T CELL HOMING IN GRAFT VERSUS HOST DISEASE

描述：(申请人描述)记忆性T细胞优先运输到不同的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(如CLA/PSGL-1)和缺乏整合素α4β7确定的皮肤归巢记忆T细胞群在皮肤中介导抗原特异性效应反应，而相互作用的记忆T细胞亚群(整合素α4β7阳性，E/P选择配体阴性)介导胃肠道(GUT)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(在生理流动条件下)对毛细血管后小静脉内皮细胞的拴系和滚动，这是它们在正常和炎症的皮肤或肠道中最终渗出所必需的。这种两极分化的记忆细胞群体被认为是在幼稚到记忆T细胞的转变过程中出现的，分别出现在引流每个上皮表面的淋巴结的特殊淋巴微环境中。移植物抗宿主病是异基因骨髓移植几乎不可避免的并发症。GVHD的发病率很大程度上源于与环境的两个主要上皮界面的参与：皮肤和肠道。目前的建议验证了一种假设，即具有相似抗原特异性的不同亚群的效应性T细胞介导了皮肤和肠道GVHC。第二个可检验的假设是，这些极化的记忆T细胞亚群S部分来自移植的原始T细胞，这些细胞分别被同种异体抗原激活在引流肠道或皮肤的淋巴结中。最后一个假设是，调理疗法的强度对这一过程有两方面的影响。首先，组织损伤和主要细胞因子释放引起的炎症导致树突状细胞从血液中排出的增加，这些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上黏附分子的表达增加，提高了记忆T细胞外溢的效率。这些假说中的每一个都将使用特征良好的小鼠异基因骨髓移植(MHC相同)进行直接测试。致命性GVHD的结果取决于同种异体移植人群中的T细胞。针对记忆和NAIVE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连相互作用至关重要的基因(例如，E/P选择素、FucTV11、β7整合素)的转基因小鼠，将分别被用于询问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直接的问题。选择性地修饰涉及其中一个或两个组织的移植物抗宿主病的能力，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全球免疫活性)是这项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.