Regulation of CD8 T cell responses to polyoma virus infection

CD8 T 细胞对多瘤病毒感染反应的调节

• 批准号: 7546027
• 负责人: CHRISTOPHER D PACK
• 金额: $ 5.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546027
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adoptive Transfer; Affect; Antigens; B-Cell Lymphomas; CD28 gene; CD8B1 gene; Cells; Competence; Condition; Dendritic Cells; Deterioration; Development; Equilibrium; Evolution; Generations; HIV; Health; Hepatitis C; Human; Human Herpesvirus 4; Immunity; Infection; Infectious Mononucleosis; Intervention; Life; Liver; Maintenance; Malignant neoplasm of cervix uteri; Medical Surveillance; Memory; Morbidity - disease rate; Mus; Oncogenic; Phase; Play; Polyomavirus; Recombinants; Recruitment Activity; Regulation; Role; Study models; T-Lymphocyte; Therapeutic Intervention; Time; Tissues; Transgenic Organisms; Viral; Viral Tumor Antigens; Virus; Virus Diseases; insight; mortality; novel; novel virus; pathogen; prevent; response; sialosyl-T antigen; tumor

DESCRIPTION (provided by applicant): Persistent viral infections are a major cause of morbidity and mortality. Examples include HIV (resulting in AIDS), Cytomegalqvirus (CMV),. Epstein Barr virus (EBV) (responsible for mononucleosis, and; B cell lymphoma), Hepatitis C (leading to liver destruction), and Human Papiloma Virus (which may result in cervical cancer). Continual surveillance of CDS T cells is required to eliminate or, at minimum, control the spread of these viruses throughout the body. Understanding why CDS T cells are incapable of eliminating a persistent viral pathogen is a critical concern for human health. This proposal attempts to address key factors that may prove to be critical interventions to tilt the balance in favor of the host, allowing the elimination of the virus and the generation of a stable memory CDS T cell pool capable of preventing reinfection. The model for these studies is polyoma virus (PyV), a small, oncogenic DMA virus that infects mice (the natural host). CDS T cell immunity is critical to control tumor formation and outgrowth following infection, and a persistent viral infection can be detected in almost all tissues for life. The first aim of the proposal compares the evolution of PyV-specific T cells primed during acute and persistent phases of infection. These studies are performed using a novel recombinant PyV expressing OVA257-264 within the middle T antigen. Key differences may exist in the restrictions or conditions necessary for optimal priming at different time points, and this novel virus will allow us to clearly address this question using adoptive transfer of OT-I transgenic T cells at various time points post infection. Aim 2 addresses the role of dendritic cells in the priming of CDS T cells in persistent phase infection. Aim 3 involves the manipulation of costimulatory molecules (specifically CD27/CD70). This costimulatory molecule plays a critical role in the maintenance and development of memory CDS T cells. This subaim will also be investigated with adoptive transfer of OT- I transgenic T cells followed by treatment with soluble CD70 during persistent infection. Collectively, these studies should provide critical insights into possible therapeutic interventions to stimulate defective CDS T cell immunity observed in numerous persistent viral infections.

描述（由申请人提供）：持续的病毒感染是发病率和死亡率的主要原因。例如HIV（导致艾滋病），巨细胞病毒（CMV）。爱泼斯坦Barr病毒（EBV）（负责单核细胞增多症和; B细胞淋巴瘤），丙型肝炎（导致肝脏破坏）和人乳头球瘤病毒（可能导致宫颈癌）。需要对CDS T细胞进行持续的监视以消除或至少控制这些病毒在整个体内的扩散。了解为什么CDS T细胞无法消除持续的病毒病原体是人类健康的关键问题。该提案试图解决可能被证明是关键干预措施的关键因素，以倾斜宿主的平衡，从而消除病毒并产生稳定的记忆CDS T细胞池，能够防止再感染。这些研究的模型是多瘤病毒（PYV），这是一种感染小鼠（天然宿主）的小型致癌DMA病毒。 CDS T细胞免疫对于控制感染后的肿瘤形成和生长至关重要，并且几乎所有组织中都可以在几乎所有组织中检测到持续的病毒感染。该提案的第一个目的比较了在感染的急性和持续阶段启动的PYV特异性T细胞的演变。这些研究是使用在中部T抗原内表达OVA257-264的新型重组PYV进行的。在不同时间点最佳启动所必需的限制或条件可能存在关键差异，这种新型病毒将使我们能够使用OT-I转基因T细胞在感染后各个时间点的产物转移来清楚地解决这个问题。 AIM 2解决了树突状细胞在CDS T细胞启动中的作用。 AIM 3涉及操纵共刺激分子（特别是CD27/CD70）。该共刺激分子在记忆CD T细胞的维持和发展中起着至关重要的作用。该SubiaM还将通过OT-I转基因T细胞的过继转移，然后在持续感染期间用可溶性CD70进行治疗。总的来说，这些研究应提供对可能的治疗干预措施的关键见解，以刺激许多持续性病毒感染中观察到的有缺陷的CDS T细胞免疫。