T CELL HOMING IN GRAFT VERSUS HOST DISEASE

（申请人描述）记忆t细胞优先转运到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，通过E/P选择素配体表达（例如CLA/PSGL-1）和整合素α 4 β 7缺失鉴定的皮肤归巢记忆t细胞群介导皮肤中抗原特异性效应反应，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（肠道）中的效应反应。重要的是，这些记忆t细胞使用这些细胞表面分子来启动毛细血管后小静脉内皮细胞的捆绑和滚动（在生理流动条件下），这是正常和炎症皮肤或肠道最终外渗所必需的。这种极化的记忆细胞群被认为是分别在引流每个上皮表面的淋巴结的特化淋巴微环境中，在幼稚t细胞向记忆t细胞转变的过程中出现的。GVHD几乎是同种异体骨髓移植不可避免的并发症。许多GVHD的发病源于与环境的两个主要上皮界面的参与：皮肤和肠道。目前的提议验证了具有相似抗原特异性的不同亚群效应t细胞介导皮肤和肠道GVHC的假设。第二个可验证的假设是，这些记忆t细胞的极化亚群部分来自移植物的幼稚t细胞，它们分别在引流肠道或皮肤的淋巴结中被同种异体抗原激活。最后一个假设是，条件调理方案的强度以两种方式影响这一过程。首先，原细胞因子释放引起的组织损伤和随之而来的炎症导致血液中树突状细胞的输出增强，树突状细胞通过传入淋巴管将受损的组织抗原携带到引流淋巴结。其次，炎症皮肤和肠道内皮细胞黏附分子表达的增加，提高了记忆t细胞外渗的效率。每个假设都将使用具有良好特征的同种异体BMT小鼠模型（MHC相同）进行直接测试。致死性移植物抗宿主病的结果依赖于同种异体移植物群体中的t细胞。特异性记忆和幼稚的抗体和阻断分子都依赖于t细胞归巢配体/受体对，以及缺乏一个或多个对这些粘附相互作用至关重要的基因的转基因小鼠（例如，E/P选择素），FucTVll， β 7整合素)，将分别用于提出关于皮肤和肠道特异性GVHD进化的细胞和分子需求的精确和定向问题。在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）的情况下，选择性修饰涉及这些组织的GVHD的能力是本研究的长期治疗目标。

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.