Role of Functionally Distinct Dendritic Cell Subsets in Tolerance and GVHD

项目4：不同功能的树突状细胞亚群在耐受性和移植物抗宿主中的作用 疾病我们最近发现，效应性T细胞亚群，包括THI、TH2和Treg细胞，可以诱导单核细胞分化为树突状细胞(DC)，树突状细胞又分别选择性地诱导初始T细胞形成THI、TH2和Treg细胞。我们推测，这种迄今未知的免疫调节机制可能在控制保护性免疫中发挥重要作用，包括促炎反应和耐受诱导，以及移植物抗宿主病(GVHD)中的病理性免疫。我们进一步认为，靶向和/或操纵这些新的DC亚群来治疗或预防这种疾病是可能的。本项目的总体目标是评估免疫调节性树突状细胞(DCrreg)在造血干细胞受者免疫耐受和GVHD中的可能作用。 有或没有器官移植的移植，并确定诱导形成和调节这些树突状细胞功能的分子。为了实现这些目标，将通过1)评估和比较免疫耐受与不免疫耐受的移植受者血液和肾脏中T细胞和非T抗原提呈细胞的表型、功能和基因表达谱，2)使用中和抗体和基因表达谱来确定由Treg细胞表达的负责诱导单核细胞分化为DCxreg的关键因素，以及DCrreg表达的负责诱导由初始T细胞形成Treg细胞的关键因素，以及3)在急性GVHD和器官移植耐受的小鼠模型中评估DCrreg以及DCrreg诱导的Treg细胞的作用。该项目高度依赖于与项目1和3以及核心B和C的互动，这些核心是临床材料、小鼠模型以及免疫和基因图谱分析的来源， 分别进行了分析。该项目的成功最终将导致在异体移植环境中实现免疫耐受的更安全和更有效的方法。

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.