Investigation of Regulatory T Cells in Veterans with Rheumatologic Disease

患有风湿病的退伍军人中调节性 T 细胞的研究

• 批准号: 8499020
• 负责人: Amit Golding
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499020
• 关键词: Address; Adrenal Cortex Hormones; Adverse effects; Advisory Committees; Affect; Allergic; Autoimmune Diseases; Autoimmune Process; Bacteria; Bioethics; Biometry; Biostatistical Methods; Blood Vessels; Brain; CD4 Positive T Lymphocytes; Caring; Cell surface; Cells; Cellular biology; Characteristics; Clinical; Clinical Research; Color; Commit; Cross-Sectional Studies; Cytokine Signaling; Data; Diagnosis; Disease; Dose; Effector Cell; Ensure; Environment; Epigenetic Process; Equilibrium; Female; General Population; Genes; Goals; Gold; Health; Heart; Homeostasis; Human; Human Identifications; Hypersensitivity; Immune; Immune System Diseases; Immune system; In Vitro; Infection; Inflammatory; Interferon Type I; Investigation; Joints; Kidney; Lead; Leukocytes; Lupus; Lymphocyte; Measures; Mediating; Mentors; Methods; Molecular; Molecular Biology; Mus; Nature; Occupations; Organ; Pathway interactions; Patients; Personal Satisfaction; Physicians; Population; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Research Methodology; Research Personnel; Research Technics; Research Training; Rheumatism; Role; Scientist; Severities; Signal Pathway; Steroid therapy; Steroids; Suppressor-Effector T-Lymphocytes; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Training; Translational Research; Veterans; Virus; Woman; Work; base; cytokine; demethylation; improved; innovation; middle age; new therapeutic target; novel marker; novel strategies; response; systemic autoimmune disease; trend

DESCRIPTION (provided by applicant): The proportion of females, in particular women of color, among veterans is increasing. This subset of veterans frequently develops lupus, a devastating systemic autoimmune disease. There is a need to understand the mechanism of lupus, and to train physician-scientists capable of managing this disease using innovative approaches. Recent research findings have suggested that a class of T lymphocytes called regulatory T cells (Tregs) is centrally involved in regulating the immune system in health and disease, including in veterans. Current approaches to identifying Tregs in humans are poorly developed, as FoxP3, the marker of these cells in mice, is not as reliable in humans. Our studies suggest that a new marker, Helios, combined with FoxP3 allows for reliable identification of human Tregs. Helios-positive Tregs are validated as committed Tregs by use of gold standard tests showing that they do not make immune-activating cytokines and also have full demethylation of the FoxP3 gene, in contrast to Helios-negative FoxP3-positive cells, which make cytokines and are only partially FoxP3 gene demethylated. We demonstrate that in patients with more clinically severe systemic lupus erythematosus, there is a trend toward a lower ratio between Helios-positive Tregs and Helios- negative FoxP3-positive cells. In addition, we have found that Helios-positive Tregs increase in direct correlation with steroid therapy in lupus patients with low to moderate clinical severity. Moreover, we have observed that an inflammatory environment high in Type I interferon inhibits regulatory T cells. Based on these observations, we hypothesize that using Helios in combination with FoxP3 for identification of Tregs provides a more reliable method to evaluate immune disturbance and response to therapy. We also hypothesize that Type I interferon suppresses Treg expansion and activation, which is likely reversed by corticosteroids. In the proposed study, we will assess the validity of these hypotheses by addressing the following Specific Aims. In Specific Aim 1, we will validate Helios, in combination with FoxP3, as a definitive marker of natural regulatory T cells by expanding our study of Tregs in a larger number of patients with systemic lupus erythematosus. In Specific Aim 2, we will assert that Type I interferon drives expansion of effector T cells at the expense of regulatory T cells. We wil determine the mechanism by which Type I interferon inhibits regulatory T cells. In Specific Aim 3, cross-sectional analyses will be performed to determine how steroids may promote Treg expansion and possibly reverse the negative effects of Type I interferon. The goal of this research is to improve the well-being of veterans, particularly female veterans, by identifying those lupus patients who could benefit from therapy specifically aimed at stimulating Tregs. By investigating the mechanisms by which Type I interferon suppresses human Tregs and the pathways by which steroids promote human Tregs, we hope to discover new therapeutic targets in the treatment of not only lupus, but also a variety of autoimmune, allergic, and inflammatory disorders prevalent among veterans. Simultaneously, this work will allow the candidate to establish himself as an independent physician-scientist with a research focus in the regulation of the immune system in order to ultimately improve the lives of patients. The training and mentoring plans outline the path toward this goal by proposing a specific plan of coursework in translational research, biostatistics, and bioethics. The proposed research plan will expose the applicant to new research techniques in molecular biology and receptor signaling under the expertise of his primary mentor, Dr. Sergei Atamas. Dr. Violeta Rus, the first co-mentor, will provide clinical and research expertise in the care and study of patients with SLE. Dr. Marc Hochberg, the second co-mentor, will provide guidance in translational research and biostatistical methods. In addition, an advisory committee composed of renowned experts in T cell biology, FoxP3 epigenetics, clinical research, and training of junior investigators will help ensure that the applicant succeeds in becoming an independent physician-scientist serving veterans.

