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: 6823173
• 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/6823173
• 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了惊人的增长。虽然已经确定过敏性哮喘是一个依赖Th2细胞的过程，但致病性Th2细胞发育的分子机制及其赋予疾病的机制目前尚不清楚。