Mechanisms Involved in T cell trafficking in GVHD

描述（由申请人提供）： 同种异体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淋巴细胞识别由主要组织相容性复合物蛋白呈递的主要和次要抗原。GVHD发生在器官的子集中，并且涉及同种异体反应性T细胞早期迁移到这些器官中，随后是T细胞扩增和随后的组织破坏。同种异体反应性T细胞迁移到GVHD靶器官中的蛋白质和机制知之甚少。对这一点的更深入了解可能会允许新形式的治疗或预防GVHD的治疗。我们的研究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。我们的研究小组是第一个证明趋化因子CCL3在CD8+ T细胞进入肝脏和肺部的运输中发挥作用的研究小组。我们也是第一组显示CCL3阻断增强了肝脏中CD4+ T细胞的扩增，并且趋化因子受体CCR5在控制CD8+和CD4+ T细胞向肝脏和肺中的扩增和迁移中发挥了重要作用。 在这项提案中，我们将调查参与运输和扩大的T细胞在肝脏和肺的机制。我们将使用遗传学和免疫学方法研究以下具体目标： 1.该机制涉及在转移不表达CCR5的T细胞后，肝脏和肺中同种异体反应性CD4+和CD8+ T细胞的数量增加。 2.我们将评估T细胞进入GVHD靶器官的运输使用不同的趋化因子受体进入特定器官的假设。具体而言，我们将研究CCR1，CCR9和CCR10在T细胞进入肝脏，胃肠道和皮肤的运输中的功能。 3.我们将研究受体APCs上的CCR5在诱导GVHD中的作用 4.我们将评估可用于临床的小肽是否能有效阻断GVHD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.