描述(由申请人提供)： 退伍军人中女性，特别是有色人种女性的比例正在增加。这部分退伍军人经常患上狼疮，这是一种毁灭性的系统性自身免疫性疾病。有必要了解狼疮的发病机制，并培训能够使用创新方法管理这种疾病的内科科学家。最近的研究结果表明，一类名为调节性T细胞(Tregs)的T淋巴细胞在调节健康和疾病中的免疫系统方面发挥着核心作用，包括退伍军人。目前识别人类Tregs的方法还很不成熟，因为小鼠Tregs的标志物FoxP3在人类身上并不可靠。我们的研究表明，一种新的标记Helios与FoxP3相结合，可以可靠地识别人类Tregs。与太阳神阴性的FoxP3阳性细胞相比，Helios阳性的Treg细胞产生细胞因子，并且FoxP3基因只有部分去甲基化，而通过金标准测试，Helios阳性的Tregs被验证为承诺Treg，表明它们不产生免疫激活细胞因子，并且FoxP3基因完全去甲基化。我们证明，在临床上更严重的系统性红斑狼疮患者中，Helios阳性的Treg细胞和Helios阴性的FoxP3阳性细胞之间的比率有降低的趋势。此外，我们还发现，在临床严重程度从轻到中度的狼疮患者中，Helios阳性Tregs的增加与类固醇治疗直接相关。此外，我们还观察到，I型干扰素含量高的炎症环境抑制了调节性T细胞。基于这些观察，我们推测联合使用Helios和FoxP3来鉴定Tregs提供了一种更可靠的方法来评估免疫紊乱和治疗反应。我们还假设I型干扰素抑制Treg的扩张和激活，这可能被皮质类固醇逆转。在拟议的研究中，我们将通过解决以下具体目标来评估这些假设的有效性。在具体目标1中，我们将通过扩大我们对更多系统性红斑狼疮患者的Tregs研究，验证Helios与FoxP3联合作为自然调节性T细胞的明确标记。在具体目标2中，我们将断言I型干扰素以调节T细胞为代价驱动效应性T细胞的扩张。我们将确定I型干扰素抑制调节性T细胞的机制。在具体目标3中，将进行横断面分析，以确定类固醇如何促进Treg的扩张，并可能逆转I型干扰素的负面影响。这项研究的目标是通过确定哪些狼疮患者可以从专门旨在刺激Tregs的治疗中受益，来改善退伍军人，特别是女退伍军人的福祉。通过研究I型干扰素抑制人类Tregs的机制和类固醇促进人类Tregs的途径，我们希望发现新的治疗靶点，不仅可以治疗狼疮，还可以治疗退伍军人中流行的各种自身免疫性、过敏性和炎症性疾病。同时，这项工作将使候选人能够将自己确立为一名独立的内科科学家，专注于免疫系统调节的研究，以最终改善患者的生活。培训和指导计划通过提出翻译研究、生物统计学和生物伦理学的具体课程计划，勾勒出通向这一目标的道路。拟议的研究计划将使申请者在其主要导师谢尔盖·阿塔马斯博士的专业知识下，接触到分子生物学和受体信号转导方面的新研究技术。Violeta Rus博士是第一位共同导师，他将在SLE患者的护理和研究方面提供临床和研究专业知识。第二位共同导师Marc Hochberg博士将在翻译研究和生物统计学方法方面提供指导。此外，由T细胞生物学、FoxP3表观遗传学、临床研究和初级调查人员培训方面的知名专家组成的咨询委员会将有助于确保申请人成功成为一名为退伍军人服务的独立内科科学家。