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 Some patients can be withdrawn from 1ST within 6 months of HCT, but most require 1ST for 2-3 years.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)是异基因造血细胞移植受者的主要并发症 移植(HCT)。对于其他致命的疾病，这一过程可以挽救生命，但GVHD 与严重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移植物抗宿主病。免疫抑制疗法 (1)在移植时适用于所有患者，但疗程各不相同。 一些患者可以在HCT后6个月内退出第一阶段，但大多数患者需要在2-3年内退出第一阶段。 获得外周耐受的潜在机制包括克隆性缺失或通过 激活诱导的细胞死亡，克隆性无能或无反应性的发展，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 慢性移植物抗宿主病活动期患者外周血中CD4+CD25+CD12710表型降低 (CGVHD)，且在cGVHD消退的患者中有增加的趋势。FoxpS的表达 调节性T细胞的功能标志基因在活动期cGVHD患者中也降低，但 在耐受性患者中，表达水平往往会增加。还有其他与免疫相关的基因。 在cGVHD患者中发现可变表达的调节，如IL10。也有基因 与可变表达的T细胞应答和效应器功能相关，如IFNG和IL17 在活动期GVHD患者和接受1ST的患者中。这些初步数据使我们测试 假设GVHD的控制需要多种调控机制。我们将使用Micro 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HCT患者T淋巴细胞和选定的亚群的转录图谱 与cGVHD不同阶段和第一阶段相关，并确定与 区分活动性cGVHD患者与获得免疫耐受的患者；及(Ii) 慢性阻塞性肺疾病患者调节性T细胞功能特征及再生能力的测定 活动性和静止性cGVHD和耐受性患者。对患者体内细胞变化的洞察 有了cGVHD的积极和解决可能导致更好的方法来监测GVHD的活动和指导 使用第一，并提出新的策略，以促进耐受性的诱导。 相关性(请参阅说明)： 接受异基因造血细胞移植并在其他情况下死亡的患者数量 疾病继续增加，但这些患者中的许多人继续患有移植物抗宿主病。这些研究 在此提出的建议旨在了解导致持续GVHD和 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，改善移植幸存者的生活质量和健康。