Monoclonal antibodies to inhibit Aspergillus germination

烟曲霉是一种普遍存在的真菌病原体， 免疫功能低下的患者，最常见于严重中性粒细胞减少症或接受器官移植的患者。 移植侵袭性曲霉病（IA）的发病率在过去三十年中稳步上升， 死亡率目前在45- 90%之间。这个提议的目的是为了增进我们对 用单克隆抗体（MAb）研究侵袭性曲霉病的宿主免疫和宿主-病原体相互作用 318)抑制萌发，从孢子形式到菌丝形式的相变是必需的， 侵袭性肺曲霉菌病小鼠的侵袭性和存活率。发芽抑制单克隆抗体 可能被开发用作免疫预防剂或诊断剂。单克隆抗体免疫疗法是 不仅越来越成功地应用于治疗难治性或耐药性微生物病原体， 到各种疾病状态，如恶性肿瘤、哮喘和自身免疫性疾病。此外，识别 与保护性单克隆抗体结合的真菌分子可能为药物开发定义新的靶点。三个具体 提出了以下目标：1.为了鉴定MAb 318结合的蛋白质并确定其结合的动力学， 在萌发期间表达; 2.单克隆抗体318与分生孢子体外相互作用的研究 肺泡巨噬细胞的存在和不存在; 3.理解保护功效的机制 被动给予的抗50 kDa抗原的单克隆抗体。预计这项研究将确定真菌 对于萌发和开始确定它们与宿主免疫应答的相互作用重要的分子。

Aspergillus fumigatus, a ubiquitous fungal pathogen, causes invasive disease in severely immunocompromised patients, most often in those with profound neutropenia or who have undergone organ transplantation. The incidence of invasive aspergillosis (IA) has risen steadily over the past three decades, and mortality rates currently range from 45-90%. The goal of this proposal is to advance our understanding of host immunity and host-pathogen interactions in invasive aspergillosis using a monoclonal antibody (MAb 318) that inhibits germination, the phase transition from the spore form to hyphal form that is required for invasion, and prolongs survival in mice with invasive pulmonary aspergillosis. Germination-inhibitory MAbs potentially could be developed for use as immunoprophylactic or diagnostic agents. MAb immunotherapy is being applied with increasing success not only to treatment of refractory or resistant microbial pathogens, but to disease states as diverse as malignancy, asthma and autoimmune disorders. Additionally, identification of fungal molecules bound by protective MAbs may define novel targets for drug development. Three specific aims are proposed: 1. To identify the protein bound by MAb 318 and determine the kinetics of its expression during germination; 2. Tounderstand the interaction between conidia and MAb 318 in vitro in the presence and absence of alveolar macrophages; 3. Tounderstand the mechanism of protective efficacy of passively administered MAbs to the 50 kDa antigen. It is anticipated that this study will identify fungal molecules important for germination and begin to define their interaction with host immune responses.