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: 8119591
• 负责人: John Andrew Hansen
• 金额: $ 39.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8119591
• 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; Immunosuppression; Instruction; Interferon Type II; Interleukin-10; Lead; Life; Methods; Monitor; Morbidity - disease rate; Pathway interactions; Patients; Phenotype; Procedures; Process; Prophylactic treatment; Quality of life; Recurrence; Regulation; Regulatory T-Lymphocyte; 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; peripheral tolerance; 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 Some patients can be withdrawn from 1ST within 6 months of HCT, but most require 1ST for 2-3 years.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）是异基因造血干细胞移植受者的主要并发症 移植（HCT）。这个程序可以挽救生命，否则致命的疾病，但移植物抗宿主病是 与显著的发病率和死亡率相关。幸运的是，免疫耐受发生在 大多数患者尽管发展为急性和慢性GVHD。免疫抑制疗法 (1ST)在移植时给予所有患者，但治疗的持续时间是可变的。 一些患者可以在HCT后6个月内退出1ST，但大多数患者需要2-3年的1ST。 实现外周耐受的潜在机制包括通过免疫抑制的克隆缺失或耗竭。 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 调节性T细胞（Treg）抑制免疫反应。初步数据显示，Treg表达 活动性慢性GVHD患者血液中CD 4 + CD 25 + CD 12710表型降低 （cGVHD）在第一ST，他们往往增加与解决cGVHD的患者。FoxpS的表达 基因，调节性T细胞的功能标志物，也在活动性cGVHD患者中减少，但 在耐受患者中表达水平趋于增加。还有其他基因与免疫相关 在cGVHD患者中发现IL-10的过度表达。还有基因 与T细胞应答和效应功能相关，如IFNG和IL 17， 这些初步的数据使我们能够测试活动性GVHD患者和接受第一次ST的患者。 GVHD的控制需要多种调节机制。我们将使用微 阵列技术用于评估整体基因表达，并解决以下问题：（i） 鉴定来自HCT患者的T淋巴细胞和所选亚群的转录谱， 与不同阶段的cGVHD和1ST相关，并确定基因和途径， 区分患有活动性cGVHD的患者与实现免疫耐受的患者;和（ii） 确定患者中调节性T细胞的功能特征和再生能力 活动期和静止期cGVHD和耐受患者。深入了解患者体内发生的细胞变化 与活动和解决cGVHD可能会导致更好的方法来监测GVHD活动和指导 使用1ST，并提出促进耐受诱导的新策略。 相关性（参见说明）： 接受异基因造血细胞移植并存活的患者数量 疾病继续增加，然而这些患者中的许多人继续遭受GVHD。研究 这里提出的目的是了解正在进行的GVHD的因素， 负责免疫耐受的机制。了解这些过程可能会导致更多 有效的治疗干预，并改善移植幸存者的生活质量和健康。