Immune response to Pneumocystis in simian model of AIDS

描述(由申请人提供)：肺孢子虫肺炎(PCP)仍然是艾滋病毒感染患者发病和死亡的重要原因。CD4T细胞对肺孢子虫(Pc)的清除至关重要，然而，其他免疫效应分子在控制这种感染或促进肺组织损伤方面的作用尚不清楚。PC存在于肺内可引起强烈的炎症反应，但这种反应的生理意义尚不清楚，而HIV感染本身可引起炎症反应，可能导致急性或慢性肺损伤。我们已经建立了一种新的非人类灵长类动物SIV和PC合并感染的模型，该模型与艾滋病的免疫功能障碍密切相关，我们建议使用该模型来研究SIV和PC的相互作用，以寻找可能被利用来更好地控制PC感染和改善肺损伤的免疫介质。这一建议的具体目的是：1)验证SIV感染的猴子中以CD8 T细胞为主的淋巴细胞性肺泡炎与PC相关的假说，以及由此产生的炎症反应导致SIV感染恶化并进展为艾滋病。将确定渗透细胞的特异性和功能，我们将确定这种反应对疾病进展具有保护作用还是有害影响；2)测试与SIV感染猴子的PC长期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的假设。我们将测量支气管肺泡灌洗液中的细胞成分和炎症介质，并将局部免疫反应的变化与肺功能的变化联系起来。此外，我们还将测试局部注射IL-10在控制肺部炎症和损伤方面的效果；3)测试局部体液反应有助于SIV感染猴子体内PC清除的假设。我们将对SIV/Pc接种动物的连续BAL和血浆样本中抗Pc抗体的性质和功能进行表征，并测试既往暴露于PC抗原和Th2偏斜对SIV/Pc接种动物控制感染能力的影响。这些研究将开始确定在艾滋病免疫抑制的背景下对PC的保护性和破坏性免疫反应，并有助于表征免疫治疗和预防艾滋病相关PC感染中免疫介导的肺损伤的新途径。

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.