Passive and Active Immunization for Pneumocystis

 描述（由申请方提供）：肺孢子虫（Pc）仍然是免疫功能低下患者中危及生命的肺炎（PcP）的常见原因。CDC估计，美国每年有7，500 - 10，000例病例。尽管抗生素的可用性，但在过去二十年中，与PCP相关的死亡率几乎没有变化。因此，高危患者可以从预防和治疗感染的新方法中受益。免疫接种，无论是主动的还是被动的，都有可能做到这两点。我们提供了初步的数据，从小鼠模型的PcP支持的好处，主动和被动免疫，包括证据表明，深刻的被动免疫的免疫调节作用。由于宿主的免疫应答明显对PcP的发病机制做出了重大贡献，因此免疫治疗的免疫调节方面是特别有吸引力的研究领域。我们已经产生了三种独特的单克隆抗体（Mab），它们具有罕见的特性，既具有体内抗Pc的生物活性，又能结合动物和人源Pc上的保守表位。这些是非常有趣的抗体，因为它们的交叉反应性质表明：1）它们识别在Pc生命周期中具有关键功能的保守蛋白质; 2）我们可以使用动物模型来合理预测它们治疗人类患者的效用。我们还分离出了被其中两种单克隆抗体识别的分子A12，并证明了其作为亚单位疫苗的有效性，以产生先前未报道的其他Pc疫苗候选物的保护水平。对这种蛋白的免疫识别的进一步研究有可能导致新的免疫疗法和提高对Pc保护机制的理解。我们的目标是解决临床相关的问题，主机和PC的因素，确定免疫反应。我们假设肺泡巨噬细胞（AM）与抗体（Ab）协同作用，通过消除Pc并将肺环境从促炎性转变为抗炎性特征来展示效应子和免疫调节功能。为了实现我们的目标，我们将：1）使用最先进的成像技术来测试AM对于针对Pc的被动免疫的抗微生物活性至关重要的假设; 2）测试AM中的Fc、IL-10依赖性转变为M2表型对于被动免疫后PcP的改善是必要的假设; 3）检验疫苗诱导的免疫受损宿主保护的最终共同途径是由B细胞产生Ab介导的假设;和4）产生我们的单克隆抗体的同种型变体以确定Fc功能对抗-HCV机制的贡献。被动免疫疗法的微生物和免疫调节作用。如果得到验证，我们的假设将导致新的治疗策略，增强真菌清除，同时减弱PcP相关的免疫发病机制。

 DESCRIPTION (provided by applicant): Pneumocystis (Pc) remains a frequent cause of life-threatening pneumonia (PcP) in immunocompromised patients. The CDC estimates that 7,500 - 10,000 cases per year occur in the United States. Despite the availability of antibiotics, PcP-related mortality rates have changed little over the past two decades. Thus, at risk patients could benefit from new approaches to prevent and treat infection. Immunization, either active or passive, has the potential to do both. We provide preliminary data from mouse models of PcP supporting the benefits of both active and passive immunization, including evidence demonstrating profound immunoregulatory effects of passive immunization. Because the host's immune response clearly makes a major contribution to the pathogenesis of PcP, the immunoregulatory aspects of immunotherapy are particularly attractive areas for study. We have produced three unique monoclonal antibodies (Mabs) with the rare characteristics of both having biological activity against Pc in vivo, and also binding to conserved epitopes on animal and human derived Pc. These are highly interesting antibodies because their cross-reactive nature suggests that: 1) they recognize conserved proteins with critical functions in the Pc life cycle; and 2) we can use animal models to reasonably predict their utility for treating human patients. We have also isolated the molecule, called A12, which is recognized by two of these Mabs, and demonstrated its efficacy as a subunit vaccine to produce a level of protection not previously reported for other Pc vaccine candidates. Further study of the immune recognition to this protein has the potential to lead to novel immunotherapies and improved understanding of mechanisms of protection against Pc. Our goal is to address clinically relevant questions regarding host and Pc factors that determine the response to immunization. We hypothesize that the alveolar macrophage (AM), acting in concert with antibody (Ab), demonstrates both effector and immunoregulatory function by eliminating Pc and shifting the pulmonary environment from one of pro- inflammatory to one of anti-inflammatory characteristics. To accomplish our goal we will: 1) use state of the art imaging technology to test the hypothesis that the AM is critical for the antimicrobial activity of passive immunization against Pc; 2) test he hypothesis that a Fc , IL-10 dependent shift in AM to an M2 phenotype is necessary for the improvement in PcP after passive immunization; 3) test the hypothesis that the final common pathway of vaccine induced protection of the immunocompromised host is mediated by B cell production of Ab; and 4) create isotype variants of our Mabs to determine the contribution of Fc function to the mechanism of anti-microbial and immunoregulatory effects of passive immunotherapy. If validated, our hypotheses should lead to novel therapeutic strategies that enhance fungal clearance while attenuating PcP- related immunopathogenesis.