Epigenetic Control of T cell Autoimmunity

T 细胞自身免疫的表观遗传控制

• 批准号: 7727443
• 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/7727443
• 关键词: 5' -Nucleotidase; Address; Adopted; Adoptive Transfer; Antigens; Arthritis; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Behavior monitoring; Biological Markers; CD4 Positive T Lymphocytes; Cells; Clinical Trials Design; Clonal Anergy; Complex; Data; Development; Disease; Epigenetic Process; Foundations; Foxes; Funding; Gene Expression; Genes; Glucosephosphate Isomerase; Grant; Histocompatibility Antigens Class II; Human; Immune Tolerance; Immune system; Immunosuppression; Individual; Infection; Inflammation; Investigation; Ions; Knowledge; Lupus; Lymphocyte; Lymphopenia; Maintenance; Malignant Neoplasms; Mediating; Minnesota; Modeling; Molecular; Molecular Target; Monitor; Mus; Peripheral; Play; Process; Proteins; Regulation; Research; Rheumatoid Arthritis; Risk; Role; Series; Surface; System; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Work; anergy; autoreactive T cell; chromatin modification; cost; 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; response; success; 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.

有效控制系统性自身免疫性疾病如类风湿关节炎（RA）目前依赖于使用强烈的全身性免疫抑制，从而增加了感染和恶性肿瘤的风险。治疗自身免疫性疾病的更好的理论方法是诱导抗原特异性耐受性，仅针对危险的自身反应性T细胞和B细胞。然而，由于我们无法在完整的免疫系统中观察和研究这些自身抗原特异性多克隆淋巴细胞，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了阻碍。此外，我们缺乏足够的知识，关于诱导克隆能量的淋巴细胞已经响应自身抗原在患病个体。最后，我们确定新的治疗靶点的典型候选方法是一个固有的缓慢过程，可能受到对能量诱导重要的分子机制的先入为主的观念的不利影响。我们现在提出了一系列临床前研究，将利用新兴的抗原/ II类四聚体技术来跟踪打破免疫耐受并引起自身免疫的多克隆CD4+ T细胞。特异性目的1将研究nt5e和Foxp3在外周血免疫系统中多克隆CD4+ T细胞初始自身抗原遭遇后克隆能量的发展和维持中的个体作用。Ecto-5′-核苷酸酶（nt5e）是一种新的候选能量因子，通过全基因组筛选发现与基因表达变化相关的染色质修饰，将评估其在控制克隆能量发展和维持抗原无反应性中的作用。特异性Aim 2将建立克隆能量在表观遗传变化中的作用，防止CD4+ T细胞介导的关节炎的发展。本实验将采用KRN tcr转基因T细胞对天然自身抗原葡萄糖-6-磷酸异构酶（GPI）反应的方法建立RA模型，并在系统性炎症或淋巴细胞减少的情况下，研究nt5e和Foxp3+CD4+ T调节细胞在克隆性能量诱导的表观遗传控制中的作用。除了增加我们对nt5e调节能量诱导和体内免疫调节的基本知识外，II类四聚体获得的结果也将作为开发生物标志物的范例，用于人体试验，旨在针对自身反应性CD4+ T细胞进行克隆能量诱导。此外，我们正在进行的CD4+ T细胞对自身抗原反应过程中基因表达的表观遗传控制的研究，为确定其他新的治疗靶点提供了机会。