Immune response to Pneumocystis in simian model of AIDS

描述（由申请方提供）：肺孢子虫肺炎（PCP）仍然是HIV感染患者发病和死亡的重要原因。CD 4 + T细胞对肺孢子虫（Pc）的清除至关重要，然而其他免疫效应物在控制这种感染或促进肺组织损伤中的作用尚不清楚。PC在肺中的存在诱导强烈的炎症反应，但这种反应的生理意义尚不清楚，并且HIV感染本身可导致可引起急性或慢性肺损伤的炎症反应。我们已经开发了一种新的，非人灵长类动物模型的SIV和PC的共同感染，密切代表了艾滋病的免疫功能障碍，我们建议使用这个模型来研究SIV和PC的相互作用，以确定免疫介质，可以利用更好地控制PC感染和改善肺损伤。本提案的具体目的是：1）检验以下假设：在SIV感染的猴中，与PC相关的CD 8 T细胞为主的淋巴细胞性肺泡炎以及由此产生的炎症反应导致SIV感染恶化并进展为AIDS。将确定浸润细胞的特异性和功能，并且我们将确定这种反应对疾病进展是否具有保护性或有害作用; 2）为了检验以下假设：与SIV感染的猴中的PC定植和感染延长相关的特异性炎症反应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联。此外，我们将测试局部递送白细胞介素-10在控制肺部炎症和损伤中的作用; 3）测试局部体液应答有助于SIV感染猴中PC的清除的假设。我们将表征来自SIV/Pc接种动物的系列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抗原和应答的Th 2偏斜对SIV/Pc接种动物控制感染的能力的影响。这些研究将开始，以确定在艾滋病免疫抑制的背景下，PC的保护性和有害的免疫反应，并有助于表征免疫治疗和预防艾滋病相关的PC感染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.