Antigen Presenting Cells in the Induction of GVHD

描述(由申请人提供)：本研究计划的目标是了解移植物抗宿主病(GVHD)的分子和细胞基础，并利用这一了解来预防GVHD引起的毒性和死亡率。这一应用利用了人类干细胞移植的小鼠模型，在该模型中，我们已经证明宿主抗原提呈细胞(APC)快速启动抗原特异性供体T细胞，这些T细胞随后将导致表型GVHD。此外，我们有新的证据表明，APC-T细胞的激活是一个多步骤的过程，这可能允许通过针对每个激活步骤进行决定性的干预。为了更直接地探索和利用这些发现，我们建议调查：1)不同的APC亚群(树突状细胞、巨噬细胞、B细胞和激活的内皮细胞)以及宿主和供体来源的APC对启动GVHD的相对贡献；2)APC刺激同种异体T细胞存活的免疫调节信号，这些信号对于随后的T细胞在体内的激活、增殖和分化是必不可少的；以及3)体外选择宿主混合供体CD44hiCD8 T细胞，或者在体内阻断APC与供体T细胞的相互作用，是否可以有效地预防GVHD。这些研究将为针对APC的治疗方法预防移植物抗宿主病奠定临床前基础。基于这些研究的结果，我们的长期目标是开发合适的试剂，在细胞和/或分子水平上靶向人类APC，包括DC和巨噬细胞，以在临床试验中预防GVHD。

DESCRIPTION (provided by applicant): The goals of this research program are to understand the molecular and cellular basis of graft-versus-host disease (GVHD), and to use this understanding to prevent the toxicity and mortality caused by GVHD. This application takes advantage of mouse models of human stem cell transplantion, in which we have shown that host antigen presenting cells (APCs) rapidly prime antigen-specific donor T cells that will later go on to cause phenotypic GVHD. Moreover, we have new evidence that APC-T cell activation is a multi-step process, which may allow decisive intervention by targeting each of these activation steps. To most directly explore and exploit these findings, we propose to investigate: 1) The relative contributions of distinct APC subsets (dendritic cells, macrophages, B cells, and activated endothelial cells), and of host- versus donor-derived APCs, to initiating GVHD; 2) The immunoregulatory signals by which APCs stimuate allogeneic T cell survival essential for subsequent T cell activation, proliferation and differentiation in vivo; and 3) Whether ex vivo selection of host miHA-acivated donor CD44hiCD8+ T cells, or in vivo blockade of APC-donor T cell linteractions, can effectively prevent GVHD. These studies will establish the preclinical basis for therapeutic approaches targeting APCs for the prevention of GVHD. Based upon the results of these studies, our long-term goal is to develop the appropriate reagents to target human APCs, including DCs and macrophages, at the cellular and/or molecular levels, to prevent GVHD in clinical trials.