T CELL HOMING IN GRAFT VERSUS HOST DISEASE

移植物抗宿主疾病中的 T 细胞归巢

• 批准号: 6504941
• 负责人: THOMAS S. KUPPER
• 金额: $ 13.53万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6504941
• 关键词: T lymphocyte; antireceptor antibody; blocking antibody; bone marrow transplantation; cell adhesion molecules; cell migration; gastrointestinal system; genetically modified animals; graft versus host disease; gut associated lymphoid tissue; histocompatibility; histopathology; immunocytochemistry; immunologic memory; inflammation; integrins; intravital microscopy; laboratory mouse; radiation immunosuppression; selectins; skin

DESCRIPTION: (Applicant's Description) The capacity of memory T-cells to traffic preferentially to distinct epithelial tissues has only recently been appreciated. Evidence is accumulating that a skin homing memory T-cell population, identified by E/P selectin ligand expression (e.g., CLA/PSGL-1) and absence of integrin alpha 4 beta 7, mediates antigen specific effector responses in skin, while a reciprocal memory T-cell subset (integrin alpha 4 beta 7 positive, E/P selecting ligand negative) mediates effector responses in the gastrointestinal tract (gut). Importantly, these memory T-cells use these cell surface molecules to initiate the tethering and rolling (under physiologic flow conditions) on endothelial cells in post capillary venules that are required for their ultimate extravasation in both normal and inflamed skin or gut. Such polarized populations of memory cells are thought to emerge during the naive to memory T-cell transition in the specialized lymphoid micro-environment of lymph nodes draining each epithelial surface, respectively. GVHD is a nearly inevitable complication of allogeneic bone marrow transplantation. Much of the morbidity from GVHD derives from the involvement of the two major epithelial interfaces with the environment: the skin and the gut. The present proposal tests the hypothesis that distinct subsets of effector T-cells with similar antigenic specificities mediate skin and gut GVHC. A second testable hypothesis is that these polarized subsets of memory T-cell s emerge in part from transferred graft naive T-cells that are activated by alloantigen in lymph node draining either gut or skin, respectively. A final hypothesis is that the strength of the conditioning regimen influences this process in two ways. First, tissue injury and attendant inflammation from primary cytokine release leads to enhanced egress of dendritic cells form blood, which in to carry damaged tissue antigen via afferent lymphatics to draining lymph nodes. Second, the increased expression of adhesion molecules on endothelial cells in inflamed skin and gut enhance the efficiency of memory T-cell extravasation. Each of these hypotheses will be directly testing using a well-characterized murine model allogeneic BMT (MHC identical). The lethal GVHD that results is dependent on T-cells in the allografted population. Both antibodies and blocking molecules specific for memory and naive is dependent on T-cell homing ligand/receptor pairs, as well as transgenic mice deficient in one or more genes critical to these adhesive interactions (e.g., E/P selectin), FucTVll, beta 7 integrin), will be used to ask precise and directed questions about the cellular and molecular requirements for the evolution of skin and gut specific GVHD, respectively. The capacity to selectively modify GVHD involving one or both of these tissues, while not suppressing ostensibly beneficial alloimmune responses (e.g., graft versus leukemia or global immunocompetence is the longterm therapeutic goal underlying this study.

描述：（申请人的描述）记忆T细胞优先运输至不同上皮组织的能力直到最近才被认识到。 越来越多的证据表明，由 E/P 选择素配体表达（例如 CLA/PSGL-1）和整合素 α 4 β 7 缺失所识别的皮肤归巢记忆 T 细胞群介导皮肤中的抗原特异性效应器反应，而相互记忆 T 细胞亚群（整合素 α 4 β 7 阳性，E/P 选择配体阴性）介导胃肠道中的效应器反应 道（肠道）。 重要的是，这些记忆 T 细胞利用这些细胞表面分子启动毛细血管后微静脉内皮细胞的束缚和滚动（在生理流动条件下），这是它们在正常和发炎的皮肤或肠道中最终外渗所必需的。 这种极化的记忆细胞群被认为是在分别引流每个上皮表面的淋巴结的特殊淋巴微环境中的幼稚T细胞向记忆T细胞转变过程中出现的。 GVHD 是同种异体骨髓移植几乎不可避免的并发症。 GVHD 的大部分发病源于两个主要上皮与环境的界面：皮肤和肠道。 本提案测试了以下假设：具有相似抗原特异性的不同效应 T 细胞亚群介导皮肤和肠道 GVHC。 第二个可检验的假设是，记忆 T 细胞的这些极化子集部分来自移植的移植物幼稚 T 细胞，这些 T 细胞分别被引流肠道或皮肤的淋巴结中的同种抗原激活。 最后一个假设是，预处理方案的强度以两种方式影响这一过程。 首先，主要细胞因子释放引起的组织损伤和随之而来的炎症导致树突状细胞从血液中流出增加，从而通过传入淋巴管将受损的组织抗原携带至引流淋巴结。 其次，发炎皮肤和肠道内皮细胞上粘附分子表达的增加提高了记忆 T 细胞外渗的效率。这些假设中的每一个都将使用充分表征的小鼠模型同种异体 BMT（MHC 相同）进行直接测试。 产生的致命性 GVHD 取决于同种异体移植群体中的 T 细胞。 记忆和幼稚特异的抗体和阻断分子都依赖于 T 细胞归巢配体/受体对，以及缺乏一种或多种对这些粘附相互作用至关重要的基因（例如 E/P 选择蛋白、FucTVII、β7 整联蛋白）的转基因小鼠，将用于提出关于皮肤和肠道特异性进化的细胞和分子要求的精确和定向问题 分别是GVHD。 选择性改变涉及其中一种或两种组织的 GVHD 的能力，同时不抑制表面上有益的同种免疫反应（例如，移植物抗白血病或整体免疫能力）是本研究的长期治疗目标。