Immunopathology mediated by RSV-specific CD4 T cells

RSV 特异性 CD4 T 细胞介导的免疫病理学

• 批准号: 7758806
• 负责人: Steven M Varga
• 金额: $ 35.29万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758806
• 关键词: Address; Biological Models; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Child; Data; Development; Disease; Elderly; Eosinophilia; Epitopes; Exhibits; Exposure to; Failure; Formalin; GTP-Binding Proteins; Goals; Human; Immune; Immunization; Inactivated Vaccines; Inbred BALB C Mice; Individual; Infant; Infection; Injury; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Mediating; Memory; Mus; Prevention; Pulmonary Eosinophilia; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Role; Severities; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Th2 Cells; Time; Vaccination; Vaccines; Vaccinia virus; Viral; Work; cytokine; design; glycoprotein G; human disease; immunopathology; memory CD4 T lymphocyte; mouse model; novel strategies; prevent; response

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection in infants and young children. In addition, RSV causes serious disease in elderly and immune compromised individuals. Immunization against RSV is associated with enhanced disease and pulmonary eosinophilia following natural infection that is thought to be caused by an exuberant memory CD4 Th2 response. As a consequence, there is currently no approved RSV vaccine and detailed studies directed towards prevention of vaccine-associated disease are a necessary first step in the development of a safe and effective vaccine. The BALB/c mouse model of RSV infection faithfully mimics the human respiratory disease including the development of extensive lung inflammation and injury, pulmonary eosinophilia, and enhanced disease in mice previously immunized with either formalin inactivated (FI)-RSV or a recombinant vaccinia virus (vv) that expresses the attachment (G) glycoprotein. Memory CD4 T cells secreting Th2 cytokines are necessary for this response because their depletion eliminates eosinophilia. Recent studies have demonstrated that RSV- specific CD8 T cells can inhibit Th2-mediated pulmonary eosinophilia in vvG-primed mice by as yet unknown mechanisms. By taking advantage of our ability to track RSV G-specific CD4 T cells, we will determine the mechanism of memory CD8 T cell inhibition of RSV G-induced pulmonary eosinophilia. Importantly, recent work has provided evidence that vvG and FI-RSV immunization may induce RSV vaccine-enhanced disease via unique mechanisms. Therefore, we will also ascertain if RSV-specific memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease. The overall goal of this proposal is to define the mechanism(s) of how RSV-specific memory CD8 T cells inhibit CD4 T cell-mediated RSV vaccine-enhanced disease and immunopathology. We propose the following Specific Aims: 1) To determine the how memory CD8 T cells inhibit RSV-specific memory Th2 cells and RSV vaccine-enhanced pulmonary eosinophilia and, 2) To determine if memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease and pulmonary injury. The underlying mechanisms of RSV vaccine-enhanced disease remain unclear. The studies in this proposal are designed to determine the role of RSV-specific memory CD8 T cells in decreasing the severity of CD4 T cell-mediated immunopathology in a model system with direct relevance to human disease.

描述（由申请人提供）：呼吸道合胞病毒（RSV）是婴幼儿病毒性下呼吸道感染的主要原因。此外，RSV 还会导致老年人和免疫功能低下的人患上严重疾病。 RSV 免疫与自然感染后疾病加重和肺部嗜酸性粒细胞增多有关，这被认为是由旺盛的记忆 CD4 Th2 反应引起的。因此，目前还没有批准的 RSV 疫苗，针对预防疫苗相关疾病的详细研究是开发安全有效疫苗的必要的第一步。 RSV 感染的 BALB/c 小鼠模型忠实地模拟了人类呼吸道疾病，包括广泛的肺部炎症和损伤、肺嗜酸性粒细胞增多以及先前用福尔马林灭活 (FI)-RSV 或重组痘苗病毒免疫的小鼠疾病的加重。 vv) 表达附着 (G) 糖蛋白。分泌 Th2 细胞因子的记忆 CD4 T 细胞对于这种反应是必要的，因为它们的消耗会消除嗜酸性粒细胞增多。最近的研究表明，RSV 特异性 CD8 T 细胞可以通过迄今未知的机制抑制 vvG 引发的小鼠中 Th2 介导的肺嗜酸性粒细胞增多。通过利用我们追踪 RSV G 特异性 CD4 T 细胞的能力，我们将确定记忆 CD8 T 细胞抑制 RSV G 诱导的肺嗜酸性粒细胞增多的机制。重要的是，最近的工作提供了证据，表明 vvG 和 FI-RSV 免疫可能通过独特的机制诱导 RSV 疫苗增强的疾病。因此，我们还将确定 RSV 特异性记忆 CD8 T 细胞是否可以预防 FI-RSV 疫苗增强的疾病。该提案的总体目标是确定 RSV 特异性记忆 CD8 T 细胞如何抑制 CD4 T 细胞介导的 RSV 疫苗增强疾病和免疫病理学的机制。我们提出以下具体目标：1) 确定记忆 CD8 T 细胞如何抑制 RSV 特异性记忆 Th2 细胞和 RSV 疫苗增强的肺嗜酸性粒细胞增多，2) 确定记忆 CD8 T 细胞是否可以预防 FI-RSV 疫苗增强的肺嗜酸性粒细胞增多症疾病和肺损伤。 RSV 疫苗增强疾病的潜在机制仍不清楚。本提案中的研究旨在确定 RSV 特异性记忆 CD8 T 细胞在降低与人类疾病直接相关的模型系统中 CD4 T 细胞介导的免疫病理学严重程度方面的作用。