Regulation of asthma by Btk and family kinases

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速度增加了一倍。鉴于目前使用皮质类固醇的方案在预防和治疗哮喘方面的成功有限，有时会出现严重的副作用，很明显，我们需要扩大对这种和其他过敏性疾病的治疗选择。我们和其他人已经证明了布鲁顿酪氨酸激酶（Btk）在B和肥大细胞（参与这些疾病的病理生理学的两种细胞类型）的活化中的至关重要性。当用btk -/-小鼠进行气道炎症实验（哮喘的疾病模型）时，我们惊讶地发现btk -/-小鼠表现出过度的炎症和免疫反应。用卵清蛋白免疫这些小鼠不仅诱导2型辅助性T细胞（Th 2）依赖性IgE和IgG 1抗体的产生增强，而且诱导1型辅助性T细胞（Th 1）相关IgG 2a抗体的产生增强。这些结果表明，缺乏功能性Btk的小鼠在暴露于吸入性过敏原时倾向于产生以Th 1和Th 2细胞为特征的过度免疫应答。许多研究指出树突状细胞（DC）在协调Th发育和激活中的中心作用。我们的初步结果表明，Btk表达于骨髓来源的DC（BMDCs）和脾DC和Btk -/-小鼠来源的BMDCs表现出增加的MHC II类分子的上调响应脂多糖，相比野生型细胞。我们的数据还表明，从btk -/-小鼠脾DCs有更强的能力，刺激抗原特异性T细胞增殖和生产的Th 1和Th 2细胞因子。这些结果促使我们研究Btk在Th 2依赖性气道炎症以及非Th 2依赖性情况下DC的发育、成熟和功能中的作用。由于BMDCs表达Tec（Btk的近亲）和几种Src家族激酶，可以调节Btk活性，因此研究这些激酶在DC生物学中的作用也将是重要的。这是DC生物学中探索较少的领域。我们的努力将有希望确定药物干预治疗哮喘和其他免疫性疾病的新靶点。

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.