Regulation of T cell migration by histamine

组胺调节 T 细胞迁移

• 批准号: 7559679
• 负责人: PAUL J BRYCE
• 金额: $ 37.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559679
• 关键词: Acute; Address; Adoptive Transfer; Allergens; Allergic; Antigens; Antihistamines; Asthma; Autoimmune Process; Binding; Biological Assay; Biological Response Modifiers; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chemicals; Chemotactic Factors; Chronic Hepatitis; Collaborations; Contact Dermatitis; Cytoplasmic Granules; Data; Delayed Hypersensitivity; Dendritic Cells; Development; Disease; Endothelium; Graft Rejection; Health; Histamine; Histamine Receptor; Histamine Release; Hypersensitivity; IgE; Immigration; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory Response; Injury; Insulin-Dependent Diabetes Mellitus; Interphase Cell; Investigation; Link; Lung; Lymphoid; Mediating; Mediator of activation protein; Modeling; Mus; Neuronal Injury; Oxazolone; Pathway interactions; Pattern; Population; Process; Property; Recombinants; Recruitment Activity; Regulation; Research Personnel; Rest; Role; Signal Transduction; Site; Skin; Source; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Work; airway inflammation; allergic airway disease; antigen challenge; base; cell motility; cell type; chemokine; chemokine receptor; cooking; cytokine; experience; in vitro Model; in vivo; inhibitor/antagonist; mast cell; migration; neutrophil; novel; prevent; receptor; reconstitution; response; trafficking; tumor

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.

描述（由申请人提供）：将T淋巴细胞募集到组织中对于健康和疾病中的局部免疫和炎症反应至关重要。调节T淋巴细胞运输到组织的机制没有很好地表征。肥大细胞在所有组织中均构成驻留，并且是预先形成的介体的丰富来源。最丰富的介体之一是组胺，在抗原介导的激活或侮辱时释放肥大细胞激活后释放。尽管是生物学领域最广泛研究的分子之一，但最近才发现组胺具有几种新型的“免疫调节性”特性，并在2000年发现了第四个受体。此外，现在还有越来越多的证据表明，其他细胞类型越来越多，表明能够使组合细胞的合成能够使人缺乏一种典型的细胞，使其具有特定的细胞。过敏原挑战的肺。缺乏H1R的小鼠也无法发展出过敏性气道疾病，但通常对T细胞衍生的介体或正常（H1R+）T细胞的反应反应。 H1R的选择性药理抑制剂对野生型小鼠的治疗也降低了过敏性气道反应。根据我们的初步观察，我们假设组胺的肥大细胞释放促进了T细胞募集到组织中，并且T细胞上H1R的表达水平可用于调节这一点。我们预测这些过程将在不同的组织中保守，并且组胺是T细胞介导的炎症和免疫的普遍调节剂。这些概念将通过体内和体外方法来解决三个特定目标：特定目标1将测试组织居民肥大细胞作为组胺的来源的作用，并测试其在过敏性气道疾病中募集T淋巴细胞的能力。具体目标2将集中于H1R对T淋巴细胞的影响，并将研究H1R对T淋巴细胞亚群的表达，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）。具体目标3将使用延迟型超敏反应的模型研究组胺驱动的T淋巴细胞募集到皮肤的涉及，并将测试组胺是一种ubiqitous机制的假说，将T淋巴细胞募集到组织中。