Antigen Presenting Cells in the Induction of GVHD

抗原呈递细胞在 GVHD 诱导中的作用

基本信息

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
项目类别：
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

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

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项目摘要

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，并利用这种理解来防止GVHD引起的毒性和死亡率。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）快速抗原特异性供体T细胞，后来将继续引起表型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，可以通过针对这些激活步骤来决定性干预。为了最直接探索和利用这些发现，我们建议研究：1）不同APC亚群（树突状细胞，巨噬细胞，B细胞和活化的内皮细胞）的相对贡献，以及宿主与供体衍生的APC的相对贡献，对GVHD的启动； 2）APC刺激随后的T细胞激活，增殖和体内分化至关重要的同种异体T细胞存活的免疫调节信号； 3）在体内选择宿主MIHA鉴定的供体CD44HICD8+ T细胞，还是对APC-Donor T细胞linteractions的体内阻断，可以有效地防止GVHD。这些研究将建立针对预防GVHD的APC的治疗方法的临床前基础。基于这些研究的结果，我们的长期目标是开发适当的试剂，以针对细胞和/或分子水平在内的人类APC，包括DC和巨噬细胞，以防止在临床试验中GVHD。