Regulation and Function of Interleukin-7 in Primary Sjogrens Syndrome

白介素7在原发性干燥综合征中的调控及作用

• 批准号: 8837000
• 负责人: Qing Yu
• 金额: $ 49.28万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837000
• 关键词: Adaptor Signaling Protein; Affect; American; Antibodies; Autoimmune Diseases; Basic Science; CXCL10 gene; Cell Line; Cells; Cessation of life; Chronic; Clinical Research; Development; Disease; Disease model; Down-Regulation; Epithelial Cells; Florida; Foundations; Functional disorder; Gene Silencing; Goals; Health; Human; IRF1 gene; Immune; In Vitro; Individual; Inflammation; Interferon Type II; Interferon-alpha; Interleukin 7 Receptor; Interleukin-7; Laboratories; Lacrimal gland structure; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutant Strains Mice; Onset of illness; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Play; Production; Publications; Receptor Signaling; Regulation; Reporting; Research; Role; STAT1 gene; Salivary Glands; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Staging; Symptoms; T-Lymphocyte; TNF receptor-associated factor 1; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Universities; Xerostomia; chronic autoimmune disease; cytokine; cytotoxic; eye dryness; in vivo; mouse model; novel diagnostics; novel therapeutics; programs; receptor; response; systemic autoimmune disease; translational study; treatment strategy

DESCRIPTION (provided by applicant): Sjögren's syndrome (SjS) is a chronic autoimmune disease that affects 2-4 million Americans and greatly affects the health and well-being of the patients. SjS is characterized by chronic inflammation and dysfunction of the salivary and lacrimal glands with dry mouth and dry eyes as the primary symptoms. Autoreactive effector T cells and T cell-derived cytokines play a crucial role in the development and onset of SjS. Interleukin-7 (IL-7) plays a crucial pathogenic role in multiple autoimmune diseases through enhancing T helper (Th) 1 and T cytotoxic (Tc) 1 responses. Elevated IL-7 levels were reported in primary SjS patients. Our preliminary studies showed that both exogenous and endogenous IL-7 promotes the development and onset of SjS in a mouse disease model, which is accompanied by enhanced Th1 and Tc1 responses. In addition, we found that IFN-α and IFN-γ can induce IL-7 production in a human salivary gland cell line. In the current study, we will characterize the in vivo functions of IL-7 and its targets in the development and the persistence of primary SjS, and define the signaling and molecular pathways that cause excessive IL-7 production in SjS. In Aim 1 of this study, we will assess the in vivo functions of IL-7 and IL-7-induced Th1/Tc1 cytokines in the development of SjS and in the persistence of SjS after disease onset. We will use in vivo antibody blockade approach to abrogate IL-7, IFN-γ or TNF-α activity at specific stages of the disease in C57BL/6.NOD-Aec1Aec2 mice, a well-defined model of primary SjS. In Aim 2, we will determine the molecular mechanisms by which IL-7 enhances Th1/Tc1 responses. We will use several genetically mutant mice, in vivo antibody blockade and in vitro gene-silencing approaches to determine the role of T-bet, PD-1 and TRAF1 in IL-7-mediated enhancement of Th1/Tc1 responses. Moreover, we will collaborate with Dr. Seunghee Cha at the University of Florida to validate these results in human T cells from SjS patients and healthy controls, using in vitro T cell stimulation cultures and gene-silencing approaches. In Aim 3, we will characterize the signaling pathways that cause excessive IL-7 production in salivary gland cells in SjS. We will use several genetically mutant mice, a human epithelial cell line and a combination of in vivo and in vitro approaches to characterize the in vivo role of IFN-α and IFN-γ in enhancing IL-7 production from salivary gland cells in the SjS setting. Completion of this project will provide crucial information and foundation for the development of novel diagnostic and therapeutic strategies for SjS by targeting IL-7 and Th1/Tc1 cytokines.

描述（由申请人提供）：干燥综合征（SjS）是一种慢性自身免疫性疾病，影响2-4百万美国人，极大地影响患者的健康和福祉。SjS的特征是唾液腺和泪腺的慢性炎症和功能障碍，以口干和眼干为主要症状。 自身反应性效应T细胞和T细胞衍生的细胞因子在SjS的发生和发作中起着至关重要的作用。白细胞介素-7（IL-7）通过增强T辅助细胞（Th）1和T细胞毒性细胞（Tc）1应答在多种自身免疫性疾病中发挥重要的致病作用。在原发性SjS患者中报告了升高的IL-7水平。我们的初步研究表明，在小鼠疾病模型中，外源性和内源性IL-7都促进了SjS的发展和发作，并伴有Th 1和Tc 1应答的增强。此外，我们发现IFN-α和IFN-γ可以诱导人唾液腺细胞系产生IL-7。在目前的研究中，我们将描述IL-7及其靶点在原发性SjS的发展和持久性中的体内功能，并确定导致SjS过度产生IL-7的信号传导和分子途径。在本研究的目的1中，我们将评估IL-7和IL-7诱导的Th 1/Tc 1细胞因子在SjS的发展和疾病发作后SjS的持续性中的体内功能。我们将在C57 BL/6. NOD-Aec 1Aec 2小鼠（一种明确的原发性SjS模型）中使用体内抗体阻断方法来消除疾病特定阶段的IL-7、IFN-γ或TNF-α活性。在目标2中，我们将确定IL-7增强Th 1/Tc 1应答的分子机制。我们将使用几种遗传突变小鼠，体内抗体阻断和体外基因沉默方法来确定T-bet，PD-1和TRAF 1在IL-7介导的Th 1/Tc 1应答增强中的作用。此外，我们将与佛罗里达大学的Seunghee Cha博士合作，使用体外T细胞刺激培养和基因沉默方法，在SjS患者和健康对照的人类T细胞中验证这些结果。在目标3中，我们将描述导致SjS唾液腺细胞产生过量IL-7的信号通路。我们将使用几个基因突变的小鼠，一个人类上皮细胞系和一个 本发明涉及体内和体外方法的组合以表征IFN-α和IFN-γ在SjS环境中增强唾液腺细胞产生IL-7中的体内作用。本项目的完成将为以IL-7和Th 1/Tc 1细胞因子为靶点开发新的诊断和治疗策略提供重要的信息和基础。