Cellular Pathology of Graft Versus Host Disease

描述(由申请人提供)：急性移植物抗宿主病(GVHD)是使用异基因干细胞移植成功治疗癌症的主要障碍。虽然早就知道GVHD是由供者骨髓中的T细胞引起的，这些T细胞是关键的靶器官(皮肤和鳞状粘膜、肝脏和肠道)的宿主和损伤，但GVHD的发病机制仍然不清楚。当人们考虑到a)异基因刺激的供者T细胞亚群，b)器官内特定的靶细胞，c)这种损伤的确切机制(S)直到最近还不清楚时，这就不足为奇了。利用相关的实验性GVHD小鼠模型，异体刺激效应T细胞家族，可通过其VP T细胞受体的使用来鉴定，现在已被鉴定为上皮靶细胞损伤的特异性效应细胞。此外，靶细胞位于小鼠舌网状突起的顶端，在那里它们独特地表达细胞角蛋白15(RLPK15细胞)，并与抗原提呈树突状细胞密切相关。这些靶细胞的死亡机制被发现是细胞凋亡。因此，现在有可能鉴定和丰富那些被特异性同种异体刺激的VP效应T细胞家族，并利用它们来诱导实验性GVHD，其中特定的靶细胞亚群现在可以被识别、分离和研究。利用这一方法，这一建议集中在与GVHD发病机制和最终的翻译治疗策略密切相关的三个基本问题上；即：i)与K15阴性的基底细胞相比，RLPK15靶细胞在各种GVHD效应通路的演变过程中是如何受到影响的；ii)损伤RLPK15靶细胞的特定凋亡途径是什么；以及iii)外周共刺激如何影响RLPK15细胞的凋亡？除了进一步定义GVHD的基本病理生物学外，我们将了解到的信息可能为新的治疗策略铺平道路，即将保护性转基因特异性地引入表达细胞角蛋白15的GVHD靶细胞。

DESCRIPTION (provided by applicant): Acute graft-versus-host disease (GVHD) is a major obstacle to successful cancer therapy using allogeneic stem cell transplantation. Although it has long been known that GVHD is caused by T cells in the donor marrow that home to and injure critical target organs (skin and squamous mucosae, liver, and gut), the pathogenesis of GVHD has remained obscure. This is not surprising when one considers that the precise identity of a) subpopulations of donor T cells that are allostimulated, b) the specific target cells within the organs that are injured, and c) the very mechanism(s) of this injury have until recently been obscure. Using a relevant murine model of experimental GVHD, families of allostimulated effector T cells, identifiable via their Vp T cell receptor usage, now have been identified as specific effectors of epithelial target cell injury. Moreover, the targeted cells reside at the tips of murine lingual rete ridge-like prominences where they distinctively express cytokeratin 15 (RLPK15 cells) and where they are intimately associated with antigen- presenting dendritic cells. The mechanism of the demise of these target cells was found to be apoptosis. Thus, it is now possible to identify and enrich those Vp effector T cell families that are specifically allostimulated and employ them to induce experimental GVHD where specific subpopulations of targets cells may now be identified, isolated, and studied. Using this approach, this proposal is focused on three fundamental questions germane to GVHD pathogenesis, and ultimately to translational strategies for therapy; namely: i) how are RLPK15 target cells, as compared to K15-negative basal cells, influenced during the evolution of various GVHD effector pathways; ii) what are the specific apoptotic pathways that injure RLPK15 target cells; and iii) how does peripheral costimulation influence apoptosis of RLPK15 cells? Aside from further defining the basic pathobiology of GVHD, the information we will learn could pave the way for novel therapeutic strategies whereby protective transgenes are introduced specifically into cytokeratin 15- expressing GVHD target cells