Complement and allergic asthma

描述(由申请人提供)：过敏性哮喘是一个主要的公共卫生问题，在过去20年中患病率显著增加。由于对其发病机制的认识不足，目前对哮喘的治疗方法，如全身应用皮质类固醇和吸入β-激动剂等，远远不是最理想的，需要开发新的治疗方法。补体系统是哮喘治疗的潜在新靶点之一。本R21的应用重点是探讨补体蛋白备解素在哮喘发病机制中的作用及其靶向治疗的可行性。备解素是一种血浆糖蛋白，也是唯一已知的补体级联的正调节因子。它通过稳定C3转换酶C3bBb来促进替代途径(AP)补体的激活。最近的证据表明，备解素还可以作为一种模式识别分子与选择性靶表面结合，启动AP补体激活。此外，在包括K/BxN关节炎在内的几种AP补体介导的组织损伤模型中，我们发现备解素参与了疾病的发病机制。这一应用的总体目标是验证以下假设：备解素通过在哮喘的致敏和/或效应期促进AP补体激活而参与过敏性哮喘的发病机制，因此可能是哮喘的一个有吸引力的治疗靶点。我们将在这一试点项目中实现三个具体目标：1)利用卵清蛋白吸入模型，确定备解素的遗传缺陷是否能保护小鼠免受过敏原诱导的气道炎症和气道高反应性(AHR)的影响；2)通过将备解素基因敲除小鼠与人备解素转基因小鼠杂交，建立该品系的过敏原诱导的气道炎症和AHR模型，并建立该品系的过敏原诱导的气道炎症和AHR模型；3)利用“备解素人源化”小鼠和抗人备解素单抗，确定备解素在变应原诱导的气道炎症和AHR中的治疗靶向的可行性。

DESCRIPTION (provided by applicant): Allergic asthma is a major public health problem that has increased markedly in prevalence in the past two decades. Due to insufficient understanding of its pathogenic mechanisms, the current treatments of asthma such as administration of systemic corticosteroids and inhaled beta agonists are far from optimal and there is a need for novel therapeutic approaches to be developed. One of the potential new targets for asthma therapy is the complement system. The focus of this R21 application is to explore the role of the complement protein properdin in the pathogenesis of asthma and the feasibility of its therapeutic targeting in this disease. Properdin is a plasma glycoprotein and th only known positive regulator of the complement cascade. It facilitates alternative pathway (AP) complement activation by stabilizing the C3 convertase C3bBb. Recent evidence has shown that properdin may also work as a pattern recognition molecule to bind to selective target surfaces and initiate AP complement activation. Moreover, in several AP complement-mediated tissue injury models including K/BxN arthritis, we have found that properdin contributed to disease pathogenesis. The overall objective of this application is to test the hypothesis that properdin is involved in the pathogenesis of allergic asthma by promoting AP complement activation in the sensitization and/or effector phase of asthma and therefore may represent an attractive therapeutic target for asthma. We will achieve three specific aims in this pilot project 1) to determine if genetic deficiency of properdin protects mice from allergen-induced airway inflammation and airway hyperresponsiveness (AHR) using the OVA inhalation model; 2) To create a "properdin-humanized" mouse by crossing properdin knockout mice and human properdin transgenic mice and establish a model of allergen-induced airway inflammation and AHR on this strain; 3) To determine the feasibility of therapeutic targeting of properdin in allergen-induced airway inflammation and AHR using "properdin- humanized" mice and anti-human properdin mAbs.