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

• 批准号: 9303189
• 负责人: Argyrios N Theofilopoulos
• 金额: $ 42.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/9303189
• 关键词: Ablation; Address; Affect; Affinity; Antibodies; Antigens; Apoptotic; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Biochemical; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Collection; Complex; Consumption; Development; Disease; Disease Progression; Down-Regulation; Experimental Autoimmune Encephalomyelitis; Family; Foundations; Frequencies; Gene Deletion; Gene Targeting; Genetic; Genetic Transcription; Goals; Homeostasis; Immune response; Immune system; Impairment; Inflammation; Interleukin-7; Intervention; Knock-in; Lead; Location; Lupus; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphoid; Lymphopenia; Measurable; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Modification; Mus; Nucleic Acids; Organ; Pathogenesis; Pathology; Peptide/MHC Complex; Peptides; Play; Process; Production; Proteolipids; Publishing; Relapse; Reporter; Research; Reticular Cell; Role; Severity of illness; Signal Pathway; Signal Transduction; Source; Stromal Cells; Syndrome; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic Intervention; Transgenic Organisms; autoreactive T cell; autoreactivity; brief intervention; congenic; cytokine; disease phenotype; innovation; mouse model; new therapeutic target; novel; novel therapeutic intervention; public health relevance; receptor; response; synergism; transcriptomics

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.

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.