CD8 T-Cells and Host Defense Against P. Carinii

描述(由申请人提供)：尽管目前有治疗艾滋病毒感染及其并发症的策略，但卡氏肺孢子虫肺炎(PCP)仍然是一个常见的临床问题。虽然众所周知，CD4+淋巴细胞计数与PC感染的风险有关，但单核巨噬细胞、CD8+细胞、γ/Delta T细胞及其分泌的细胞因子在宿主防御PC感染中的作用远不清楚。在之前的资助期间，我们已经证明，在没有CD4+T细胞的情况下，TCL CD8+T细胞(由强大的内源性干扰素-伽马(IFN)产生所定义)与根除PC有关。我们实验室使用一种新的体外PC杀伤实验进行的初步研究表明，TCL CD8+T细胞具有优先的PC杀伤活性，并增强巨噬细胞介导的杀伤。基于这些研究，我们假设CD8+T细胞的特定亚群是抗PC的效应细胞。我们将通过以下具体目标来检验这一假设。具体目的1.我们的假设预测，使用腺病毒介导的基因转移(ADIFN)过表达干扰素-g将促进具有TCL表型的CXCR3+，CD8+T细胞的募集。我们的假设预测在AdlFN模型中，这些CXCR3+细胞是CD8+T细胞介导的PC清除所必需的。具体目的3.我们的假设预测，与其他CD8+T细胞相比，CXCR3+/TCL+/CD8+T细胞在体外对PC具有优先杀伤作用，并在重组的SCID小鼠模型中对卡氏肺孢子虫具有清除作用。这些研究将利用一种针对一种重要的机会性病原体的新形式的免疫疗法来调查非CD4依赖的宿主防御。这些研究的结果不仅有助于我们进一步了解肺宿主的防御，而且可能导致治疗机会性感染的新方法。

DESCRIPTION (provided by applicant): Despite current strategies to treat HIV infection and its complications, Pneumocystis carinii pneumonia (PCP) remains a common clinical problem. Although there is a well-known relationship between CD4+ lymphocyte count and the risk of PC infection, the role of mononuclear phagocytes, CD8+ cells, gamma/delta T cells, and their secreted cytokines in host defense against this infection are far less clear. During the prior funding period, we have demonstrated that Tcl CD8+ T-cells, as defined by strong endogenous interferon-gamma (IFN) production, are associated with eradication of PC in the absence of CD4+ T-cells. Preliminary studies in our lab using a novel in vitro PC killing assay demonstrate that Tcl CD8+ T-cells have preferential PC killing activity and also augment macrophage-mediated killing. Based on these studies we hypothesize that specific subsets of CD8+ T-cells are effector cells against PC. We will test this hypothesis with the following Specific Aims. Specific Aim 1. Our hypothesis predicts that overexpression of IFN-g, using adenoviral-mediated gene transfer (ADIFN) will enhance recruitment of CXCR3+, CD8 + T-cells with a Tcl phenotype. Specific Aim 2. Our hypothesis predicts that these CXCR3+ cells are required for CD8+ T-cell mediated clearance of PC in the AdlFN model. Specific Aim 3. Our hypothesis predicts that CXCR3+/Tcl+/CD8+ T-cells have preferential killing of PC in vitro and effect clearance of P. carinii in the reconstituted scid mouse model, compared to other CD8+ T-cell populations. These studies will investigate non-CD4 dependent host defenses utilizing a novel form of immunotherapy against an important opportunistic pathogen. The results of these studies will not only aid us in further understanding lung host defenses, but also may lead to novel methods of therapy for opportunistic infections.