IL-7 Biology and Role in Systemic Autoimmunity

IL-7 生物学及其在系统性自身免疫中的作用

基本信息

批准号：
8719533
负责人：
Argyrios N Theofilopoulos
金额：
$ 41.69万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-11 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719533
关键词：
Ablation Address Affect Affinity Antibodies Antigens Apoptotic Autoimmune Diseases Autoimmunity Automobile Driving Biochemical Biology CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Collection Complex Consumption Development Disease Disease Progression Down-Regulation Experimental Autoimmune Encephalomyelitis Family Foundations Frequencies Gene Deletion Genetic Goals Health Homeostasis Immune response Immune system Inflammation Interleukin-7 Intervention Knock-in Mouse Lead Location Lupus Lymphatic Diseases Lymphatic Endothelial Cells Lymphoid Lymphopenia Mediating Mediator of activation protein Metabolic Metabolism Modeling Modification Mus Nucleic Acids Organ Pathogenesis Pathology Peptide/MHC Complex Peptides Play Production Proteolipids Publishing Relapse Reporter Research Reticular Cell Role Severity of illness Signal Pathway Signal Transduction Source Stromal Cells T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Intervention Transgenic Organisms autoimmune lymphoproliferative syndrome autoreactive T cell base brief intervention congenic cytokine disease phenotype innovation mouse model new therapeutic target novel novel therapeutic intervention receptor response transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Cytokines constitute a vast and complex network of molecules involved in almost every aspect of the immune system. Among these, IL-7 has emerged as a major T cell trophic cytokine affecting survival and homeostasis of T cells, processes that are highly disturbed in lupus-associated systemic autoimmunity. Consequently, we have made a concerted effort to define the role of IL-7 in the pathogenesis of this disease in mouse models. Our published and preliminary findings showed that blockade of IL-7R signaling effectively reduces disease severity in both murine lupus and EAE. Brief application of this treatment preferentially eliminated autoreactive T cells undergoing activation and, strikingly, additional studies showed that IL-7 provides a third signal beyond TCR and constimulatory receptor engagement to enhance activation and proliferation of low-affinity autoreactive T cells. Moreover, lymphadenopathy in murine lupus was associated with expansion of IL-7-producing lymphoid stromal cells, specifically fibroblastic reticular cells (FRCs). Accordingly, in this proposal, Specific Aim 1 will address the biochemical basis for IL-7-mediated enhancement of T cell activation, proliferation, survival, and metabolic status, while Specific Aim 2 will investigae the location and frequency of cellular sources of IL-7 in secondary lymphoid organs, the influence of inflammation-promoting TLRs and type I IFNs on IL-7 production and transcriptional status of these cells, and disease-modifying effects of genetic modifications that ablate IL-7 production by stromal and lymphatic endothelial cells (LECs). These biologic and mechanistic studies on IL-7 and its cellular producers will reveal novel aspects of autoimmune disease pathogenesis and may identify new therapeutic targets for intervention.

描述（由申请人提供）：细胞因子几乎构成了与免疫系统几乎各个方面有关的庞大而复杂的分子网络。其中，IL-7已成为主要的T细胞营养细胞因子，影响T细胞的生存和稳态，这在与狼疮相关的全身自身免疫性中受到高度干扰的过程。因此，我们进行了一致的努力，以定义IL-7在小鼠模型中这种疾病发病机理中的作用。我们发表的初步发现表明，IL-7R信号的阻断有效地降低了鼠狼疮和EAE的疾病严重程度。该处理的简要应用优先消除了经历激活的自动反应性T细胞，并引人注目的是，进一步的研究表明，IL-7提供了第三个信号，超出了TCR和结构受体参与，以增强低亲和力自动反应性T细胞的激活和增殖。此外，鼠狼疮中的淋巴结肿大与IL-7产生淋巴样细胞的扩展有关，特异性成纤维细胞网状细胞（FRCS）。 Accordingly, in this proposal, Specific Aim 1 will address the biochemical basis for IL-7-mediated enhancement of T cell activation, proliferation, survival, and metabolic status, while Specific Aim 2 will investigae the location and frequency of cellular sources of IL-7 in secondary lymphoid organs, the influence of inflammation-promoting TLRs and type I IFNs on IL-7 production and transcriptional status of these cells, and遗传修饰的疾病改良作用，使基质和淋巴内皮细胞产生IL-7的遗传修饰（LEC）。这些关于IL-7及其细胞生产者的生物学和机械研究将揭示自身免疫性疾病发病机理的新方面，并可能确定新的干预治疗靶标。