Antigen Presenting Cells in the Induction of GVHD

抗原呈递细胞在 GVHD 诱导中的作用

• 批准号: 7176119
• 负责人: STEPHEN G EMERSON
• 金额: $ 27.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176119
• 关键词: Alloantigen; Allogenic; Antigen-Presenting Cells; Antigens; Attention; B-Lymphocytes; Bone Marrow Stem Cell Transplantation; CD44 gene; CD8B1 gene; Cell Communication; Cell Survival; Cells; Characteristics; Clinical Trials; Commit; Dendritic Cells; Disease; Endothelial Cells; Goals; Hour; Human; Immune response; Immunosuppressive Agents; Inflammatory Response; Intervention; Major Histocompatibility Complex; Malignant - descriptor; Marrow; Mediating; Minor Histocompatibility Antigens; Molecular; Mus; Non-Malignant; Pathway interactions; Play; Prevention; Process; Prophylactic treatment; Reagent; Relative (related person); Research; Role; Signal Transduction; Staging; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Therapeutic; Thinking; Tissues; Toxic effect; base; cytokine; graft versus host disease induction; graft vs host disease; human stem cells; in vivo; inhibitor/antagonist; macrophage; mortality; mouse model; pre-clinical; prevent; programs; response

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.

描述（由申请人提供）：该研究项目的目标是了解移植物抗宿主病（GVHD）的分子和细胞基础，并利用这种理解来预防 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，在该模型中，我们证明宿主抗原呈递细胞 (APC) 会快速启动抗原特异性供体 T 细胞，这些细胞随后会导致表型 GVHD。此外，我们有新的证据表明 APC-T 细胞激活是一个多步骤过程，这可能允许通过针对每个激活步骤进行决定性干预。为了最直接地探索和利用这些发现，我们建议研究：1）不同的 APC 亚群（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 对启动的相对贡献移植物抗宿主病； 2) APC 刺激同种异体 T 细胞存活的免疫调节信号，这对于随后的体内 T 细胞激活、增殖和分化至关重要； 3)无论是体外选择宿主miHA激活的供体CD44hiCD8+T细胞，还是体内阻断APC-供体T细胞相互作用，都可以有效预防GVHD。这些研究将为针对 APC 预防 GVHD 的治疗方法奠定临床前基础。根据这些研究的结果，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，以预防临床试验中的GVHD。