CD8 T-Cells and Host Defense Against P. Carinii

CD8 T 细胞和宿主对卡氏疟原虫的防御

• 批准号: 7822469
• 负责人: JAY K KOLLS
• 金额: $ 0.77万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822469
• 关键词: Adoptive Transfer; Antigens; Biological Assay; Bone Marrow; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR3 gene; Cells; Clinical; Complication; Data; Dendritic Cells; Effector Cell; Funding; Gene Transfer; Genes; Grant; HIV Infections; Host Defense; Host Defense Mechanism; Immunocompromised Host; Immunotherapy; In Vitro; Infection; Interferon Type II; Interferons; Interleukin-15; Knockout Mice; Lead; Liquid substance; Lung; Maintenance; Mediating; Methods; Modeling; Mononuclear; Mus; Opportunistic Infections; Patients; Phagocytes; Phenotype; Physiologic pulse; Pneumocystis Infections; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Population; Production; Proteins; Publishing; Recruitment Activity; Risk; Role; Signal Transduction; Small Inducible Cytokine B9; Structure of parenchyma of lung; T memory cell; T-Lymphocyte; Testing; Time; adenoviral-mediated; base; chemokine; chemokine receptor; cytokine; design; in vitro activity; in vivo; killings; macrophage; mouse model; novel; overexpression; pathogen; receptor; reconstitution; research study; response

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.

描述（由申请人提供）：尽管目前的策略来治疗艾滋病毒感染及其并发症，卡氏肺孢子虫肺炎（PCP）仍然是一个常见的临床问题。尽管CD 4+淋巴细胞计数与PC感染风险之间存在众所周知的关系，但单核吞噬细胞、CD 8+细胞、γ/δ T细胞及其分泌的细胞因子在宿主防御这种感染中的作用远不清楚。在之前的资助期间，我们已经证明了Tcl CD 8 + T细胞，如由强内源性干扰素-γ（IFN）产生所定义的，与在不存在CD 4 + T细胞的情况下PC的根除相关。在我们实验室中使用新的体外PC杀伤测定的初步研究表明，Tcl CD 8 + T细胞具有优先的PC杀伤活性，并且还增强巨噬细胞介导的杀伤。基于这些研究，我们假设CD 8 + T细胞的特定亚群是抗PC的效应细胞。我们将用以下具体目标来检验这一假设。具体目标1。我们的假设预测，使用腺病毒介导的基因转移（ADIFN）过表达IFN-γ将增强具有Tcl表型的CXCR 3+、CD 8 + T细胞的募集。具体目标2。我们的假设预测这些CXCR 3+细胞是AdIFN模型中CD 8 + T细胞介导的PC清除所需的。具体目标3。我们的假设预测，与其他CD 8 + T细胞群体相比，CXCR 3 +/Tcl+/CD 8 + T细胞在体外优先杀死PC，并在重建的scid小鼠模型中影响卡氏肺孢子虫的清除。这些研究将调查非CD 4依赖性宿主防御利用一种新形式的免疫疗法对一个重要的机会病原体。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机制，而且可能导致治疗机会性感染的新方法。