KSHV REGULATION OF INNATE CYTOKINE RESPONSES AND T CELL ACTIVATION

KSHV 对先天细胞因子反应和 T 细胞激活的调节

• 批准号: 7959784
• 负责人: Christopher H Parsons
• 金额: $ 16.53万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959784
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Biological Assay; Biological Models; Cancer Etiology; Cell Culture Techniques; Cell physiology; Cell secretion; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Data; Environment; Funding; Gene Transfer; Genes; Grant; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; Infection; Institution; Interleukin-10; Interleukin-6; Intervention; Kaposi Sarcoma; Mus; Oral health; Outcome Measure; Palate Kaposi' s Sarcoma; Patients; Prevention; Production; Reactive Nitrogen Species; Regulation; Research; Research Design; Research Personnel; Resistance; Resources; Signal Transduction; Source; South Carolina; System; T-Cell Activation; T-Lymphocyte; Testing; United States National Institutes of Health; base; cytokine; malignant mouth neoplasm; outcome forecast; response; treatment strategy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS). Existing data suggest that T cell responses are critical for the control of KS progression, and antigen-presenting cells (APC) provide important activation signals for generating these responses. Whether KSHV infection of APC impairs effective T cell responses thereby promoting KS progression is unknown. Our model systems show that KSHV impairs T cell activation through multiple KSHV-encoded mechanisms involving infection of APC, including alteration of cytokine production by APC. Therefore, we propose to use these systems, including primary cells from human patients, to identify mechanisms for KSHV regulation of APC function and T cell activation. Rationale KSHV is the most common cause of cancer, and specifically oral cancers, arising in HIV-infected patients. Oral KS is resistant to existing therapies and portends an ominous prognosis. A better understanding of how KSHV regulates T cell activation through the infection of APC may provide new opportunites for developing immune-based or anti-inflammatory strategies for the treatment or prevention of oral KS. Study design and outcome measures Using human and murine APC as targets of KSHV infection and gene transfer in cell culture, we will first identify specific KSHV-encoded genes involved in APC secretion of immunoinhibitory molecules, including IL-6, IL-10, and reactive nitrogen species (RNS). Next, using antigen-independent and antigen-dependent T cell activation assays, we will test interventional strategies for reducing IL-6, IL-10, and RNS secretion by KSHV-infected APC and restoring T cell activation in this environment.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 背景 卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体。现有数据表明，T 细胞反应对于控制 KS 进展至关重要，而抗原呈递细胞 (APC) 为产生这些反应提供了重要的激活信号。 APC 的 KSHV 感染是否会损害有效的 T 细胞反应，从而促进 KS 进展尚不清楚。我们的模型系统表明，KSHV 通过涉及 APC 感染的多种 KSHV 编码机制损害 T 细胞活化，包括改变 APC 产生的细胞因子。因此，我们建议使用这些系统，包括来自人类患者的原代细胞，来确定 KSHV 调节 APC 功能和 T 细胞激活的机制。 基本原理 KSHV 是 HIV 感染者中最常见的癌症（特别是口腔癌）病因。口服 KS 对现有疗法有抵抗力，预示着不祥的预后。更好地了解 KSHV 如何通过 APC 感染调节 T 细胞活化可能为开发基于免疫或抗炎的策略来治疗或预防口腔 KS 提供新的机会。 研究设计和结果衡量 使用人和鼠 APC 作为 KSHV 感染和细胞培养中基因转移的靶标，我们将首先鉴定参与 APC 分泌免疫抑制分子的特定 KSHV 编码基因，包括 IL-6、IL-10 和活性氮 (RNS) 。接下来，使用抗原非依赖性和抗原依赖性 T 细胞活化测定，我们将测试减少 KSHV 感染的 APC 分泌 IL-6、IL-10 和 RNS 并在此环境中恢复 T 细胞活化的干预策略。