Monoclonal Antibodies for the Study of P. carinii

描述(申请人提供)：这项正在进行的研究项目的长期目标是利用单抗(MAb)生产技术作为更好地了解卡氏肺孢子虫宿主与寄生虫相互作用的工具。我们对利用被动和主动免疫疗法来预防或治疗卡氏肺孢子虫肺炎(PCP)特别感兴趣。在上一次授权期内，我们发现我们生产的单抗之一对PCP具有显著的保护作用。此外，我们已经能够使用该单抗来识别抗体识别的“保护性”表位，以及识别包含该感兴趣表位的两个卡氏肺孢子虫抗原(A12和KEX1)。根据我们到目前为止的进展，我们为这个项目提出两个压倒一切的目标。我们的第一个目标是表征和利用这种保护性的抗原-抗体相互作用，以发展预防PCP的主动和被动免疫。我们的第二个目标是确定被动免疫治疗对主动性PCP结局的影响，特别强调抗体在PCP期间肺损伤的免疫发病机制中的作用。为了实现这两个目标，我们提出了以下具体目标： 1)克隆和鉴定编码A12多肽基因的全长cDNA，并确定A12抗原是否定位于卡氏肺吸虫表面。 2)我们将确定含有单抗4F11识别表位的重组抗原主动免疫的免疫原性和有效性。 3)我们将研究被动抗体注射对已建立的PCP的影响。具体地说，我们将确定被动抗体治疗对PCP期间观察到的免疫介导的肺损伤的影响。我们还将确定被动抗体治疗与常规抗菌治疗相结合的微生物学效果。

DESCRIPTION (provided by applicant): This ongoing research project has had as its long-term goal utilizing the technology of monoclonal antibody (mab) production as a tool to better understand P. carinii host-parasite interactions. We are particularly interested in utilizing passive and active immunotherapy to prevent or treat P. carinii pneumonia (Pcp). During the last grant period we showed that one of the mab that we produced conferred significant protection against Pcp. Furthermore, we have been able to use that mab to identify the "protective" epitope recognized by the antibody as well as identifying two P. carinii antigens (A12 and KEX1) which contain this epitope of interest. Based on our progress to date, we propose two overriding goals for this project. Our first goal is to characterize and exploit this protective antigen-antibody interaction for the purpose of developing active and passive immunization for the prevention of Pcp. Our second goal is to define the effect of passive immunotherapy, with specific antibody, on the outcome of active Pcp with particular emphasis on the effect of antibody on the immunopathogenesis of lung injury during Pcp. To achieve these two goals we propose the following specific aims: 1) We will clone and characterize the complete cDNA of the gene encoding the A12 polypeptide and determine whether the A12 antigen is localized to the surface of P. carinii. 2) We will define the immunogenicity and efficacy of active immunization with recombinant antigens containing the epitopes recognized by mab 4F11. 3) We will examine the effect of passive antibody administration on established Pcp. Specifically, we will define the effect of passive antibody therapy on immune-mediated lung injury observed during Pcp. We will also determine the microbiologic effect of combining passive antibody therapy with conventional antimicrobial therapy.