Complement in Allergic Asthma: The role of C3a and C5a

补体在过敏性哮喘中的作用：C3a 和 C5a 的作用

• 批准号: 7052073
• 负责人: JOERG KOEHL
• 金额: $ 36.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052073
• 关键词: anaphylatoxins; asthma; cell differentiation; cellular polarity; complement; dendritic cells; enzyme activity; genetically modified animals; helper T lymphocyte; immune response; immunoregulation; inflammation; laboratory mouse; lung lavage; mitogen activated protein kinase; molecular pathology; muscle contraction; protein structure function; smooth muscle

DESCRIPTION (provided by applicant): Alarming increases in the incidence, morbidity and mortality of allergic asthma have been noted over the last few decades. Although it is well established that allergic asthma is a Th2 cell dependent process, the molecular mechanisms underlying the development of pathogenic Th2 cells and the mechanisms by which they confer disease are currently unknown. Recent studies in murine models of asthma provide compelling evidence that mediators of the innate immune response, the anaphylatoxins (AT) C3a and C5a, play important roles in the pathophysiology of experimental asthma. Both ATs are long recognized as mediators of proinflammatory functions and inductors of smooth muscle contraction, features that are both relevant to the allergic phenotype. However, recent data suggest novel opposing immunoregulatory roles for the ATs at the level of T-cell polarization. Specifically, genetic deletion of the C3a receptor attenuates the allergic phenotype associated with diminished Th2 cytokine production, while genetic deficiency of C5 or blockade of the C5a/C5aR interaction has the opposite effect. The exact mechanisms underlying the pivotal roles of these ATs in allergic responses remain unknown. Our preliminary data strongly suggest that C5a regulates Th differentiation by the induction of the Th1-promoting cytokine IL-12 from antigen presenting cells. Thus the central goal of the proposed studies is to define the complex role of ATs in the pathogenesis of allergic asthma. Specifically, we will test the hypotheses that ATs regulate the allergic response at two levels: (A) the initiation and maintenance of T cell polarization; and (B) the regulation of the allergic effector mechanisms by direct and indirect effects on airway smooth muscle activation. The specific aims are: (1) to determine the kinetics and dynamics of the mechanistic roles played by C3a and C5a in regulating allergic asthma in vivo; (2) to define the mechanisms by which C3a and CSa bias T cell differentiation during the sensitization phase; and (3) to determine downstream mechanisms of C3a- and C5a mediated airway contraction and inflammation during the effector phase. The results of these studies should provide valuable insight into the immunopathogenic mechanisms involved in the development of allergic asthma and may lead to the development of novel immunotherapeutic strategies for the treatment of this ever-increasing disease.

描述(由申请人提供)：在过去的几十年里，过敏性哮喘的发病率、发病率和死亡率都有惊人的增长。虽然众所周知，过敏性哮喘是Th2细胞依赖的过程，但致病Th2细胞发展的分子机制及其导致疾病的机制目前尚不清楚。 最近对小鼠哮喘模型的研究提供了令人信服的证据，表明天然免疫反应的介质--过敏性毒素(AT)C3a和C5a在实验性哮喘的病理生理学中发挥着重要作用。这两种ATS长期以来都被认为是促炎功能的介质和平滑肌收缩的诱导剂，这两个特征都与过敏性表型相关。然而，最近的数据表明，ATS在T细胞极化水平上具有新的相反的免疫调节作用。具体地说，C3a受体的基因缺失可以减弱与Th2细胞因子产生减少相关的过敏表型，而C5的遗传缺陷或C5a/C5aR相互作用的阻断具有相反的效果。这些ATS在过敏反应中起关键作用的确切机制尚不清楚。我们的初步数据有力地表明，C5a通过从抗原提呈细胞诱导Th1促进细胞因子IL-12来调节Th的分化。 因此，拟议研究的中心目标是确定ATS在过敏性哮喘发病机制中的复杂作用。具体地说，我们将检验ATS在两个水平上调节过敏反应的假设：(A)启动和维持T细胞极化；(B)通过直接和间接作用于气道平滑肌激活来调节过敏效应机制。其具体目的是：(1)确定C3a和C5a在体内调节过敏性哮喘中的作用的动力学和动力学；(2)确定C3a和CsA在致敏阶段偏向T细胞分化的机制；(3)确定C3a和C5a在效应期介导呼吸道收缩和炎症的下游机制。 这些研究的结果将对过敏性哮喘的发生发展中涉及的免疫致病机制提供有价值的见解，并可能导致开发新的免疫治疗策略来治疗这种日益增长的疾病。