Protective Immunity Against Herpesvirus Infections

针对疱疹病毒感染的保护性免疫力

• 批准号: 7212913
• 负责人: Ann Arvin
• 金额: $ 17.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212913
• 关键词: Adoptive Transfer; Allogenic; Animals; Antigens; Antiviral Agents; Appearance; Biological Assay; CD4 Positive T Lymphocytes; Cell Therapy; Cell Transplantation; Cells; Clinical; Clinical Management; Clinical Research; Cytomegalovirus; Disease; Evaluation; Firefly Luciferases; Flow Cytometry; Frequencies; Goals; Harvest; Hematopoietic; Herpesviridae; Herpesviridae Infections; Herpesvirus Type 3; Human; Immune; Immune response; Immunity; Immunohistochemistry; Immunotherapy; Infection; Infection Control; Infusion procedures; Interferons; Interleukin-15; Intervention; Intraperitoneal Injections; Invasive; Killer Cells; Kinetics; Lymphocyte; Measures; Medical Surveillance; Methods; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; NF-kappa B; NFKB Signaling Pathway; Natural Killer Cells; Neuroglia; Neurons; Neurotropism; Nuclear; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Polymerase Chain Reaction; Population; Principal Investigator; Production; Prophylactic treatment; Prospective Studies; Proteins; Recombinant Cytokines; Recombinant Interferon; Recovery; Regression Analysis; Regulation; Relapse; Relative (related person); Reporter; SCID Mice; Saline; Sensory Ganglia; Simplexvirus; Skin; Spinal Ganglia; Structure; System; T-Lymphocyte; Testing; Tissues; Transcriptional Activation; Treatment Protocols; Up-Regulation; Vaccines; Viremia; Virus; Virus Diseases; Virus Replication; Xenograft procedure; conditioning; cytokine; day; graft vs host disease; improved; in vivo; insight; intravenous administration; killer inhibitory receptor; mouse model; programs; prospective; receptor; reconstitution; research study; response; restoration; rituximab

Herpesvirus infections cause serious morbidity and can be fatal after hematopoietic cell transplantation (HCT). The goal of Project 8 is to explore the hypothesis that early reconstitution of innate antiviral immunity acts in concert with adaptive immunity to control these infections. Specific Aim 1 will assess relationships between reconstitution of natural killer (NK) cells and varicella-zoster virus (VZV)- specific and cytomegalovirus (CMV)-specific T cells and VZV and CMV reactivation. Allogeneic HCT patients will be evaluated at 30 and 90 days and 6 and 12 months after HCT using flow cytometry methods to assess NK cell maturity, receptor repertoire and T cell-dependent IFN^y production and for virus-specific CD4 and CDS T cell frequencies. To establish correlations with protection, patients will be monitored for clinical VZV and CMV disease and subclinical infections, detected by PCR testing of peripheral blood mononuclear cells for viremia. Statistical analyses of relationships among measures of immune reconstitution, viral infection and clinical variables will be done. In Specific Aim 2, we will evaluate innate control of VZV infection in dorsal root ganglia (DRG) xenografts in the SCIDhu mouse model. Innate responses will be investigated using immunohistochemistry to assess interferon (IFN) and Nuclear Factor K-B (NFicB) up-regulation and interleukin-15 (IL-15) expression in VZV-infected and uninfected neurons and non-neuronal cells. Modulation of VZV infection by exogenous IFN-a, IFN-y or IL-15 will be determined by infecting DRG with VZV rOkaF62/63RL, which has a firefly luciferase reporter cassette allowing non-invasive assessment of VZV replication. Whether adoptive transfer of NK cells or cytokine-induced killer cells limits VZV replication in DRG will also be investigated. The SCIDhu DRG model offers a unique opportunity to assess the antiviral effects of cytokines and cellular immunotherapy on VZV replication in sensory ganglia in vivo and should demonstrate whether innate responses can restrict VZV replication in a system that mimics allogeneic HCT. Profiling innate and adaptive immune responses in HCT patients along with surveillance for VZV and CMV reactivation and disease will identify antiviral mechanisms that are important for modifying herpesvirus infections after HCT. Exogenous IFNs and IL-15 are modalities that can be considered as adjunctive therapies in HCT recipients. Adoptive cell therapies, including CIK cells are being evaluated for tumoricidal activity in HCT recipients and could have the incremental benefit of controlling herpesvirus infections. These prospective clinical studies of innate and adaptive immunity to VZV and CMV and experiments in VZV- infected SCIDhu DRG have the potential to yield new insights about antiviral immune mechanisms and to suggest new measures for minimizing the burden of herpesvirus-related disease after HCT.

疱疹病毒感染会引起严重的发病率，造血细胞后可能是致命的 移植（HCT）。项目8的目的是探讨以下假设： 抗病毒免疫与适应性免疫共同控制这些感染。具体目标1将 评估自然杀手（NK）细胞重建与水疗菌病毒（VZV）之间的关系 - 特异性和巨细胞病毒（CMV）特异性T细胞以及VZV和CMV重新激活。同种异体HCT患者 将在HCT后使用流式细胞术方法在HCT后的30和90天和第12个月进行评估以评估评估 NK细胞成熟度，受体库和T细胞依赖性IFN^y产生以及病毒特异性CD4和 CDS T细胞频率。为了建立与保护的相关性，将监控患者的临床VZV 和CMV疾病和亚临床感染，通过PCR检测外周血单核细胞检测 用于病毒血症。免疫重建，病毒感染测量指标之间关系的统计分析 将完成临床变量。在特定目标2中，我们将评估对背部VZV感染的先天控制 Scidhu小鼠模型中的根神经节（DRG）异种移植物。天生的回应将使用 免疫组织化学评估干扰素（IFN）和核因子K-B（NFICB）上调以及 白介素15（IL-15）在VZV感染和未感染神经元和非神经元细胞中的表达。调制 通过外源IFN-A，IFN-Y或IL-15感染的VZV感染将通过感染VZV来确定 ROKAF62/63RL，具有萤火虫荧光素酶报告器盒，允许对VZV进行非侵入性评估 复制。 NK细胞的过继转移还是细胞因子诱导的杀伤细胞限制VZV复制 DRG也将进行调查。 Scidhu DRG模型提供了一个独特的机会来评估抗病毒 细胞因子和细胞免疫疗法对体内感觉神经节中VZV复制的影响，应 证明先天反应是否可以限制模仿同种异体HCT的系统中的VZV复制。 分析HCT患者的先天和适应性免疫反应以及VZV和CMV的监视 重新激活和疾病将确定对于修饰疱疹病毒重要的抗病毒机制 HCT后感染。外源IFN和IL-15是可以认为是辅助的方式 HCT接受者的疗法。收养细胞疗法，包括CIK细胞的肿瘤细胞正在评估 HCT接受者的活动，可能具有控制疱疹病毒感染的增量益处。这些 对VZV和CMV的先天和适应性免疫的前瞻性临床研究以及VZV-的实验 受感染的Scidhu DRG有可能产生有关抗病毒机制的新见解，并且 建议采取新的措施，以最大程度地减少HCT后与疱疹病毒相关疾病的负担。