Mechanisms Involved in T cell trafficking in GVHD

描述(由申请人提供)： 异基因干细胞移植的限制因素是GVHD的发生，这是由于同种异体反应性T淋巴细胞识别主要组织相容性复合体蛋白提出的主要和次要抗原。移植物抗宿主病发生在器官的一个子集，涉及同种异体反应性T细胞进入这些器官的早期迁移，随后是T细胞的扩张和后来的组织破坏。同种异体反应性T细胞向GVHD靶器官迁移的蛋白质和机制尚不清楚。更好地了解这一点可能会为治疗或预防GVHD提供新的治疗形式。我们的小组主要关注趋化因子、趋化因子受体和整合素在同种异体反应性T细胞迁移到胃肠道、肝脏、肺和皮肤中的作用。我们小组是第一个发现趋化因子CCL3在CD8+T细胞进入肝脏和肺的过程中起作用的。我们也是第一个证明CCL3阻断增强了肝脏中的CD4+T细胞的扩张，以及趋化因子受体CCR5在控制CD8+和CD4+T细胞的扩张和迁移到肝脏和肺中的重要作用的小组。 在这项研究中，我们将研究T细胞在肝脏和肺内的运输和扩增机制。我们将使用遗传学和免疫学方法来研究以下具体目标： 1.移植不表达CCR5的T细胞后，肝脏和肺组织中同种异体反应性的CD4+和CD8+T细胞数量增加的机制。 2.我们将评估T细胞进入GVHD靶器官使用不同的趋化因子受体进入特定器官的假说。具体地说，我们将分别研究CCR1、CCR9和CCR10在T细胞进入肝脏、胃肠道和皮肤中的作用。 3.我们将研究CCR5在受体APC诱导GVHD中的作用 4.我们将评估可用于临床的小肽是否有效地阻止移植物抗宿主病的发生，作为其在I期临床试验中使用的前奏。

DESCRIPTION (provided by applicant): The limiting factor to allogeneic stem cell transplantation is the occurrence of GVHD, which is due to the recognition by alloreactive T lymphocytes of major and minor antigens presented by major histocompatibility complex proteins. GVHD occurs in a subset of organs and involves early migration of alloreactive T cells into these organs followed by T cell expansion and later tissue destruction. The proteins and mechanisms involved in the migration of alloreactive T cells into GVHD target organs is poorly understood. A greater understanding of this might allow for new forms of therapy for the treatment or prevention of GVHD. Our group has focused on the roles of chemokines, chemokine receptors and integrins in the migration of alloreactive T cells into the GI tract, liver, lung and skin. Our group was the first to show that a chemokine, CCL3, plays a role in the trafficking of CD8+ T cells into the liver and lung. We were also the first group to show that CCL3 blockade enhanced the expansion of CD4+ T cells in the liver and that the chemokine receptor CCR5 played a significant role in controlling the expansion and migration of both CD8+and CD4+ T cells into the liver and lung. In this proposal, we will investigate the mechanisms involved in the trafficking and expansion of T cells in the liver and lung. We will use genetic and immunological methods to investigate the following specific aims: 1. The mechanism involved in the increased number of alloreactive CD4+ and CD8+ T cells in the liver and lung after the transfer of T cells that do not express CCR5. 2. We will evaluate the hypothesis that trafficking of T cells into GVHD target organs uses different chemokine receptors for entrance into the specific organs. Specifically, we will investigate the functions of CCR1, CCR9 and CCR10 in the trafficking of T cells into the liver, GI tract and skin respectively. 3. We will investigate the function of CCR5 on recipient APCs in the induction of GVHD 4. We will evaluate if small peptides that could be used clinically are effective in blocking the occurrence of GVHD as a prelude to their use in phase I clinical trials.