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: 6890426
• 负责人: JOERG KOEHL
• 金额: $ 37.25万
• 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/6890426
• 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）：过去几十年来，人们注意到过敏性哮喘的发病率、发病率和死亡率惊人地增加。尽管众所周知，过敏性哮喘是 Th2 细胞依赖性过程，但致病性 Th2 细胞发育的分子机制以及它们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，表明先天免疫反应的介质过敏毒素 (AT) C3a 和 C5a 在实验性哮喘的病理生理学中发挥着重要作用。长期以来，这两种 AT 都被认为是促炎功能的介体和平滑肌收缩的诱导剂，这些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。具体来说，C3a 受体的遗传缺失会减弱与 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 相互作用的阻断则具有相反的效果。这些 AT 在过敏反应中发挥关键作用的确切机制仍不清楚。我们的初步数据强烈表明，C5a 通过诱导来自抗原呈递细胞的 Th1 促进细胞因子 IL-12 来调节 Th 分化。 因此，本研究的中心目标是明确 AT 在过敏性哮喘发病机制中的复杂作用。具体来说，我们将测试 AT 在两个层面上调节过敏反应的假设：(A) T 细胞极化的启动和维持； (B) 通过直接和间接影响气道平滑肌激活来调节过敏效应机制。具体目标是：（1）确定C3a和C5a在调节体内过敏性哮喘中所发挥的机制作用的动力学和动力学； (2) 明确 C3a 和 CSa 在致敏阶段偏向 T 细胞分化的机制； (3) 确定效应期 C3a 和 C5a 介导的气道收缩和炎症的下游机制。 这些研究的结果应该为过敏性哮喘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不断增加的疾病。