Preventing and Curing Persistent Infections with Transient FTY720 Treatment

通过瞬时 FTY720 治疗预防和治疗持续性感染

• 批准号: 7356831
• 负责人: MARY F PREMENKO-LANIER
• 金额: $ 8.78万
• 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: 2008-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356831
• 关键词: Acute; Address; Adjuvant; Antigens; Antiviral Agents; Architecture; Binding; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Chronic Disease; Dendritic Cells; Development; Disease; Early treatment; Environment; Goals; Grant; HIV; Hepatitis B Virus; Hepatitis C virus; Immune; Immune response; Immune system; Immunity; Immunologic Adjuvants; Infection; Kinetics; Lead; Localized; Location; Lymphocyte; Lymphocytic choriomeningitis virus; Lymphoid; Lymphoid Tissue; Maintenance; Mediating; Memory; Mus; Organ; Pharmaceutical Preparations; Plasmids; Play; Population; Property; Recruitment Activity; Role; Sphingosine-1-Phosphate Receptor; T-Lymphocyte; TNFSF5 gene; Time; Vaccine Antigen; Vaccine Therapy; Vaccines; Virus; Virus Diseases; cytokine; desire; human disease; immunogenicity; macrophage; prevent; receptor; research study; response; therapy development; trafficking

DESCRIPTION (provided by applicant): Understanding differences between acute and chronic infections is important for the development of therapies to cure chronic diseases. By following a bystander naive T cell population, I found that a dramatic sequestration of lymphocytes into secondary lymphoid tissues occurred early following acute LCMV Armstrong infection, though not following infection with the chronic LMCV strain, cl-13. I hypothesized that the lack of early sequestration during persistent LCMV cl-13 contributed to the establishment of the chronic infection. I discovered that transient administration of the sequestration drug FTY720 enhanced immunity and prevented the establishment of chronic LCMV. Additionally, I found that FTY720 treatment cleared a previously established cl-13 infection. FTY720 has no antiviral properties and its treatment led to immune mediated clearance that is dependent on CD4 T cells. The goal of this grant is to understand the immune enhancing effects of FTY720 and apply the findings toward developing therapies and vaccines for chronic diseases. I hypothesize that transient treatment with FTY720 directly alters the location and interaction of lymphocytes with APCs that leads to enhanced immune activation, while indirectly preventing the establishment of chronic infection and promoting immune memory formation. In this grant, I will study both the mechanism of FTY720 immune enhancement, and its application. The three aims are: 1) to understand the role of CD4+ T cells in the enhancement of CD8+ T cell function during FTY720 treatment. 2) To understand the effects of FTY720 on dendritic cells and macrophages during FTY720 treatment, and on the general maintenance of immune architecture. 3) To understand whether FTY720 can act as an immune adjuvant, and enhance immunity against weak vaccine antigens that do not invoke a robust innate immune rsponse. Using FTY720 as an immune enhancing therapy to clear persistent infections is relevent for human diseases such as HIV, hepatitis B virus, and hepatitis C virus. Understanding the mechanism of immune enhancement is key for development of appropriate therapies for persistent diseases and for developing targeted adjuvants for desired vaccine responses. These experiments will help determine the mechanisms of FTY720 mediated immune enhancement.

描述（由申请人提供）：了解急性和慢性感染之间的差异对于开发治疗慢性疾病的疗法非常重要。通过观察旁观者的幼稚T细胞群，我发现淋巴细胞在急性LCMV Armstrong感染后早期发生了显著的隔离，进入次级淋巴组织，尽管在慢性LMCV株cl-13感染后没有发生。我假设在持续LCMV cl-13期间缺乏早期隔离有助于慢性感染的建立。我发现暂时给予隔离药物FTY 720增强了免疫力，防止了慢性LCMV的建立。此外，我发现FTY 720治疗清除了先前建立的cl-13感染。FTY 720没有抗病毒特性，其治疗导致依赖于CD 4 T细胞的免疫介导的清除。该基金的目的是了解FTY 720的免疫增强作用，并将研究结果应用于开发慢性疾病的治疗和疫苗。我推测FTY 720的短暂治疗直接改变了淋巴细胞与APC的位置和相互作用，导致增强的免疫激活，同时间接阻止慢性感染的建立并促进免疫记忆的形成。在本研究计划中，我将研究FTY 720的免疫增强机制及其应用。本研究的三个目的是：1）了解FTY 720治疗过程中CD 4 + T细胞在增强CD 8 + T细胞功能中的作用。2)了解FTY 720治疗期间FTY 720对树突状细胞和巨噬细胞的影响，以及对免疫结构的一般维持的影响。3)了解FTY 720是否可以作为免疫佐剂，增强对不引起强大先天免疫应答的弱疫苗抗原的免疫力。使用FTY 720作为免疫增强疗法以清除持续感染与人类疾病如HIV、B型肝炎病毒和丙型肝炎病毒有关。了解免疫增强的机制是开发针对持续性疾病的适当疗法和开发针对所需疫苗应答的靶向佐剂的关键。这些实验将有助于确定FTY 720介导的免疫增强机制。