Mechanisms Involved in T cell trafficking in GVHD

GVHD 中 T 细胞运输的机制

• 批准号: 6672206
• 负责人: Jonathan S. Serody
• 金额: $ 32.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672206
• 关键词: T cell receptor; T lymphocyte; antigen presenting cell; cell migration; cytokine receptors; enzyme linked immunosorbent assay; flow cytometry; gastrointestinal system; graft versus host disease; immunocytochemistry; laboratory mouse; leukocyte activation /transformation; liver; lung; receptor binding; receptor expression; skin; statistics /biometry; vascular endothelium

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.

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淋巴细胞对主要组织相容性复合体蛋白呈递的主要和次要抗原的识别所致。 GVHD 发生在一部分器官中，涉及同种反应性 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。同种反应性 T 细胞迁移至 GVHD 靶器官所涉及的蛋白质和机制尚不清楚。对此有更深入的了解可能会带来治疗或预防 GVHD 的新疗法。我们小组重点研究趋化因子、趋化因子受体和整合素在同种反应性 T 细胞迁移到胃肠道、肝脏、肺和皮肤中的作用。我们的研究小组首次证明趋化因子 CCL3 在 CD8+ T 细胞转运至肝脏和肺中发挥作用。我们也是第一组证明 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着重要作用。 在本提案中，我们将研究 T 细胞在肝脏和肺部的运输和扩增所涉及的机制。我们将利用遗传学和免疫学方法来研究以下具体目标： 1. 不表达 CCR5 的 T 细胞转移后，肝脏和肺中同种异体反应性 CD4+ 和 CD8+ T 细胞数量增加的机制。 2. 我们将评估以下假设：T 细胞运输到 GVHD 靶器官时使用不同的趋化因子受体进入特定器官。具体来说，我们将研究 CCR1、CCR9 和 CCR10 分别在 T 细胞转运至肝脏、胃肠道和皮肤中的功能。 3. 我们将研究CCR5在受体APC上诱导GVHD的功能 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。