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.