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: 7680791
• 负责人: Andrew Lee Mellor
• 金额: $ 155.67万
• 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/7680791
• 关键词: Abbreviations; Ablation; Allergic; Antigen-Presenting Cells; Attenuated; Autoimmune Process; Cells; Cessation of life; Chronic; Clonal Expansion; Cytotoxic T-Lymphocytes; Dendritic Cells; Dioxygenases; Fetal Tissues; Flu virus; Generations; Healed; 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; Risk; Role; Signal Transduction; Site; Skin; Syndrome; 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; transcription factor CHOP; 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（流感）病毒感染和流感疫苗对涉及吲哚胺2,3二氧酶（IDO）表达的天然宿主T细胞调节机制的影响。 IDO介导的T细胞抑制有助于临床相关性的慢性炎症综合征，包括肿瘤生长，自身免疫性，过敏和移植物抗宿主疾病。 IDO活性阻止了怀孕期间T细胞对胎儿组织的反应，IDO过表达增强了移植存活率。流感感染引起了肺IDO活性的急剧增加，IDO活性促进了继发性感染，例如肺炎。我们假设IDO减弱了对流感感染和预防性疫苗的效应T细胞免疫反应。这种作用可能会促进组织愈合，但可能会钝化T细胞对流感感染的反应，阻碍产生的保护性免疫，并增加继发感染的风险。某些浆细胞样树突状细胞（PDC）的IDO表达抑制炎症部位的T细胞反应。在初步研究中，我们表明，化学诱导的皮肤炎症会诱导皮肤排水淋巴结（DLN）表达IDO的PDC。 IDO+ PDC获得了阻断T细胞克隆扩张的有效T细胞调节功能，并触发调节性T细胞（Tregs）以获得抑制活性。在提出的研究中，我们将在既定的鼠流感感染模型中使用新的小鼠菌株和病毒载体来消融IDO，并评估IDO消融对流感特异性免疫，记忆产生和感染动力学的影响。我们将确定表达IDO的肺部细胞以及刺激IDO的炎症信号（AIM 1）。同时，我们将阐明肺IDO+细胞对流感特异性效应子和记忆T细胞的影响（AIM 2）。相关研究将集中于IDO消融对流感疫苗预防和功效的影响（AIM 3），以及一种增强治疗性疫苗接种以打击流感感染的新颖手段（AIM 4）。提议的研究完成将提高人们对IDO在调节T细胞对流感反应的作用的理解，并将为改善治疗干预措施提供新的机会来预防流感。