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和先天性和适应性免疫应答的调节剂，在实验性过敏性脑脊髓炎（EAE）的发病机制中起重要作用，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，称为组胺H1、H2、H3和H4受体（H1 R、H2 R、H3 R和H4 R）。H1 R在慢性MS斑块中表达，接受H1 R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H1 R拮抗剂的使用与MS风险降低相关。在MS和EAE中，组胺由于其对血管和血脑屏障通透性的影响而主要被视为炎症介质。然而，组胺和组胺受体（HR）缺陷小鼠的数据表明，组胺也发挥了调节致脑炎原特异性T细胞效应反应的作用。我们发表了与野生型小鼠相比，H1 RKO小鼠产生不太严重的EAE和Th 2样抗MOG 35 -55 CD 4 T细胞应答。我们现在表明，H1 R调节IFN 3生产的CD 4效应T细胞作为其初始激活过程中的直接信号的结果。此外，我们目前的数据显示，所有四个HR在EAE中发挥作用。此外，除了表达H1 R之外，初始CD 4 T细胞还表达H2 R和H4 R，但不表达H3 R，并且在活化后下调所有三种HR类型的表达;然而，CD 4记忆T细胞获得H3 R的表达。我们的总体工作假设是，在初始和记忆CD 4 T细胞活化期间直接HR信号传导调节效应子应答。在本申请中，我们提出：1）描述调节CD 4 T细胞中IFN 3分泌的H1 R信号传导途径，并测试H1 R信号传导也调节EAE易感性的假设。（B6.TgTcrMOG W B6.TgIghMOG）F1杂交小鼠; 2）检验初始CD 4 T细胞中的H2 R和H4 R信号传导直接调节致脑炎原特异性T细胞效应子应答的假设，和3）检验H3 R信号传导调节MOG 35 -55特异性CD 4记忆T细胞应答的假设。阐明EAE中HR调节的CD 4效应T细胞应答可能有助于开发治疗MS的新策略，并通常修饰原发性和记忆性CD 4 T细胞应答。在这方面，GPCR是用于开发临床有效的小分子药物的最易处理的靶标组之一。在临床上用于人类的药物中，约50%靶向GPCR。