Passive and Active Immunization for Pneumocystis

肺孢子虫的被动和主动免疫

• 批准号: 9182862
• 负责人: Francis Gigliotti
• 金额: $ 46.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182862
• 关键词: Ablation; Acridine Orange; Active Immunization; Address; Alveolar Macrophages; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibodies; Antibody Formation; Antibody Response; Antibody-mediated protection; Antigens; Area; Attenuated; B-Lymphocytes; Basic Science; Binding; Biological; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Complement; Contracts; Data; Data Science; Development; Effector Cell; Environment; Epitopes; Ferrets; Generations; Goals; Human; Imaging technology; Immune; Immune response; Immune system; Immunization; Immunocompromised Host; Immunoglobulin Class Switching; Immunotherapy; Infection; Inflammatory; Intention; Interleukin-10; Lead; Life; Life Cycle Stages; Lung; Mediating; Mission; Monkeys; Monoclonal Antibodies; Morality; Mus; Mutagenesis; Nature; Organism; Outcome; Passive Immunization; Passive Immunotherapy; Pathogenesis; Pathway interactions; Patient Care; Patient risk; Patients; Phenotype; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Pneumonia; Production; Prophylactic treatment; Proteins; Rattus; Reporting; Research; Resolution; Specificity; Subunit Vaccines; Testing; Therapeutic Intervention; Translating; United States; United States National Institutes of Health; Vaccines; Variant; Ventilator; Work; antimicrobial; base; clinically relevant; cross reactivity; immunoregulation; immunosuppressed; improved; in vivo; inflammatory milieu; macrophage; mortality; mouse model; novel; novel strategies; novel therapeutics; passive antibodies; prevent; public health relevance; response; vaccine candidate; vaccine response; vaccine trial; vaccine-induced immunity

 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.

 描述（由申请人提供）：肺孢子虫 (Pc) 仍然是免疫功能低下患者危及生命的肺炎 (PcP) 的常见原因。 CDC 估计，尽管有抗生素，美国每年仍会发生 7,500 - 10,000 例 PcP 病例。过去二十年来，相关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，无论是主动免疫还是治疗免疫。我们提供了 PcP 小鼠模型的初步数据，支持主动免疫和被动免疫的益处，包括证明被动免疫具有深远免疫调节作用的证据，因为宿主的免疫反应显然对主动免疫有重要贡献。 PcP 的发病机制、免疫治疗的免疫调节方面是特别有吸引力的研究领域，我们已经生产了三种独特的单克隆抗体 (Mab)，其具有罕见的特性，既具有体内抗 Pc 的生物活性，又与保守的结合。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的效用。我们还分离出了一种名为 A12 的分子，它被其中两种 Mab 所识别，并证明了其作为亚单位疫苗的功效，可以产生之前其他 PC 候选疫苗未报道过的保护水平。免疫识别这种蛋白质有可能带来新的免疫疗法，并提高对 PC 保护机制的理解。我们的目标是解决决定免疫反应的宿主和 PC 因素的临床相关问题。与抗体 (Ab) 协同作用，通过消除 Pc 并将肺部环境从促炎特征转变为抗炎特征之一，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 Pc 的状态。艺术成像技术来检验 AM 对于 Pc 被动免疫的抗菌活性至关重要的假设；2) 检验 AM 向 M2 表型的 Fc、IL-10 依赖性转变对于 PcP 的改善是必要的假设；被动免疫；3) 测试疫苗诱导的免疫受损宿主保护的最终共同途径是由 B 细胞产生抗体介导的假设；4) 创建我们的单克隆抗体的同种型变体，以确定Fc 对被动免疫疗法的抗微生物和免疫调节作用机制的作用如果得到验证，我们的假设应该会产生新的治疗策略，增强真菌清除率，同时减弱 PcP 相关的免疫发病机制。