Regulation of asthma by Btk and family kinases

Btk 和家族激酶对哮喘的调节

• 批准号: 7248798
• 负责人: TOSHIAKI KAWAKAMI
• 金额: $ 44.99万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248798
• 关键词: Adrenal Cortex Hormones; Adverse effects; Agammaglobulinaemia tyrosine kinase; Allergens; Allergic; Animal Model; Antibodies; Antigens; Area; Asthma; Biological; Bone Marrow; Breathing; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Cellular biology; Data; Dendritic Cells; Developed Countries; Developing Countries; Development; Disease; Disease model; Exhibits; Exposure to; Family; Functional disorder; Genetic; Helper-Inducer T-Lymphocyte; Hematopoietic; Histocompatibility Antigens Class II; IgE; IgG1; Immune System Diseases; Immune response; Immunization; In Vitro; Incidence; Inflammatory; Intervention; Knockout Mice; Lipopolysaccharides; Mus; Ovalbumin; Pharmacologic Substance; Phosphotransferases; Principal Investigator; Production; Purpose; Regulation; Relative (related person); Role; Signal Transduction; Stimulus; T-Cell Proliferation; Th2 Cells; Therapeutic; Treatment Protocols; Up-Regulation; airway inflammation; allergic airway inflammation; cell type; cytokine; immunogenic; in vivo; insight; knockout gene; mast cell; member; mouse model; novel; prevent; research study; response; src-Family Kinases; success; uptake

DESCRIPTION (provided by applicant): The incidence of allergic diseases, particularly asthma, has been increasing at the troubling pace of doubling during the last two decades in developed countries. Given the limited success in preventing and treating asthma and sometimes serious side effects of the current regimen with corticosteroids, it is obvious that we need to broaden our therapeutic choices for this and other allergic diseases. We and others have demonstrated the critical importance of Bruton's tyrosine kinase (Btk) in the activation of B and mast cells, two cell types that are involved in the pathophysiology of these diseases. When airway inflammation experiments, a disease model of asthma, were performed with btk -/- mice, we were surprised to find that btk -/- mice exhibited exaggerated inflammatory and immune responses. Immunization of these mice with ovalbumin induced an enhancement in production of not only type 2 helper T cell (Th2)-dependent IgE and IgG1 antibodies but also type 1 helper T cell (Th1)-associated IgG2a antibodies. These results suggest that mice lacking functional Btk tend to develop exaggerated immune responses characterized by both Th1 and Th2 cells upon exposure to inhaled allergen. Numerous studies point to the central role of dendritic cells (DCs) in orchestrating the Th development and activation. Our preliminary results demonstrated that Btk is expressed in bone marrow derived DCs (BMDCs) and splenic DCs and that BMDCs derived from btk -/- mice exhibit increased upregulation of MHC class II molecules in response to lipopolysaccharides, compared to wild-type cells. Our data also indicate that splenic DCs from btk -/- mice have a stronger ability to stimulate antigen-specific T cell proliferation and production of both Th1 and Th2 cytokines. These results prompt us to investigate roles of Btk in the development, maturation and function of DCs in the context of Th2-dependent airway inflammation as well as in non-Th2-dependent situations. Since BMDCs express Tec, a close relative of Btk, and several Src family kinases, that can regulate Btk activity, it will also be important to study roles of these kinases in DC biology. This is a poorly explored area in DC biology. Our efforts will hopefully identify novel targets for pharmaceutical intervention to treat asthma and other immune diseases.

描述（由申请人提供）：在发达国家，过敏性疾病，特别是哮喘的发病率在过去二十年中以令人不安的翻倍速度增长。鉴于在预防和治疗哮喘方面的有限成功，以及目前使用皮质类固醇治疗方案有时会产生严重的副作用，很明显，我们需要拓宽治疗选择，以治疗哮喘和其他过敏性疾病。我们和其他人已经证明了布鲁顿酪氨酸激酶（Btk）在B细胞和肥大细胞的激活中至关重要，这两种细胞类型参与了这些疾病的病理生理。当用btk -/-小鼠进行气道炎症实验（哮喘疾病模型）时，我们惊讶地发现btk -/-小鼠表现出夸大的炎症和免疫反应。用卵清蛋白免疫这些小鼠，不仅诱导了2型辅助性T细胞（Th2）依赖性IgE和IgG1抗体的产生，而且还诱导了1型辅助性T细胞（Th1）相关IgG2a抗体的产生。这些结果表明，缺乏功能性Btk的小鼠在暴露于吸入过敏原后往往会产生以Th1和Th2细胞为特征的夸大免疫反应。许多研究指出树突状细胞（dc）在协调Th的发育和激活中的核心作用。我们的初步结果表明，Btk在骨髓来源的dc （BMDCs）和脾dc中表达，并且与野生型细胞相比，Btk -/-小鼠来源的BMDCs在脂多糖的作用下表现出更高的MHC II类分子上调。我们的数据还表明，btk -/-小鼠的脾dc具有更强的刺激抗原特异性T细胞增殖和Th1和Th2细胞因子产生的能力。这些结果促使我们研究Btk在th2依赖性气道炎症和非th2依赖性气道炎症背景下dc的发育、成熟和功能中的作用。由于BMDCs表达Btk的近亲Tec和几种Src家族激酶，这些激酶可以调节Btk的活性，因此研究这些激酶在DC生物学中的作用也很重要。在DC生物学中，这是一个很少被探索的领域。我们的努力将有望确定药物干预治疗哮喘和其他免疫疾病的新靶点。