Histamine Receptor Signaling in CNS Autoimmune Disease

描述(申请人提供)：组胺是一种炎症介质，调节先天和获得性免疫反应，在实验性变态反应性脑脊髓炎(EAE)的发病机制中发挥重要作用，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蛋白偶联受体发挥作用，分别命名为组胺H1、H2、H3和H4受体(H1R、H2 R、H3R和H4R)。H1R在慢性MS斑块中表达，接受H1R拮抗剂羟基锌治疗的MS患者保持稳定或神经学改善。此外，流行病学数据表明，使用H1R拮抗剂与降低MS风险相关。在MS和EAE中，组胺主要被视为炎症介质，因为它对血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，组胺也在调节脑组织特异性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小鼠出现不那么严重的EAE和Th2样抗MOG35-55CD4T细胞反应。我们现在证明，H1R调节由CD4效应T细胞产生的IFN3，这是在其初始激活过程中通过直接信号传递的结果。此外，我们提供的数据显示，所有四个HR在EAE中都发挥了作用。此外，除了表达H1R外，幼稚的CD4T细胞表达H2R和H4R，但不表达H3R，并且在激活时下调所有三种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，在幼稚和记忆的CD4T细胞激活期间，直接的HR信号调节效应器的反应。在这一应用中，我们建议：1)描述调节CD4T细胞分泌IFN3的H1R信号通路，并检验H1R信号也调节(B6.TgTcrMOG W B6.TgIghMOG)F1杂交小鼠患自发性EAE的敏感性的假设；2)检验初始CD4T细胞中的H2 R和H4R信号直接调节脑组织原特异性T细胞效应反应的假设；以及3)检验H3R信号调节MOG35-55特异性的CD4记忆T细胞反应的假设。阐明EAE中HRs调节的CD4效应T细胞反应可能有助于开发治疗MS的新策略，以及总体上改变原发和既往的CD4T细胞反应。在这方面，GPCRs是开发临床有效的小分子药物的最容易处理的一组目标之一。在MAN临床使用的药物中，约有50%靶向GPCRs。

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.