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Prevention and Treatment of Pneumocystis Pneumonia

肺孢子虫肺炎的防治

基本信息

批准号：
10382422
负责人：
Karen A Norris
金额：
$ 72.99万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-21 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10382422
关键词：
Acute Address Adverse reactions Aging Animals Antibiotics Antibodies Antibody titer measurement Autoimmune Diseases Bone Marrow Transplantation Cancer Patient Chemotherapy-Oncologic Procedure Chronic Obstructive Pulmonary Disease Clinical Clinical Research Clinical Trials Collagen Crohn&apos s disease Data Defect Development Diagnosis Diagnostic Disease Exposure to Generations Goals Guidelines HIV Hematologic Neoplasms Human Humoral Immunities Hyperimmunoglobulin M Syndrome Immune Immune response Immune system Immunity Immunization Immunocompromised Host Immunosuppression Immunotherapeutic agent Impairment Incidence Individual Infection Infection Control Inflammatory Life Lung Macaca mulatta Memory Modeling Monkeys Monoclonal Antibodies Morbidity - disease rate Nature Obstructive Lung Diseases Opportunistic Infections Organ Organ Transplantation Organism Patients Persons Pharmaceutical Preparations Pneumocystis Pneumocystis Infections Pneumocystis carinii Pneumocystis carinii Pneumonia Pneumonia Population Pre-Clinical Model Prevention Prevention strategy Preventive Prophylactic treatment Prospective Studies Protein Subunits Pulmonary Pathology Recombinant Proteins Regimen Reporting Research Resolution Resource-limited setting Rheumatoid Arthritis Risk Role SIV Severe Combined Immunodeficiency Solid Solid Neoplasm Subunit Vaccines Testing Therapeutic Therapeutic Uses Therapeutic immunosuppression Transplant Recipients Treatment Failure Trimethoprim-Sulfamethoxazole Vaccines Vascular Diseases Virus Diseases Work antiretroviral therapy clinically relevant experience immunosuppressed improved innovation innovative technologies insight lung injury mortality natural antibodies nonhuman primate novel therapeutics opportunistic pathogen organ transplant recipient pathogenic fungus patient population pre-clinical prevent prophylactic protective efficacy public health relevance pulmonary function response seropositive vaccine candidate vaccine development ward

项目摘要

The fungal opportunistic pathogen, Pneumocystis (Pc) jirovecii is the causative agent of Pneumocystis pneumonia (PCP), which is of increasing concern in persons receiving immunosuppressive therapies, including organ transplant recipients, cancer patients, individuals with inflammatory disease and in persons experiencing natural immunosuppression due to aging, congenital or acquired immunosuppressive states. In addition, in clinical studies and in non-human primate models, we have shown that persistent Pc colonization is also associated with the development of chronic obstructive pulmonary disease (COPD). Long-term goals of our work are to develop vaccine strategies for the prevention of Pc infection and related pulmonary sequelae in immunocompromised populations and to develop innovative strategies for improved therapies for acute PCP in immunocompromised individuals. To achieve these goals, we have developed pre-clinical, non-human primate models of PCP in drug-induced immunosuppressed animals. We have previously identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pc immunity in non-human primates that is durable and protective against PCP following profound immunosuppression induced by simian immunodeficiency virus infection (SIV) and reported that antibodies to KEX1 are associated with prevention of PCP in human immunocompromised individuals. The objectives to be addressed in the proposed studies are 1) to determine the protective efficacy of the KEX1 vaccine in pre-clinical models of therapeutic immunosuppressive regimens, (e.g., as in organ transplantation) and 2), to harness our extensive data regarding the protective nature of the humoral responses to KEX1 for the development and testing of monoclonal antibodies (mAb) for use in treating acute PCP. We hypothesize that the KEX1 vaccine will induce durable and protective immunity against PCP in immunocompromised individuals. We further hypothesize that treatment of acute PCP with KEX1 mAbs will contribute to resolution of pneumonia and mitigate pulmonary damage associated with the infection. Aim 1 will test the hypothesis that immunization with KEX1 vaccine will elicit protective memory responses and will provide protection from PCP in immunocompromised NHPs. We will evaluate the durability and protective efficacy of the immune response during immunosuppressive therapy. NHPs will be challenged via natural exposure to Pneumocystis and evaluated for clinical disease, immunity, pulmonary function and pathology. Aim 2 will test the hypothesis that KEX1-specific mAbs will effectively treat established PCP in an immunosuppression NHP model. Our innovative technology in mAb generation, combined with a unique and clinically relevant model of PCP in immunosuppressed monkeys, will allow us to define the utility of KEX1 mAbs in treating PCP and advance a novel therapeutic avenue for this disease.

真菌条件致病菌耶氏肺孢子虫是肺孢子虫病的病原体肺炎（PCP），在接受免疫抑制治疗的患者中日益受到关注，包括器官移植受者、癌症患者、患有炎性疾病的个体和经历过癌症的人。由于衰老、先天性或获得性免疫抑制状态而导致的天然免疫抑制。另外在临床研究和非人灵长类动物模型中，我们已经表明持续的Pc定植也是与慢性阻塞性肺疾病（COPD）的发展有关。我们的长期目标目前的工作是开发预防Pc感染和相关肺部疾病的疫苗策略。免疫功能低下人群的后遗症，并制定创新的战略，免疫功能低下个体的急性PCP治疗。为了实现这些目标，我们制定了药物诱导免疫抑制动物中PCP的临床前非人灵长类动物模型。我们有先前鉴定了一种重组蛋白亚单位疫苗KEX1，其在小鼠中诱导了稳健的抗Pc免疫，非人灵长类动物在严重免疫抑制后对五氯苯酚具有持久的保护作用猴免疫缺陷病毒感染（SIV）诱导，并报道KEX 1抗体与预防免疫力低下的人感染PCP。《行动纲领》所要达到的目标拟议的研究是1）确定KEX 1疫苗在临床前模型中的保护效力，治疗性免疫抑制方案，（例如，如器官移植）和2），利用我们广泛的关于对KEX 1的体液应答的保护性质的数据，用于开发和测试用于治疗急性PCP的单克隆抗体（mAb）。我们假设KEX1疫苗会诱导免疫力低下者对五氯苯酚具有持久的保护性免疫力。我们进一步假设，用KEX1单克隆抗体治疗急性PCP将有助于肺炎的消退，与感染有关的损伤。目的1将检验用KEX 1疫苗免疫将引发保护性记忆反应，并将为免疫功能低下的NHP提供保护。我们将评估免疫抑制治疗期间免疫应答的持久性和保护效力。 NHP将通过自然暴露于肺孢子虫进行挑战，并评价临床疾病、免疫力，肺功能和病理学。目的2将检验KEX 1特异性mAb将有效治疗在免疫抑制NHP模型中建立PCP。我们在mAb生成方面的创新技术，结合免疫抑制猴中PCP的独特和临床相关模型，将使我们能够明确KEX1单克隆抗体在治疗PCP中的作用，并为这种疾病提供新的治疗途径。