Manipulating natural host immunoregulation via IDO during viral Infection

病毒感染期间通过 IDO 操纵自然宿主免疫调节

• 批准号: 8261985
• 负责人: Andrew Lee Mellor
• 金额: $ 254.42万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261985
• 关键词: Abbreviations; Ablation; Allergic; Antigen-Presenting Cells; Attenuated; Autoimmune Process; CCAAT-Enhancer-Binding Proteins; Cells; Cessation of life; Chronic; Clonal Expansion; Cytotoxic T-Lymphocytes; Dendritic Cells; Dioxygenases; Fetal Tissues; Flu virus; Generations; Healed; Homologous Protein; IFNAR1 gene; IL2RA gene; Immune response; Immunity; Infection; Inflammation; Inflammatory; Influenza; Interferons; Kinetics; Ligands; Lung; Mediating; Memory; Modeling; Mouse Strains; Mus; Myelogenous; Pneumonia; Pregnancy; Process; Prophylactic treatment; Receptor Signaling; Regulatory T-Lymphocyte; Risk; Role; Signal Transduction; Site; Skin; Syndrome; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toll-like receptors; Transplantation; Treatment Efficacy; Vaccination; Vaccines; Viral Vector; Virus Diseases; clinically relevant; combat; flu; graft vs host disease; healing; immunoregulation; improved; indoleamine; influenza virus vaccine; lymph nodes; novel; programs; receptor; response; secondary infection; tumor growth

DESCRIPTION (provided by applicant): The objective is to elucidate the effects of influenza (flu) virus infection and flu vaccines on a natural host T cell regulatory mechanism involving expression of indoleamine 2,3 dioxygenase (IDO). IDO-mediated T cell suppression contributes to chronic inflammatory syndromes of clinical relevance, including tumor growth, autoimmune, allergic, and graft-versus-host diseases. IDO activity blocks T cell responses to fetal tissues during pregnancy, and IDO over-expression enhances transplant survival. Flu infection induces a dramatic increase in IDO activity in lungs, and IDO activity facilitates secondary infections such as pneumonia. We hypothesize that IDO attenuates effector T cell immune responses to flu infection and to preventative vaccines. Such effects may promote tissue healing, but may blunt T cell responses to flu infection, impede generation protective immunity, and increase the risk of secondary infections. IDO expression by some plasmacytoid dendritic cells (pDCs) inhibits T cell responses at sites of inflammation. In preliminary studies we show that chemically-induced skin inflammation induced pDCs in skin draining lymph nodes (dLNs) to express IDO. IDO+ pDCs acquired potent T cell regulatory functions that blocked T cell clonal expansion, and triggered regulatory T cells (Tregs) to acquire suppressor activity. In studies proposed, we will employ new mouse strains and viral vectors to ablate IDO in an established murine flu infection model, and assess the effects of IDO ablation on flu-specific immunity, memory generation, and infection kinetics. We will identify lung cells expressing IDO, and inflammatory signals that stimulate IDO (Aim 1). In parallel, we will elucidate the effects of lung IDO+ cells on flu-specific effector and memory T cells (Aim 2). Related studies will focus on the effects of IDO ablation on flu vaccine prophylaxis and efficacy (Aim 3), and a novel means to enhance therapeutic vaccination to combat flu infections (Aim 4). Completion of studies proposed will improve understanding of the role of IDO in regulating T cell responses to flu, and will create novel opportunities for improving therapeutic interventions protect against flu.

描述（由申请人提供）：目的是阐明流感病毒感染和流感疫苗对涉及吲哚胺 2,3 双加氧酶 (IDO) 表达的天然宿主 T 细胞调节机制的影响。 IDO 介导的 T 细胞抑制导致临床相关的慢性炎症综合征，包括肿瘤生长、自身免疫、过敏和移植物抗宿主疾病。 IDO 活性可阻断妊娠期间 T 细胞对胎儿组织的反应，IDO 过度表达可增强移植物的存活率。流感感染会导致肺部 IDO 活性急剧增加，而 IDO 活性会促进肺炎等继发感染。我们假设 IDO 会减弱效应 T 细胞对流感感染和预防性疫苗的免疫反应。这种作用可能会促进组织愈合，但可能会削弱 T 细胞对流感感染的反应，阻碍保护性免疫力的产生，并增加继发感染的风险。一些浆细胞样树突状细胞 (pDC) 表达的 IDO 会抑制炎症部位的 T 细胞反应。在初步研究中，我们表明化学诱导的皮肤炎症诱导皮肤引流淋巴结 (dLN) 中的 pDC 表达 IDO。 IDO+ pDC 获得了有效的 T 细胞调节功能，可阻止 T 细胞克隆扩张，并触发调节性 T 细胞 (Treg) 获得抑制活性。在拟议的研究中，我们将采用新的小鼠品系和病毒载体在已建立的鼠流感感染模型中消除 IDO，并评估 IDO 消除对流感特异性免疫、记忆生成和感染动力学的影响。我们将识别表达 IDO 的肺细胞以及刺激 IDO 的炎症信号（目标 1）。与此同时，我们将阐明肺 IDO+ 细胞对流感特异性效应细胞和记忆 T 细胞的影响（目标 2）。相关研究将重点关注 IDO 消融对流感疫苗预防和功效的影响（目标 3），以及增强治疗性疫苗接种以对抗流感感染的新方法（目标 4）。完成拟议的研究将提高对 IDO 在调节 T 细胞对流感反应中的作用的理解，并将为改善流感治疗干预措施创造新的机会。