CD4 T cell-mediated lung damage in Pneumocystis pneumonia

描述（由申请人提供）：开始HAART治疗的AIDS患者在CD 4 T细胞活性化时可能发生肺部炎症性疾病（如IRIS）。我们最近已经表明，在没有B细胞的情况下，CD 4 T细胞可以响应于肺孢子虫属（PC）真菌的感染而在小鼠的肺中积聚，导致严重的肺损伤而不清除PC。然而，我们以前发现，在免疫活性小鼠中产生的CD 4 T细胞转移到PC感染的SCID小鼠中，清除了受体小鼠中的PC感染。此外，隆德等人最近的研究表明，来自野生型小鼠的PC免疫CD 4 T细胞被动转移到PC感染的SCID小鼠中清除了感染，而来自免疫MT小鼠的CD 4 T细胞的转移则不能。这些数据有力地表明，具有不同保护性和破坏性效应子功能的CD 4 T细胞亚群可在PC肺炎中产生。因此，我们假设，随着CD 4细胞重新填充CD 4 T细胞缺陷的宿主，可以诱导不同的CD 4 T细胞亚群，其清除PC和/或引起肺损伤的能力不同。为了解决这一假设，我们建议实现以下具体目标：目标1。目的2.描述CD 4 T细胞缺陷小鼠在CD 4 T细胞数量恢复时对PC感染的免疫和炎症反应。确定在PC诱导的IRIS期间，CD 4 T细胞与CD 8 T细胞、CD 4 Treg细胞和B细胞的相互作用如何影响肺损伤;目的3.确定效应CD 4 T细胞引起肺损伤的机制。为了合理地开发治疗方法来改善IRIS中CD 4 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CD 4 T细胞介导的肺损伤，如发生在IRIS。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IRIS和肺动脉高压等疾病的靶点。

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.