Epigenetic Control of T cell Autoimmunity

T 细胞自身免疫的表观遗传控制

• 批准号: 7914393
• 负责人: Daniel L Mueller
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914393
• 关键词: 5' -Nucleotidase; Adoptive Transfer; Antigens; Arthritis; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Behavior monitoring; Biological Markers; CD4 Positive T Lymphocytes; Clinical Trials Design; Clonal Anergy; Complex; Development; Disease; Epigenetic Process; Gene Expression; Genes; Glucosephosphate Isomerase; Histocompatibility Antigens Class II; Human; Immune Tolerance; Immune system; Immunosuppression; Individual; Infection; Inflammation; Investigation; Knowledge; Lymphocyte; Lymphopenia; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Monitor; Mus; Peripheral; Play; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Risk; Role; Series; Surface; T cell response; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic Intervention; Transgenic Organisms; Work; anergy; autoreactive T cell; chromatin modification; design; effective therapy; genome wide association study; immune self tolerance; immunoregulation; in vivo; mouse model; new therapeutic target; novel; preclinical study; public health relevance; research study; systemic autoimmune disease; therapeutic target; therapy design; tool

Effective control of systemic autoimmune diseases such as rheumatoid arthritis (RA) currently relies on the use of intense generalized immunosuppression, thus increasing the risk of infection and malignancy. A better theoretical approach to the treatment of autoimmune disease is the induction of an antigen-specific tolerance that targets only the dangerous self-reactive T and B cells. The design of such effective therapies with the potential to cure autoimmune disease, however, is hampered by our inability to visualize and study those self antigen-specific polyclonal lymphocytes within the intact immune system. Furthermore, we lack sufficient knowledge regarding the induction of clonal anergy in lymphocytes that are already responding to self antigens within the diseased individual. Finally, our typical candidate approach to the identification of new therapeutic targets is an inherently slow process that can be adversely influenced by preconceived notions about the molecular mechanisms that are important to the induction of anergy. We now propose a series of pre-clinical studies that will make use of emerging antigen/class II tetramer technologies to track polyclonal CD4+ T cells that break immune tolerance and cause autoimmunity. Specific Aim 1 will investigate the individual roles of NT5'E and Foxp3 in the development and maintenance of clonal anergy following initial self antigen encounter by polyclonal CD4+ T cells in the peripheral immune system. Ecto-5'-nucleotidase (NT5'E), a novel candidate anergy factor discovered using a genome-wide screen for chromatin modifications in association with changes in gene expression, will be evaluated for its role in the control of clonal anergy development and maintenance of antigen unresponsiveness. Specific Aim 2 will establish the role of clonal anergy in the epigenetic changes that protect against the development of CD4+ T cell-mediated arthritis. Experiments under this aim will model RA using an adoptive transfer of KRN TCR-transgenic T cells reactive to the natural autoantigen glucose-6-phosphate isomerase (GPI), and investigate in the setting of systemic inflammation or lymphopenia the roles of NT5'E and Foxp3+CD4+ T regulatory cells in the epigenetic control of clonal anergy induction. In addition to increasing our fundamental knowledge about the regulation of anergy induction by NT5'E and immunoregulation in vivo, the results obtained with the class II tetramers will also serve as a paradigm for the development of biomarkers for use in human trials designed to target autoreactive CD4+ T cells for clonal anergy induction. Furthermore, our ongoing investigation of the epigenetic control of gene expression during CD4+ T cell responses to self antigen offers the opportunity to identify additional novel therapeutic targets.

有效控制全身性自身免疫性疾病，如类风湿性关节炎（RA）目前依赖于使用强烈的全身免疫抑制，从而增加感染和恶性肿瘤的风险。治疗自身免疫性疾病的一种更好的理论方法是诱导抗原特异性耐受，其仅靶向危险的自身反应性T和B细胞。然而，这种具有治愈自身免疫性疾病潜力的有效疗法的设计受到阻碍，因为我们无法可视化和研究完整免疫系统内的那些自身抗原特异性多克隆淋巴细胞。此外，我们缺乏足够的知识，诱导克隆无反应性淋巴细胞已经响应于自身抗原的患病个体。最后，我们的典型候选方法来识别新的治疗靶点是一个固有的缓慢的过程，可以受到不利的影响，先入为主的观念的分子机制是重要的诱导无能。我们现在提出了一系列的临床前研究，将利用新兴的抗原/II类四聚体技术来跟踪破坏免疫耐受和引起自身免疫的多克隆CD 4 + T细胞。具体目标1将研究NT 5 'E和Foxp 3在外周免疫系统中多克隆CD 4 + T细胞最初遇到自身抗原后克隆无反应性的发展和维持中的各自作用。外切-5 '-核苷酸酶（NT 5' E），一种新的候选无反应因子，发现使用全基因组筛选染色质修饰与基因表达的变化，将评估其在控制克隆无反应发展和维持抗原无反应性中的作用。特异性目标2将确立克隆无反应性在表观遗传变化中的作用，表观遗传变化可防止CD 4 + T细胞介导的关节炎的发展。在此目的下的实验将使用对天然自身抗原葡萄糖-6-磷酸异构酶（GPI）反应的KRN TCR转基因T细胞的过继转移来模拟RA，并在全身性炎症或淋巴细胞减少症的情况下研究NT 5 + E和Foxp 3 + CD 4 + T调节细胞在克隆无反应性诱导的表观遗传控制中的作用。除了增加我们关于NT 5 ′ E对无反应性诱导的调节和体内免疫调节的基础知识外，用II类四聚体获得的结果还将作为开发用于人体试验的生物标志物的范例，所述人体试验设计为靶向自身反应性CD 4 + T细胞以进行克隆无反应性诱导。此外，我们正在进行的研究CD 4 + T细胞对自身抗原反应过程中基因表达的表观遗传控制提供了确定其他新的治疗靶点的机会。