Histamine Receptor Signaling in CNS Autoimmune Disease

中枢神经系统自身免疫性疾病中的组胺受体信号传导

• 批准号: 8015316
• 负责人: CORY TEUSCHER
• 金额: $ 61.39万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-19 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015316
• 关键词: 1,2-diacylglycerol; Amino Acids; Antigen-Presenting Cells; Autoimmune Process; Blood - brain barrier anatomy; CD4 Positive T Lymphocytes; CNS autoimmune disease; Central Nervous System Diseases; Chronic; Data; Development; Diglycerides; Distal; Drug usage; Epidemiology; Experimental Autoimmune Encephalomyelitis; Freund' s Adjuvant; G-Protein-Coupled Receptors; Genes; HRH2 gene; Histamine; Histamine H1 Receptors; Histamine H2 Receptors; Histamine H3 Receptors; Histamine Receptor; Histidine Decarboxylase; Hybrids; Hydroxyzine; Immune; Immune response; Inflammation Mediators; Inflammatory; Inositol; Interleukin-4; Length; MAP2K6 gene; Mediating; Memory; Modeling; Modification; Monoclonal Antibodies; Multiple Sclerosis; Mus; Names; Neuraxis; Pathogenesis; Patients; Peptides; Permeability; Pertussis Toxin; Pharmacologic Substance; Play; Predisposition; Principal Investigator; Production; Publishing; Receptor Signaling; Regulation; Research; Resource Sharing; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Spinal Cord; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Time; Transcript; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; Work; cytokine; improved; intraperitoneal; man; mast cell; memory CD4 T lymphocyte; oligodendrocyte-myelin glycoprotein; programs; promoter; receptor; response; small molecule; treatment strategy; tripolyphosphate

DESCRIPTION (provided by applicant): Histamine, a mediator of inflammation and regulator of innate and adaptive immune responses, plays a significant role in the pathogenesis of experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS). Histamine exerts its effect through four G-protein coupled receptors (GPCRs) designated histamine H1, H2, H3, and H4 receptor (H1R, H2R, H3R, and H4R). H1R is expressed in chronic MS plaques and MS patients receiving the H1R antagonist hydroxyzine remain stable or improve neurologically. Moreover, epidemiological data indicate that H1R antagonist use is associated with decreased MS risk. In MS and EAE histamine is viewed primarily as a mediator of inflammation due to its effect on the vasculature and blood brain barrier permeability. However, data in histamine- and histamine receptor- (HR) deficient mice indicate that histamine also plays a role in regulating encephalitogen-specific T-cell effector responses. We published that compared to wild-type mice, H1RKO mice develop less severe EAE and Th2-like anti-MOG35-55 CD4 T-cell responses. We now show that the H1R regulates IFN3 production by CD4 effector T-cells as a result of direct signaling during their initial activation. Additionally, we present data showing that all four HRs play a role in EAE. Moreover, in addition to expressing the H1R naive CD4 T-cells express the H2R and H4R but not the H3R, and upon activation down regulate the expression of all three HR types; however, CD4 memory T-cells gain expression of the H3R. Our overall working hypothesis is that direct HR signaling during activation of naive and memory CD4 T-cells regulates effector responses. In this application we propose to: 1) delineate the H1R signaling pathway regulating IFN3 secretion in CD4 T-cells and test the hypothesis that H1R signaling also regulates susceptibility to spontaneous EAE in (B6.TgTcrMOG W B6.TgIghMOG) F1 hybrid mice; 2) test the hypothesis that H2R and H4R signaling in naive CD4 T-cells directly regulate encephalitogen-specific T-cell effector responses, and 3) test the hypothesis that H3R signaling regulates MOG35-55-specific CD4 memory T-cell responses. Delineating the CD4 effector T-cell responses regulated by HRs in EAE may aid in the development of new strategies for the treatment of MS and modification of primary and anamnestic CD4 T-cell responses in general. In this regard, GPCRs are one of the most tractable set of targets for the development of clinically effective, small molecule pharmaceuticals. Of the drugs used clinically in man ~50% target GPCRs.

描述（由申请人提供）：组胺是一种炎症介质以及先天性和适应性免疫反应的调节剂，在实验性过敏性脑脊髓炎（EAE）的发病机制中发挥着重要作用，EAE是多发性硬化症（MS）的主要自身免疫模型。组胺通过四种 G 蛋白偶联受体 (GPCR) 发挥作用，即组胺 H1、H2、H3 和 H4 受体（H1R、H2R、H3R 和 H4R）。 H1R 在慢性 MS 斑块中表达，接受 H1R 拮抗剂羟嗪的 MS 患者神经功能保持稳定或改善。此外，流行病学数据表明，H1R 拮抗剂的使用与 MS 风险降低相关。在 MS 和 EAE 中，组胺主要被视为炎症介质，因为它对脉管系统和血脑屏障通透性有影响。然而，组胺和组胺受体 (HR) 缺陷小鼠的数据表明，组胺还在调节脑炎原特异性 T 细胞效应反应中发挥作用。我们发表了与野生型小鼠相比，H1RKO 小鼠产生不太严重的 EAE 和 Th2 样抗 MOG35-55 CD4 T 细胞反应。我们现在表明，H1R 通过 CD4 效应 T 细胞初始激活过程中直接信号传导来调节 IFN3 的产生。此外，我们提供的数据显示所有四个 HR 在 EAE 中都发挥着作用。此外，除了表达 H1R 初始 CD4 T 细胞外，还表达 H2R 和 H4R，但不表达 H3R，并且在激活后下调所有三种 HR 类型的表达；然而，CD4 记忆 T 细胞获得 H3R 的表达。我们的总体工作假设是，幼稚和记忆 CD4 T 细胞激活期间的直接 HR 信号传导调节效应反应。在本申请中，我们建议：1) 描述调节 CD4 T 细胞中 IFN3 分泌的 H1R 信号通路，并测试 H1R 信号通路也调节 (B6.TgTcrMOG W B6.TgIghMOG) F1 杂交小鼠对自发性 EAE 易感性的假设； 2) 检验初始 CD4 T 细胞中的 H2R 和 H4R 信号传导直接调节脑炎原特异性 T 细胞效应反应的假设，以及 3) 检验 H3R 信号传导调节 MOG35-55 特异性 CD4 记忆 T 细胞反应的假设。描述 EAE 中 HR 调节的 CD4 效应 T 细胞反应可能有助于制定治疗 MS 的新策略，并总体上改变原发性和记忆性 CD4 T 细胞反应。在这方面，GPCR 是开发临床有效的小分子药物最容易处理的靶标之一。临床上用于人类的药物中，约 50% 的目标是 GPCR。