Regulation of T cell migration by histamine

描述（由申请人提供）：在健康和疾病中，将T淋巴细胞募集到组织中对于局部免疫和炎症反应是必不可少的。调节T淋巴细胞运输进入组织的机制尚未很好地表征。肥大细胞存在于所有组织中，是预先形成的介质的丰富来源。其中最丰富的介质之一是组胺，在肥大细胞被抗原介导的激活或损伤激活时释放。尽管是生物学中研究最广泛的分子之一，但直到最近才发现组胺具有几种新的“免疫调节”特性，第四个受体是在2000年发现的。此外，现在有越来越多的证据表明，其他类型的细胞也能够合成组胺，包括树突状细胞和中性粒细胞。我们已经取得了令人兴奋的发现，缺乏组胺特异性受体（H1R）的T细胞在过敏原攻击时无法迁移到肺部。缺乏H1R的小鼠也不会发生过敏性气道疾病，但对T细胞衍生介质或正常（H1R+） T细胞过继转移反应正常。用H1R的选择性药理学抑制剂治疗野生型小鼠也减少了过敏性气道反应。根据我们的初步观察，我们假设肥大细胞释放组胺促进T细胞向组织募集，而T细胞上H1R的表达水平起到调节作用。我们预测这些过程将在不同的组织中保守，组胺作为T细胞介导的炎症和免疫的普遍调节剂。这些概念将通过使用体内和体外方法的三个特定目的来解决：特异性目的1将测试组织驻留肥大细胞作为组胺来源的作用，并测试它们在过敏性气道疾病中募集T淋巴细胞的能力。特异性目标2将侧重于H1R对T淋巴细胞的影响，并将研究H1R在T淋巴细胞亚群中的表达以及H1R在迁移和跨内皮运输中的功能参与（与Joan Cook-Mills博士合作）。特异性目的3将研究组胺驱动的T淋巴细胞募集到皮肤的参与，使用延迟型超敏反应模型，并将检验组胺是T淋巴细胞募集到组织的普遍机制的假设。

DESCRIPTION (provided by applicant): The recruitment of T lymphocytes into tissues is essential for local immune and inflammatory responses in both health and disease. The mechanisms that regulate T lymphocyte trafficking into tissues are not well characterized. Mast cells are constitutively resident in all tissues and are a rich source of preformed mediators. One of the most abundant mediators is histamine which is release upon mast cell activation by antigen- mediated activation or to insult. Despite being one of the most extensively studied molecules in biology, histamine has only recently been found to have several novel "immunoregulatory" properties and a fourth receptor was discovered in 2000. In addition, there is now growing evidence that other cell types are capable of synthesizing histamine, including dendritic cells and neutrophils.We have made the exciting finding that T cells that lack a specific receptor for histamine, H1R, fail to migrate into the lung upon allergen challenge. Mice lacking H1R also fail to develop allergic airway disease but respond normally to T cell derived mediators or when normal (H1R+) T cells are adoptively transferred. Treatment of wildtype mice with selective pharmacological inhibitors of H1R also reduced allergic airway responses. Based on our preliminary observations, we hypothesize that mast cell release of histamine promotes the recruitment of T cells into tissues and that the expression levels of H1R on T cells serves to regulate this. We predict these processes will be conserved across different tissues and that histamine serves as a ubiquitous regulator of T cell mediated inflammation and immunity. These concepts will be addressed by three specific aims using both in vivo and in vitro approaches: Specific Aim 1 will test the role of tissue-resident mast cells as a source of histamine and test their ability to recruit T lymphocytes in allergic airway disease. Specific Aim 2 will focus on the influence of H1R on T lymphocytes and will investigate the expression of H1R on subsets of T lymphocytes and the functional involvement of H1R in migration and transendothelial trafficking (in collaboration with Dr Joan Cook-Mills). Specific Aim 3 will investigate the involvement of histamine-driven T lymphocyte recruitment to the skin, using models of delayed-type hypersensitivity, and will test the hypothesis that histamine is a ubiqitous mechanism by which T lymphocytes are recruited into tissues.