CD4 T cell-mediated lung damage in Pneumocystis pneumonia

描述（由申请人提供）：接受HAART治疗的艾滋病患者随着CD4 T细胞能力的增强，可能会发展为肺部炎症性疾病（如IRIS）。我们最近的研究表明，在没有B细胞的情况下，CD4 T细胞可以在小鼠肺部积聚，以响应肺囊虫属真菌（PC）的感染，导致严重的肺损伤，而不清除PC。然而，我们之前发现，在免疫正常小鼠中产生的CD4 T细胞转移到感染PC的SCID小鼠中，清除了受体小鼠的PC感染。此外，Lund等人最近的研究表明，将野生型小鼠的pc免疫CD4 T细胞被动转移到pc感染的SCID小鼠中可以清除感染，而从免疫MT小鼠转移的CD4 T细胞则不能清除感染。这些数据强烈提示，在PC肺炎中可产生具有不同保护和破坏效应功能的CD4 T细胞亚群。因此，我们假设当CD4细胞重新填充CD4 T细胞缺陷宿主时，可以诱导不同的CD4 T细胞亚群，其清除PC和/或引起肺损伤的能力各不相同。为了解决这一假设，我们建议实现以下具体目标：目标1。描述CD4 T细胞缺陷小鼠在CD4 T细胞数量恢复时对PC感染的免疫和炎症反应；目标2。确定CD4 T细胞与CD8 T细胞、CD4 Treg细胞和B细胞的相互作用如何影响pc诱导的IRIS肺损伤；目标3。确定效应CD4 T细胞在肺部造成损伤的机制。为了合理开发治疗方法来改善IRIS中CD4 T细胞介导的肺损伤，我们必须了解这种损伤发生的机制。提出的具体目标将确定细胞因子，细胞，细胞相互作用和细胞功能，负责CD4 T细胞介导的肺损伤，如发生在IRIS中。确定这些参与者和调节这些反应的分子将反过来确定治疗艾滋病患者的IRIS和肺动脉高压等疾病的靶点。公共卫生相关性：尽管HAART已被证明在改善艾滋病毒感染者的生活质量方面取得了成功，但这些患者中的许多人正在经历其他问题，包括炎症性疾病，如IRIS和肺动脉高压。我们的初步证据表明，这些类型的问题可能是由CD4 T细胞引起的，因为它们重新填充了先前耗尽的宿主。这里提出的这些研究将使我们更好地了解在这些情况下对宿主造成损害的机制，从而导致合理开发治疗诸如IRIS和与HIV感染相关的肺动脉高压等疾病的疗法。

DESCRIPTION (provided by applicant): AIDS patients that have initiated HAART treatment can develop lung inflammatory disease (such as IRIS) as they become CD4 T cell-competent. We have recently shown that CD4 T cells, in the absence of B cells, can accumulate in the lungs of mice in response to infection by the fungi of the genus Pneumocystis (PC) resulting in severe lung damage without clearance of the PC. However, we found previously that CD4 T cells generated in immunocompetent mice and transferred to PC-infected SCID mice, clear the PC infection in the recipient mice. In addition, recent studies by Lund et al. indicate that PC-immune CD4 T cells from wild type mice passively transferred into PC-infected SCID mice clear the infection, whereas transfer of CD4 T cells from immune ¿MT mice do not. These data strongly suggest that subpopulations of CD4 T cells, with different protective and damaging effector functions, can be generated in PC pneumonia. Thus, we hypothesize that as CD4 cells repopulate a CD4 T cell-deficient host, different subpopulations of CD4 T cells can be induced that vary in their ability to clear PC and/or cause lung damage. To address this hypothesis we propose to accomplish the following specific aims: Aim 1. To describe the immune and inflammatory responses to PC infection in CD4 T cell-deficient mice as CD4 T cell numbers are restored; Aim 2. To determine how CD4 T cell interactions with CD8 T cells, CD4 Treg cells, and B cells affects lung damage during PC-induced IRIS; Aim 3. To determine the mechanisms by which effector CD4 T cells cause damage in the lungs. In order to rationally develop treatments to ameliorate CD4 T cell-mediated damage in the lungs in IRIS, we must understand the mechanisms by which this damage occurs. The proposed specific aims will identify cytokines, cells, cell interactions, and cell functions that are responsible for CD4 T cell-mediated lung damage such as that which occurs in IRIS. Identifying these players and the molecules that regulate these responses will in turn identify targets for therapies for conditions such as IRIS and pulmonary hypertension in AIDS patients. PUBLIC HEALTH RELEVANCE: Although HAART has proved successful in improving the quality of life of HIV-infected individuals, many of these patients are experiencing other problems including inflammatory disease such as IRIS and pulmonary hypertension. Our preliminary evidence indicates that these types of problems can be caused by CD4 T cells as they repopulate a previously depleted host. Studies as these proposed here will result in a better understanding of the mechanisms that cause damage to the host in these conditions which in turn can lead to the rational development of therapies to treat conditions such as IRIS and pulmonary hypertension associated with HIV infection.