Complement in Allergic Asthma: The role of C3a and C5a

描述（由申请人提供）：在过去的几十年中，过敏性哮喘的发病率、发病率和死亡率惊人地增加。虽然过敏性哮喘是一个Th 2细胞依赖性过程，但致病性Th 2细胞发展的分子机制及其致病机制目前尚不清楚。 最近在小鼠哮喘模型中的研究提供了令人信服的证据，即先天免疫应答的介质，过敏毒素（AT）C3 a和C5 a，在实验性哮喘的病理生理学中起重要作用。这两种AT长期以来被认为是促炎功能的介质和平滑肌收缩的诱导剂，其特征都与过敏表型相关。然而，最近的数据表明，AT在T细胞极化水平上具有新的相反的免疫调节作用。具体而言，C3 a受体的遗传缺失减弱了与Th 2细胞因子产生减少相关的过敏性表型，而C5的遗传缺陷或C5 a/C5 aR相互作用的阻断具有相反的效果。这些AT在过敏反应中的关键作用的确切机制仍不清楚。我们的初步数据有力地表明，C5 a调节Th分化的诱导Th 1促进细胞因子IL-12从抗原呈递细胞。 因此，拟议研究的中心目标是确定AT在过敏性哮喘发病机制中的复杂作用。具体而言，我们将测试的假设，AT调节过敏反应在两个水平：（A）的启动和维持T细胞极化;和（B）调节过敏效应机制的直接和间接影响气道平滑肌激活。具体目标是：（1）确定C3 a和C5 a在体内调节过敏性哮喘中所起的机制作用的动力学和动力学;（2）确定C3 a和C5 a在致敏阶段偏向T细胞分化的机制;和（3）确定C3 a和C5 a在效应阶段介导的气道收缩和炎症的下游机制。 这些研究的结果应该提供有价值的洞察过敏性哮喘的发展所涉及的免疫病理机制，并可能导致新的免疫治疗策略的发展，用于治疗这种不断增加的疾病。

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.