T CELL HOMING IN GRAFT VERSUS HOST DISEASE

产品说明：（申请人的描述）记忆T细胞优先运输到不同上皮组织的能力最近才被认识到。 越来越多的证据表明，通过E/P选择素配体表达鉴定的皮肤归巢记忆T细胞群（例如，CLA/PSGL-1）和缺乏整联蛋白α 4 β 7介导皮肤中的抗原特异性效应子应答，而相互记忆T细胞亚群（整联蛋白α 4 β 7阳性，E/P选择配体阴性）介导胃肠道（肠道）中的效应子应答。 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微静脉中的内皮细胞上的束缚和滚动（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需的。 这种极化的记忆细胞群被认为是在幼稚T细胞向记忆T细胞转变期间分别在引流每个上皮表面的淋巴结的专门淋巴微环境中出现的。 GVHD是异基因骨髓移植几乎不可避免的并发症。 GVHD的大部分发病率来自于两个主要的上皮界面与环境的参与：皮肤和肠道。 本提案检验了具有相似抗原特异性的效应T细胞的不同亚群介导皮肤和肠道GVHC的假设。 第二个可验证的假设是，这些极化的记忆T细胞亚群部分来自转移的移植物幼稚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异体抗原激活。 最后一个假设是，条件反射疗法的强度以两种方式影响这一过程。 首先，来自初级细胞因子释放的组织损伤和伴随的炎症导致树突状细胞从血液中的流出增强，其通过传入神经系统将受损的组织抗原携带到引流淋巴结。 第二，炎症皮肤和肠道中内皮细胞上粘附分子表达的增加增强了记忆性T细胞外渗的效率。将使用充分表征的小鼠模型同种异体BMT（MHC相同）直接检验这些假设中的每一个。 导致的致死性GVHD依赖于同种异体移植群体中的T细胞。 特异于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，以及缺乏对这些粘附相互作用至关重要的一个或多个基因的转基因小鼠（例如，E/P选择素）、FucTVII、β 7整联蛋白）将分别用于提出关于皮肤和肠道特异性GVHD进化的细胞和分子要求的精确和定向问题。 选择性修饰涉及这些组织中的一个或两个的GVHD，同时不抑制表面上有益的同种免疫应答（例如，移植物抗白血病或整体免疫活性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.