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; 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）是婴儿和幼儿病毒下呼吸道感染的主要原因。此外，RSV在老年人和免疫受损的个体中引起严重疾病。自然感染后，针对RSV的免疫与疾病和肺嗜酸性粒细胞增强有关，这被认为是由旺盛的记忆CD4 TH2反应引起的。结果，目前尚无批准的RSV疫苗和用于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第一步。 RSV感染的BALB/C小鼠模型忠实地模仿了人类呼吸系统疾病，包括开发广泛的肺部炎症和损伤，肺嗜酸性粒细胞增多，并在先前用福尔马林失活（FI）-RSV或重组疫苗（VV）（VV）（VV）的小鼠中的小鼠中增强了疾病（VV）。分泌Th2细胞因子的记忆CD4 T细胞对于这种反应是必要的，因为它们的耗竭消除了嗜酸性粒细胞。最近的研究表明，RSV-特异性CD8 T细胞可以通过未知机制抑制VVG培养的小鼠中Th2介导的肺嗜酸性小鼠。通过利用我们跟踪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诱导的肺嗜酸性嗜酸性嗜酸性嗜酸性嗜酸性粒细胞的机理。重要的是，最近的工作提供了证据，表明VVG和FI-RSV免疫可以通过独特的机制诱导RSV疫苗增强疾病。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的：1）确定记忆CD8 T细胞如何抑制RSV特异性记忆Th2细胞和RSV疫苗增强型肺嗜酸性嗜酸性嗜酸性嗜酸性嗜酸性嗜酸性嗜酸性嗜酸痛和2）确定记忆CD8 T细胞是否可以防止FI-RSV疫苗增强疾病和肺损伤。 RSV疫苗增强疾病的基本机制尚不清楚。该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中的作用。