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: 7359486
• 负责人: CORY TEUSCHER
• 金额: $ 62.57万
• 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: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7359486
• 关键词: 1,2-diacylglycerol; Affect; Amino Acids; Antigen-Presenting Cells; Autoimmune Process; Blood - brain barrier anatomy; CD4 Positive T Lymphocytes; CNS autoimmune disease; Cells; Central Nervous System Diseases; Chronic; Data; Development; Diglycerides; Disease susceptibility; Distal; Drug usage; Effector Cell; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Freund' s Adjuvant; G-Protein-Coupled Receptors; Gene Family; Generations; Genes; HRH2 gene; Histamine; Histamine H1 Receptors; Histamine H2 Receptors; Histamine H3 Receptors; Histamine Receptor; Histidine Decarboxylase; Human Genome; Hybrids; Hydroxyzine; Immune; Immune response; Inflammation Mediators; Inflammatory; Inositol; Interferons; Interleukin-4; Length; MAP2K6 gene; Mediating; Memory; Modeling; Modification; Monoclonal Antibodies; Multiple Sclerosis; Mus; Neuraxis; Pathogenesis; Patients; Peptides; Peripheral; Permeability; Pertussis Toxin; Pharmacologic Substance; Play; Polymerase Chain Reaction; Predisposition; Production; Protein Isoforms; Publishing; Receptor Signaling; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Spinal Cord; 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; promoter; receptor; response; selective expression; small molecule; 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）：组胺是炎症和适应性免疫反应的调节剂的介体，在实验性过敏性脑脊髓炎（EAE）的发病机理中起重要作用，这是多发性硬化症的主要自免疫模型（MS）。组胺通过指定组胺H1，H2，H3和H4受体（H1R，H2R，H3R和H4R）的四个G蛋白偶联受体（GPCR）发挥作用。 H1R在慢性MS斑块中表达，接受H1R拮抗剂羟嗪的MS患者保持稳定或神经学改善。此外，流行病学数据表明H1R拮抗剂的使用与MS风险降低有关。在MS和EAE组胺中，由于其对脉管系统和血脑屏障渗透性的影响，主要被视为炎症的介体。然而，组胺和组胺受体（HR）缺乏小鼠的数据表明，组胺还在调节脑植物特异性T细胞效应子反应中起作用。我们发表了与野生型小鼠相比，H1RKO小鼠的生长不那么严重和Th2样抗MOG35-55 CD4 T细胞反应。现在，我们表明，H1R通过CD4效应T细胞在初始激活过程中调节IFN3的产生。此外，我们提供数据，显示所有四个小时在EAE中都起着作用。此外，除了表达H1R幼稚的CD4 T细胞外，表达了H2R和H4R，而不是H3R，而激活后，调节了所有三种HR类型的表达。但是，CD4存储器T细胞获得H3R的表达。我们的整体工作假设是，在幼稚和记忆CD4 T细胞激活过程中的直接HR信号调节效应子响应。在此应用中，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信号还调节自发EAE的敏感性（B6.TGTCRMOG W B6.TGIGHMOG）F1 HYBRID小鼠； 2）检验了幼稚CD4 T细胞中H2R和H4R信号的假设，直接调节脑脑体特异性T细胞效应子响应，3）检验假设H3R信号调节MOG35-55特异性CD4 MOMEMING T-CELL T-CELL T-CELL响应。描述EAE中HRS调节的CD4效应T细胞响应可能有助于制定新的策略，以治疗MS的新策略以及一般来说的原始和原始CD4 T细胞响应。在这方面，GPCR是开发临床上有效的小分子药物的最容易理解的目标之一。在临床上使用的药物中，靶向GPCR的50％。