Role of Functionally Distinct Dendritic Cell Subsets in Tolerance and GVHD

功能不同的树突状细胞亚群在耐受性和 GVHD 中的作用

• 批准号: 8375902
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 27.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8375902
• 关键词: Acute Graft Versus Host Disease; Alloantigen; Allografting; Antibodies; Antigen-Presenting Cells; B-Lymphocytes; Biological Assay; Blood; CD14 gene; CD19 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD40 Antigens; CD80 gene; CD8B1 gene; Cell Lineage; Cells; Clinical; Clinical Trials; Coculture Techniques; Color; Dendritic Cells; Disease; Fluorescein-5-isothiocyanate; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; HLA-DR Antigens; Haplotypes; Histocompatibility Antigens Class I; Homologous Transplantation; IL2RA gene; IL3RA gene; IL7R gene; ITGAX gene; Immune; Immune Tolerance; Immunity; Immunologics; Immunosuppressive Agents; Immunotherapy; Kidney; Kidney Transplantation; Lead; Mediating; Modeling; Molecular Profiling; Monoclonal Antibodies; Mononuclear; Mus; Myelogenous; NCAM1 gene; Natural Killer Cells; Nature; Organ Transplantation; Pathologic; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Play; Regulatory T-Lymphocyte; Role; Sorting - Cell Movement; Source; Staining method; Stains; Stem cell transplant; Surface; T-Lymphocyte; T-Lymphocyte Subsets; TFRC gene; Transplant Recipients; Transplantation; base; cell preparation; cell type; clinical material; cohort; cytokine; functional status; graft vs host disease; interleukin-12 receptor; monocyte; mouse model; neutralizing antibody; novel; peripheral blood; prevent; research study; response; success

Project 4. Role of Functionally Distinct Dendritic Cell Subsets in Tolerance and Graft-Versus-Host Disease We recently discovered that effector T cell subsets, including THI, TH2 and Treg cells, can induce monocytes to differentiate into dendritic cells (DCs) that, in turn, selectively induce the formation of THI, TH2 and Treg cells from naive T cells, respectively. We hypothesize that this heretofore unknown immunoregulatory mechanism may play an important role in the control of protective immunity, including proinflammatory responses and tolerance induction, as well as pathologic immunity such as that seen in graft versus host disease (GVHD). We further believe that it may be possible to target and /or manipulate these novel DC subsets to treat or prevent such disorders. The overall goals of this project are to assess the possible role of immunoregulatory DCs (DCrreg) in immune tolerance and GVHD in recipients of hematopoetic stem cell transplants with or without organ transplants, and identify molecules that induce the formation and mediate the functions of these DCs. These goals will be pursued by 1) assessing and comparing the phenotypic, functional and gene expression profiles of T cells and non-T antigen presenting cells in the blood and kidneys of transplant recipients who are immunologically tolerant of their grafts versus those who are not, 2) using neutralizing antibodies and gene expression profiling to identify key factors expressed by Treg cells that are responsible for inducing monocytes to differentiate into DCxreg, as well as the key factors expressed by DCrreg that are responsible for inducing the formation of Treg cells from naive T cells, and 3) evaluating the effects of DCrreg, as well as Treg cells induced by DCrreg, in a murine model of acute GVHD and organ transplant tolerance. This Project is highly dependent on interactions with Projects 1 and 3 as well as Cores B and C, which are the sources of clinical materials, mouse models and immune and gene profiling assays, respectively. Success in this project should ultimately lead to safer and more effective ways to achieve immune tolerance in the setting of allogeneic transplantation.

项目4。功能不同的树突状细胞亚群在免疫耐受和移植物抗宿主中的作用 我们最近发现，效应T细胞亚群，包括TH 1、TH 2和Treg细胞，可以诱导单核细胞分化成树突细胞（DC），树突细胞（DC）进而分别选择性地诱导来自初始T细胞的TH 1、TH 2和Treg细胞的形成。我们推测，这种迄今未知的免疫调节机制可能在保护性免疫的控制中发挥重要作用，包括促炎反应和耐受诱导，以及病理性免疫，如移植物抗宿主病（GVHD）。我们进一步相信，有可能靶向和/或操纵这些新的DC亚群来治疗或预防此类疾病。本课题的总体目标是探讨免疫调节性DCs（DCrreg）在造血干细胞移植受者免疫耐受和GVHD中的作用 有或没有器官移植的移植，并鉴定诱导这些DC形成和介导这些DC功能的分子。这些目标将通过以下方式实现：1）评估和比较T细胞和非T抗原呈递细胞在移植受体的血液和肾脏中的表型、功能和基因表达谱，所述移植受体对其移植物具有免疫耐受性，而所述移植受体对其移植物不具有免疫耐受性，（二）使用中和抗体和基因表达谱来鉴定由Treg细胞表达的负责诱导单核细胞分化成DCxreg的关键因子，以及由DCrreg表达的负责诱导由初始T细胞形成Treg细胞的关键因子，和3）评估DCrreg以及由DCrreg诱导的Treg细胞在急性GVHD和器官移植耐受性的鼠模型中的作用。本项目高度依赖于与项目1和3以及核心B和C的相互作用，这些核心是临床材料、小鼠模型以及免疫和基因分析测定的来源， 分别该项目的成功最终将导致在同种异体移植中实现免疫耐受的更安全和更有效的方法。