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 Some patients can be withdrawn from 1ST within 6 months of HCT, but most require 1ST for 2-3 years.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.

移植物抗宿主病（GVHD）是同种异体造血细胞受者的主要并发症 移植（HCT）。该手术可以挽救其他致命疾病的生命，但 GVHD 是 与显着的发病率和死亡率相关。幸运的是，免疫耐受发生在 大多数患者尽管发生了急性和慢性 GVHD。免疫抑制治疗 (1ST) 在移植时对所有患者进行，但治疗持续时间各不相同。 有些患者可以在 HCT 后 6 个月内退出 1ST，但大多数患者需要 1ST 2-3 年。 实现外周耐受的潜在机制包括通过克隆删除或耗尽 激活诱导的细胞死亡、克隆无反应性或无反应性的发展以及 抑制免疫反应的调节性 T 细胞 (Treg)。初步数据显示，Treg 表达 活动性慢性 GVHD 患者血液中 CD4+CD25+CD12710 表型降低 (cGVHD) 第一天，并且在解决 cGVHD 的患者中它们往往会增加。 FoxpS的表达 基因（调节性 T 细胞的功能标记）在活动性 cGVHD 患者中也减少，但 耐受患者的表达水平往往会增加。还有其他与免疫相关的基因 IL10 等调节因子在 cGVHD 患者中的表达存在差异。还有基因 与不同表达的 IFNG 和 IL17 等 T 细胞应答器和效应器功能相关 在患有活动性 GVHD 的患者和接受 1ST 的患者中。这些初步数据使我们能够测试 假设控制 GVHD 需要多种调节机制。我们将使用微 用于评估全局基因表达的阵列技术并解决以下问题：（i） 鉴定 T 淋巴细胞的转录谱以及来自 HCT 患者的选定亚群 与 cGVHD 和 1ST 的不同阶段相关，并确定基因和途径 区分患有活动性 cGVHD 的患者和实现免疫耐受的患者； (二) 确定患者调节性 T 细胞的功能特征和再生能力 活动性和静止性cGVHD以及耐受性患者。洞察患者发生的细胞变化 积极和解决 cGVHD 可能会带来更好的方法来监测 GVHD 活动并指导 使用 1ST，并提出促进耐受诱导的新策略。 相关性（参见说明）： 接受同种异体造血细胞移植并幸存的患者人数 疾病继续增加，然而其中许多患者仍然患有 GVHD。研究 这里提出的建议旨在了解导致持续 GVHD 的因素以及 负责免疫耐受的机制。了解这些过程可能会带来更多 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。