Antigen Presenting Cells in the Induction of GVHD

描述（由申请人提供）：本研究项目的目的是了解移植物抗宿主病（GVHD）的分子和细胞基础，并利用这种了解来预防GVHD引起的毒性和死亡。该应用利用了人类干细胞移植的小鼠模型，其中我们已经表明宿主抗原呈递细胞（APC）快速引发抗原特异性供体T细胞，这些T细胞随后将继续引起表型GVHD。此外，我们有新的证据表明APC-T细胞活化是一个多步骤的过程，这可能允许通过靶向这些活化步骤中的每一个进行决定性干预。为了最直接地探索和利用这些发现，我们建议调查：1）不同APC亚群的相对贡献（树突状细胞、巨噬细胞、B细胞和活化的内皮细胞）以及宿主与供体来源的APC的免疫调节信号，以引发GVHD; 2）APC刺激同种异体T细胞存活的免疫调节信号，所述同种异体T细胞存活对于随后的体内T细胞活化、增殖和分化是必需的;（3）无论是体外选择miHA活化的供体CD 44 hiCD 8 + T细胞，还是体内阻断APC-供体T细胞相互作用，都能有效预防GVHD。这些研究将为靶向APC预防GVHD的治疗方法建立临床前基础。基于这些研究的结果，我们的长期目标是在细胞和/或分子水平上开发靶向人APC（包括DC和巨噬细胞）的适当试剂，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.