Role of Tissue Antigen Presenting Cells in GVHD

描述(申请人提供)：异基因干细胞移植(AllSCT)可以治疗恶性血液病和非恶性血液病。同种异体移植T细胞是T细胞重建的关键，并介导了强大的抗白血病/淋巴瘤作用。不幸的是，供者T细胞可以广泛攻击受者，导致移植物抗宿主病(GVHD)。在尽量减少移植物抗宿主病的同时促进捐献者T细胞的积极作用的方法一直难以捉摸。许多GVHD研究集中在抗原提呈细胞(APC)最初如何启动次级淋巴组织(SLT)中的供体T细胞。然而，APC并不局限于SLT。组织浸润性抗原前体细胞(t-APC)在抗病原体和自身免疫反应中发挥重要作用。T-APC在功能和个体发育上是不同的，不同器官之间不同，并且与炎症有关。它们与T细胞在原位相互作用，并可以运输到引流的淋巴结处，在那里它们可以启动T细胞或将抗原转移到其他APC。虽然GVHD需要T细胞，但GVHD器官中的细胞浸润物中含有丰富的MHCII+t-APC。与t-APC在GVHD中的作用一致，CD4细胞可以间接介导GVHD，而不会使TCR：MHCII与靶组织接触；这些小鼠的组织学显示，CD4细胞与MHCII+造血细胞相邻。我们假设GVHD病变中的T细胞由t-APC局部激活，反之，t-APC由供者T细胞激活。为了支持这一假设，我们对活体小鼠的GVHD组织进行了多光子活体显微镜(MPIM)观察，证明供者的CD4+和CD8+T细胞与供者来源的CD11c+或LysM+细胞有稳定的相互作用。对T细胞和t-APC之间相互作用的详细了解应该会确定抑制GVHD的新靶点。我们建议使用新型荧光蛋白转基因小鼠、t-APC亚群可诱导缺失的小鼠骨髓和MPIM来研究t-APC在GVHD中的作用。具体地说，我们将：1)确定GVHD中t-APC的身份，并确定这些细胞是如何被招募的；2)检验T细胞与GVHD影响的皮肤和肠道中的t-APC进行抗原特异性稳定相互作用的假设；以及3)确定这些相互作用是否有助于GVHD。

DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (alloSCT) can cure hematologic malignancies and nonmalignant disorders of hematopoiesis. Allograft T cells are critical for T cell reconstitution and mediate a potent anti- leukemia/lymphoma effect. Unfortunately donor T cells can broadly attack the recipient causing graft-vs-host disease (GVHD). Methods of promoting the positive effects of donor T cells while minimizing GVHD have been elusive. Much GVHD research has focused on how antigen presenting cells (APCs) initially prime donor T cells in secondary lymphoid tissues (SLTs). However, APCs are not limited to SLTs. Tissue infiltrative APCs (t-APCs) that are resident and are recruited during inflammation play important roles in anti-pathogen and autoimmune responses. t-APCs are heterogeneous in function and ontogeny, differ from organ to organ, and with inflammation. They interact with T cells in situ and can traffic to draining lymph nodes where they can prime T cells or transfer antigen to other APCs. While T cells are required for GVHD, cellular infiltrates in organs with GVHD have abundant MHCII+ t-APCs. Consistent with a role for t-APCs in GVHD, CD4 cells can mediate GVHD indirectly, without making TCR:MHCII contacts with target tissues; histology in these mice reveal CD4 cells adjacent to MHCII+ hematopoietic cells. We hypothesize that T cells in GVHD lesions are activated locally by t-APCs and that conversely t-APCs are activated by donor T cells. In support of this hypothesis we have employed multiphoton intravital microscopy (MPIM) of GVHD tissues in living mice to demonstrate that donor CD4+ and CD8+ T cells make stable interactions with donor-derived CD11c+ or LysM+ cells. A detailed understanding of the interactions between T cells and t-APCs should identify new targets for suppressing GVHD. We propose to investigate t-APCs in GVHD using novel fluorescent protein-transgenic mice, bone marrow from mice in which t-APC subsets can be inducibly deleted and MPIM. Specifically we will: 1) define the identities of t-APCs in GVHD and determine how those cells are recruited; 2) test the hypothesis that T cells make antigen-specific stable interactions with t-APCs in skin and bowel affected by GVHD; and 3) determine whether these interactions contribute to GVHD.