory CD4 T cells are sfill unknown and need to be tested. The goal of this study is to identify functional phenotype of memory CD4 T cells providing help for alloreacfive B cells and to investigate the characteristic features and requirements for this help. We have developed a mouse model of kidney transplantation to study donor-specific alloAb responses induced by memory CD4 T cells. We hypothesize that compared to naive cells, memory CD4 T cells inifiate enhanced development of GCs and greater proliferation of B cells, promote production of alloAb with higher affinifies for donor antigens and induce enhanced development of long-lived Ab secrefing plasma cells and memory B cells. We further propose that while follicular helper memory T cells are superior in inducing alloAb responses compared to other lineages, help by memory CD4 T cells can occur outside of typical germinal centers and can bypass the requirement for CD40/CD154 interacfion via alternative molecular pathways such as TLR and BAFF/APRIL signaling. We will test this hypothesis in three Specific Aims: Aim 1. To investigate the mechanisms of superior alloantibody production induced by donor-specific memory CD4 T cells in response to renal allografts. Aim 2. To identify functional phenotype of memory CD4 T cells capable of providing help for alloantibody production after renal allograft placement. Aim 3. To determine the location and molecular requirements of help provided by memory CD4 T cells for alloantibody production.