Function & Fate of Alloantigen-specific CD8 Cell in GVHD

描述（由申请人提供）：既往的移植物抗宿主研究 在动物模型和人类中研究GVHD的困难阻碍了研究的进展。 根据供体T细胞群的能力鉴定它们， 识别受体同种异体抗原。通过开发一个 一种新的小鼠模型，其中可识别的供体CD8 T细胞群 识别受体同种异体抗原并保持功能活性， 在过继转移到 致死辐射的同种异体受体。初步研究结果显示， 显示供体CD8上T细胞受体的中间亲合力刺激 细胞导致持续的GVHD，但高亲和力刺激导致 失败的移植物抗宿主反应，在第14天达到峰值，并随时间消退 28、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， 移植物抗宿主反应失败的受体，表明 活化诱导的细胞凋亡不能解释GVHD的消退。 具体目标1中提出的实验将检验三个假设， 解释为什么供体CD8细胞具有对受体具有高亲和力的TCR 同种异体抗原不引起持续GVHD。供体CD8的高亲和力刺激 细胞可能导致效应功能丧失，加速消除 受体抗原呈递细胞，或改变的CD8效应细胞迁移， 从而终止GVHD的进展。具体实验 目的2评价炎症介质对供体CD 8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细胞源性的 炎性细胞因子在组织巨噬细胞活化中导致GVHD， 但最近的研究强调了炎性细胞因子的作用 对活化T细胞的存活和功能的影响实验已经 旨在检验在炎症存在下激活的假设 介质增强供体CD8细胞的存活和功能， 受体同种异体抗原，从而加剧GVHD的严重性。实验 具体目标3中提出的方法将检验CD8应答 从记忆细胞启动的应答导致比启动的应答更严重的GVHD 从幼稚细胞。具体目标4中提出的实验旨在 通过以下方式检验CD4有助于加重GVHD严重程度的假设： 增强CD8细胞的存活和功能。本报告中提出的研究 应用将有助于澄清特定供体的关键功能和命运 导致GVHD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.