Function & Fate of Alloantigen-specific CD8 Cell in GVHD

描述(申请人提供)：以往移植物抗宿主研究 在动物模型和人类中的疾病(GVHD)一直受到以下困难的阻碍 根据供者T细胞群的能力识别供者T细胞群 识别受体同种异体抗原。这个问题已经通过开发一种 一种新的小鼠模型，在该模型中，可识别的供体CD8 T细胞群 识别受体同种异体抗原，并在功能上保持活跃 在体内长期致病后，收养转移到 受过致命照射的同种异体移植受者。初步研究结果如下： 显示T细胞受体对供者CD8的中等亲和力刺激 细胞会导致持续的GVHD，但高亲和力刺激会导致 流产的移植物抗宿主反应，在第14天达到顶峰，并在第二天消退 28例移植后。识别受体同种异体抗原的供体CD8细胞 在移植后第28天，脾和淋巴结中都有 移植物抗宿主反应流产的受者，表明 激活诱导的细胞凋亡并不能解决移植物抗宿主病。 在特定目标1中提出的实验将测试三个假设，这些假设可能 解释为什么供者CD8细胞对受者具有高亲和力的TCR 同种异体抗原不能引起持续性GVHD。供体CD8的高亲和力刺激 细胞可能导致效应器功能丧失，加速消除 受体抗原提呈细胞，或CD8效应细胞的异常迁移， 从而终止GVHD的进展。在具体建议中提出的实验 目的2评价炎症介质对供者CD8细胞的影响 导致移植物抗宿主病。以前的研究已经阐明了T细胞来源的作用 炎症细胞因子在导致GVHD的组织巨噬细胞激活中的作用 但最近的研究强调了炎性细胞因子的作用 关于激活的T细胞的生存和功能。实验已经被 旨在测试在存在炎症的情况下激活的假设 介体增强供体CD8细胞的存活率和功能 受体同种异体抗原，从而加剧了移植物抗宿主病的严重性。实验 在特定目标3中提出的将检验CD8反应的假设 从记忆细胞启动会导致比启动的反应更严重的GVHD 来自幼稚的细胞。在具体目标4中提出的实验旨在 测试CD4帮助将通过以下方式加重GVHD严重性的假设 增强CD8细胞的存活和功能。在这篇文章中提出的研究 应用程序将有助于澄清特定捐赠者的关键功能和命运 导致移植物抗宿主病的CD8细胞群。

DESCRIPTION (PROVIDED BY APPLICANT): Previous studies of graft-versus-host disease (GVHD) in animal models and humans have been hampered by difficulty in the identification of donor T cell populations according to their ability to recognize recipient alloantigens. This problem has been solved by developing a novel murine model in which an identifiable donor CD8 T cell population recognizes a recipient alloantigen and remains functionally active and pathogenic in vivo for a prolonged period of time after adoptive transfer into lethally irradiated allogeneic recipients. Results of preliminary studies have shown that intermediate avidity stimulation of T cell receptors on donor CD8 cells leads to sustained GVHD, but high avidity stimulation leads to an abortive graft-versus-host response that peaked at day 14 and subsided by day 28 after the transplant. Donor CD8 cells that recognize a recipient alloantigen were present in the spleen and lymph nodes on day 28 after the transplant in recipients with an abortive graft-versus-host response, indicating that activation-induced apoptosis did not account for the resolution of GVHD. Experiments proposed in Specific Aim 1 will test three hypotheses that might explain why donor CD8 cells having a TCR with high avidity for a recipient alloantigen did not cause sustained GVHD. High avidity stimulation of donor CD8 cells might lead to loss of effector function, accelerated elimination of recipient antigen-presenting cells, or altered migration of CD8 effector cells, thereby terminating the progression of GVHD. Experiments proposed in Specific Aim 2 will evaluate the effects of inflammatory mediators on donor CD8 cells that cause GVHD. Previous studies have elucidated the role of T cell-derived inflammatory cytokines in the activation of tissue macrophages leading GVHD, but more recent studies have emphasized the effects of inflammatory cytokines on the survival and function of activated T cells. Experiments have been designed to test the hypothesis that activation in the presence of inflammatory mediators enhances the survival and function of donor CD8 cells that recognize recipient alloantigens, thereby exacerbating the severity of GVHD. Experiments proposed in Specific Aim 3 will test the hypothesis that a CD8 response initiated from memory cells leads to more severe GVHD than a response initiated from naive cells. Experiments proposed in Specific Aim 4 have been designed to test the hypothesis that CD4 help will exacerbate the severity of GVHD by enhancing the survival and function of CD8 cells. The studies proposed in this application will help clarify the critical functions and fate of specific donor CD8 cell population that cause GVHD.