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）是使用同种异体干细胞移植成功治疗癌症的主要障碍。虽然人们早就知道GVHD是由供体骨髓中的T细胞引起的，这些T细胞会进入并损伤关键的靶器官（皮肤和鳞状黏膜、肝脏和肠道），但GVHD的发病机制仍然不清楚。这并不奇怪，当人们考虑到a)同种异体刺激的供体T细胞亚群的确切身份，b)受损器官内的特定靶细胞，以及c)这种损伤的机制直到最近才变得模糊。使用相关的实验性GVHD小鼠模型，同种异体刺激效应T细胞家族，通过其Vp T细胞受体的使用可识别，现在已被确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嵴状突起的尖端，在那里它们独特地表达细胞角蛋白15 （RLPK15细胞），并且与抗原呈递树突状细胞密切相关。这些靶细胞的死亡机制是细胞凋亡。因此，现在有可能鉴定和丰富那些特异性异位刺激的Vp效应T细胞家族，并利用它们来诱导实验性GVHD，现在可以鉴定、分离和研究特定亚群的靶细胞。使用这种方法，本提案主要关注与GVHD发病机制相关的三个基本问题，并最终转化为治疗策略；即：i)与k15阴性基底细胞相比，RLPK15靶细胞在各种GVHD效应途径的进化过程中是如何受到影响的；ii)损伤RLPK15靶细胞的特异性凋亡通路有哪些；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，我们将学到的信息可以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GVHD的细胞角蛋白15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