Immune response to Pneumocystis in simian model of AIDS

艾滋病猿模型对肺孢子菌的免疫反应

• 批准号: 7325716
• 负责人: Karen A Norris
• 金额: $ 58.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325716
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Alveolar; Alveolitis; Animal Testing; Animals; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Biological Response Modifiers; Blood specimen; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Clinical; Collaborations; Data; Development; Disease; Disease Progression; Event; Exhibits; Exposure to; HIV; HIV Infections; Humoral Immunities; IL8 gene; Immune; Immune System Diseases; Immune response; Immunoglobulin Class Switching; Immunology; Immunosuppression; Immunotherapy; Infection; Infection Control; Infiltration; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Interleukin-10; Liquid substance; Longitudinal Studies; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Macaca; Measures; Mediating; Mediator of activation protein; Memory; Modeling; Monkeys; Morbidity - disease rate; Nature; Numbers; Outcome; Pathogenesis; Pathology; Patients; Phase; Physiological; Physiology; Plasma; Pneumocystis; Pneumocystis carinii Pneumonia; Prevention; Production; Recombinants; Reporting; Research Personnel; Respiratory physiology; Role; SIV; Sampling; Specificity; Structure of parenchyma of lung; Symptoms; T-Lymphocyte; Testing; Therapeutic immunosuppression; Tissues; Virus; Virus Replication; Week; Whole Body Plethysmography; base; cytokine; immunosuppressed; lung injury; macrophage; mortality; neutrophil; nonhuman primate; novel; pathogen; peripheral blood; protective effect; pulmonary function; respiratory; response

DESCRIPTION (provided by applicant): Pneumocystis pneumonia (PCP) remains an important cause of morbidity and mortality in HIV-infected patients. CD4+ T cells are critical to clearance of Pneumocystis (Pc), however the role of other immune effectors in controlling this infection or in promoting lung tissue injury is less clear. The presence PC in the lung induces an intense inflammatory response, but the physiologic significance of this response is not well understood, and HIV infection itself can result in inflammatory responses that may cause acute or chronic lung injury. We have developed a novel, non-human primate model of SIV and PC co-infection that closely represents the immune dysfunctions of AIDS, and we propose to use this model to study the interaction of SIV and PC to identify immune mediators that may be exploited to better control PC infection and ameliorate lung injury. The specific aims of this proposal are: 1) To test the hypothesis that the CD8 T cell-predominant lymphocytic alveolitis associated with PC in SIV-infected monkeys and the resultant inflammatory response leads to worsening SIV infection and progression to AIDS. The specificity and function of the infiltrating cells will be determined, and we will determine whether this response has a protective or detrimental effect on disease progression; 2) To test the hypothesis that specific inflammatory responses associated with prolonged PC colonization and infection in SIV-infected monkeys leads to chronic lung injury and worsening pulmonary function. We will measure cellular composition and inflammatory mediators in bronchoalveolar lavage fluid and correlate changes in local immune responses with alterations in lung function. In addition, we will test the effect of local delivery of interleukin-10 in control of lung inflammation and injury; 3) To test the hypothesis that a local humoral response contributes to clearance of PC in SIV-infected monkeys. We will characterize the nature and function of anti-Pc antibodies in serial BAL and plasma samples from SIV/Pc inoculated animals and test the effect of previous exposure to PC antigens and Th2 skewing of the response on the capacity of SIV/Pc-inoculated animals to control the infection. These studies will begin to identify both protective and detrimental immune responses to PC in the context of AIDS immunosuppression and help to characterize novel avenues for immunotherapy and prevention of immune-mediated lung injury in AIDS-associated PC infection.

描述（由申请人提供）：肺炎囊肿（PCP）仍然是HIV感染患者发病率和死亡率的重要原因。 CD4+ T细胞对于清除肺炎（PC）至关重要，但是其他免疫效应子在控制这种感染或促进肺组织损伤中的作用尚不清楚。肺中的PC存在引起强烈的炎症反应，但是该反应的生理意义尚不清楚，HIV感染本身可能导致炎症反应，可能导致急性或慢性肺损伤。我们已经开发了一种新型的，非人类的灵长类动物模型的SIV和PC共同感染，该模型密切代表了艾滋病的免疫功能障碍，我们建议使用该模型研究SIV和PC的相互作用，以鉴定可以利用的免疫介体，以更好地控制PC感染并延伸肺损伤。该提案的具体目的是：1）检验以下假设：与PC相关的CD8 T细胞促性淋巴细胞肺泡炎与SIV感染的猴子相关，并且由此产生的炎症反应会导致SIV感染恶化和对AIDS的进展。将确定浸润细胞的特异性和功能，我们将确定该反应对疾病进展是否具有保护性或有害作用。 2）检验以下假设：SIV感染猴子中与长时间PC定植和感染相关的特定炎症反应会导致慢性肺损伤和肺功能恶化。我们将测量支气管肺泡灌洗液中的细胞组成和炎症介质，并将局部免疫反应的变化与肺功能的改变相关。此外，我们将测试白介素10在控制肺部炎症和损伤方面的局部递送的影响； 3）测试局部体液反应有助于在SIV感染的猴子中清除PC的假设。我们将表征来自SIV/PC接种动物的连续BAL和血浆样品中抗PC抗体的性质和功能，并测试先前暴露于PC抗原的接触以及TH2反应对SIV/PC内部动物的能力控制感染的影响。这些研究将在AIDS免疫抑制的背景下开始鉴定对PC的保护性和有害免疫反应，并有助于表征与AIDS相关PC感染中免疫疗法和预防免疫介导的肺损伤的新型途径。