CD4 T cell-mediated lung damage in Pneumocystis pneumonia

描述(由申请人提供)：已开始HAART治疗的艾滋病患者，当他们变得具有CD4T细胞能力时，可能会发展为肺部炎症性疾病(如IRIS)。我们最近发现，在没有B细胞的情况下，肺孢子虫属(PC)真菌感染可以在小鼠的肺内积聚CD4T细胞，导致严重的肺损伤，而不清除PC。然而，我们先前发现，CD4T细胞在免疫活性小鼠中产生并转移到PC感染的SCID小鼠中，清除了受体小鼠中的PC感染。此外，Lund等人最近的研究。这表明，来自野生型小鼠的PC免疫的CD4T细胞被动地转移到PC感染的SCID小鼠体内可以清除感染，而从免疫的MT小鼠转移的CD4T细胞则不能清除感染。这些数据有力地表明，在肺炎肺炎中可以产生具有不同保护和破坏效应功能的CD4T细胞亚群。因此，我们假设，当CD4细胞重新填充CD4T细胞缺陷的宿主时，可以诱导出不同的CD4T细胞亚群，它们清除PC和/或导致肺损伤的能力不同。为了解决这一假说，我们建议实现以下特定目标：目的1.描述随着CD4T细胞数量的恢复，CD4 T细胞缺陷小鼠对PC感染的免疫和炎症反应；目的2.确定在PC诱导的IRIS过程中，CD4T细胞与CD8 T细胞、CD4 Treg细胞和B细胞的相互作用如何影响肺损伤；目的3.确定效应器CD4T细胞导致肺损伤的机制。为了合理地开发治疗方法来改善IRIS中CD4T细胞介导的肺损伤，我们必须了解这种损伤发生的机制。拟议的特定目标将确定导致CD4T细胞介导的肺损伤的细胞因子、细胞、细胞相互作用和细胞功能，例如IRIS中发生的损伤。确定这些因子和调节这些反应的分子将反过来确定艾滋病患者IRIS和肺动脉高压等疾病的治疗靶点。

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.