Regulatory T Cells in Graft-versus-Host Disease

移植物抗宿主病中的调节性 T 细胞

• 批准号: 7676416
• 负责人: John Andrew Hansen
• 金额: $ 38.65万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676416
• 关键词: Acute; Address; Allogenic; Blood; Cell Death; Cell Transplantation; Cell Transplants; Cells; Characteristics; Clinical; Clonal Anergy; Clonal Deletion; Complication; Data; Development; Disease; Gene Expression; Genes; Goals; Health; Hematopoietic; IL17 gene; Immune; Immune response; Immunobiology; Instruction; Interferon Type II; Interleukin-10; Lead; Life; Methods; Monitor; Morbidity - disease rate; Pathway interactions; Patients; Peripheral; Phenotype; Procedures; Process; Prophylactic treatment; Quality of life; Recurrence; Regulation; Staging; Survivors; T-Lymphocyte; Technology Assessment; Testing; Therapeutic Intervention; Time; Transplant Recipients; Transplantation; anergy; chronic graft versus host disease; clinically significant; exhaustion; graft vs host disease; improved; insight; mortality; regenerative; therapy duration

Graft-versus host disease (GVHD) is a major complication in recipients of allogeneic hematopoietic cell transplants (HCT). This procedure can be life saving for otherwise fatal disease, however GVHD is associated with significant morbidity and mortality. Fortunately, immunological tolerance occurs in a majority of patients despite the.development of acute and chronic GVHD. Immune suppression therapy (1ST) is administered to all patients at the time of transplantation, but the duration of therapy is variable. Some patients can be withdrawn from 1ST within 6 months of HCT, but most require 1ST for 2-3 years. Potential mechanisms for achieving peripheral tolerance include clonal deletion or exhaustion through activation-induced cell death, development of clonal anergy or non-responsiveness, and development of regulatory T cells (Treg) that suppress the immune response. Preliminary data shows that Treg expressing the CD4+CD25+CD12710 phenotype are decreased in the blood of patients with active chronic GVHD (cGVHD) on 1ST,and they tend to increase in patients with resolving cGVHD. Expression of the FoxpS gene, a functional marker for regulatory T cells, is also decreased in patients with active cGVHD, but expression levels tend to increase in tolerant patients. There are also other genes associated with immune regulation such as IL10 that are found variably expressed in cGVHD patients. There are also genes associated with T cell responder and effector functions such as IFNG and IL17 that are variably expressed in patients with active GVHD and patients receiving 1ST.These preliminary data lead us to test the hypothesis that multiple regulatory mechanisms are required for the control of GVHD. We will use micro array technology for the assessment of global gene expression and address the following questions: (i) identify the transcriptional profiles of T lymphocytes and selected subsets from HCT patients that are associated with the different stages of cGVHD and with 1ST,and identify the genes and pathways that distinguish patients with active cGVHD from patients achieving immunological tolerance; and (ii) determine the functional characteristics and regenerative capacity of regulatory T cells in patients with active and quiescent cGVHD and tolerant patients. Insight into the cellular changes occurring in patients with active and resolving cGVHD may lead to better methods for monitoring GVHD activity and guiding the use of 1ST,and suggest new strategies for facilitating the induction of tolerance. RELEVANCE (See instructions): The number of patients receiving allogeneic hematopoietic cell transplants and surviving otherwise fatal disease continues to increase, however many of these patients continue to suffer from GVHD. The studies proposed here are aimed at understanding the factors responsible for ongoing GVHD and the mechanisms responsible for immunological tolerance. Understanding these processes may lead to more effective therapeutic interventions, and improve the quality of life and health of transplant survivors.

移植物与宿主疾病（GVHD）是同种异体造血细胞接受者的主要并发症 移植（HCT）。该程序可以为其他致命疾病挽救生命，但是GVHD是 与明显的发病率和死亡率相关。幸运的是，免疫耐受性发生在 尽管急性和慢性GVHD开发了大多数患者。免疫抑制疗法 （第1）在移植时对所有患者施用，但治疗持续时间是可变的。 一些患者可以在HCT的6个月内从第1位撤回，但大多数需要2 - 3年。 实现外围耐受性的潜在机制包括克隆删除或精疲力尽 激活诱导的细胞死亡，克隆语音的发育或无反应性以及发展 调节T细胞（Treg）抑制免疫反应。初步数据表明Treg表达 活性慢性GVHD患者的血液中CD4+CD25+CD12710表型降低 （CGVHD）在第1位，而解决CGVHD的患者往往会增加。狐狸的表达 基因是调节性T细胞的功能标记，活性CGVHD患者也有所降低，但 耐受性患者的表达水平往往会增加。还有其他与免疫相关的基因 在CGVHD患者中发现的调节，例如IL10。也有基因 与T细胞响应器和效应子函数（例如IFNG和IL17）相关的可变表达 在活跃GVHD和接受第一名患者的患者中。这些初步数据导致我们测试 假设控制GVHD需要多种调节机制。我们将使用微型 用于评估全球基因表达的阵列技术并解决以下问题：（i） 确定T淋巴细胞的转录曲线和来自HCT患者的选定子集 与CGVHD的不同阶段和第1阶段相关，并确定基因和途径 区分活性CGVHD的患者与获得免疫耐受性的患者； （ii） 确定调节性T细胞的功能特征和再生能力 活跃和静止的CGVHD和耐受性患者。洞悉患者的细胞变化 通过主动和解决的CGVHD，可能会导致更好的方法来监视GVHD活动并指导 使用第一，并提出新的策略来促进耐受性的诱导。 相关性（请参阅说明）： 接受同种异性造血细胞移植和致命存活的患者人数 疾病继续增加，但是其中许多患者继续患有GVHD。研究 这里提出的旨在了解负责持续GVHD的因素和 负责免疫耐受性的机制。了解这些过程可能会导致更多 有效的治疗干预措施，并改善移植幸存者的生活质量和健康。