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.

疱疹病毒感染会导致严重的发病率，并可在造血细胞后致命 移植(HCT)。项目8的目标是探索这样一种假设，即先天的早期重建 抗病毒免疫与获得性免疫协同作用以控制这些感染。具体目标1将 评估自然杀伤(NK)细胞重建与水痘带状疱疹病毒(VZV)的关系 特异性和巨细胞病毒(CMV)特异性T细胞以及VZV和CMV的重新激活。异基因血细胞移植患者 将在HCT后30天和90天以及6个月和12个月使用流式细胞仪方法评估 NK细胞成熟度、受体谱系和T细胞依赖的干扰素的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，将对患者进行临床VZV监测 外周血单个核细胞的聚合酶链式反应检测到巨细胞病毒病和亚临床感染 治疗病毒血症。免疫重建指标与病毒感染关系的统计分析 临床变量将会被计算出来。在特定的目标2中，我们将评估VZV感染在背部的先天控制 SCIDhu小鼠模型的异种根神经节移植。先天反应将被用来研究 免疫组织化学检测干扰素和核因子K-B的表达 白介素15(IL-15)在VZV感染和未感染神经元及非神经细胞中的表达调变 外源性干扰素-a、干扰素-γ或IL-15感染VZV的可能性将通过感染VZV来确定 ROkaF62/63RL，它有一个萤火虫荧光素酶报告盒，允许对VZV进行非侵入性评估 复制。过继转移NK细胞或细胞因子诱导的杀伤细胞是否限制VZV的复制 DRG也将接受调查。SCIDhu DRG模型提供了一个独特的机会来评估抗病毒药物 细胞因子和细胞免疫治疗对感觉神经节VZV复制的影响 证明先天反应是否可以限制VZV在模仿同种异体血细胞移植系统中的复制。 血细胞移植患者的先天和获得性免疫反应特征及VZV和CMV监测 重新激活和疾病将确定对修改疱疹病毒很重要的抗病毒机制 HCT后感染。外源性IFN和IL-15是可以被认为是附加的方式 血细胞移植受者的治疗。包括CIK细胞在内的过继细胞疗法正在评估其杀瘤作用 这可能会增加控制疱疹病毒感染的益处。这些 VZV和CMV先天免疫和获得性免疫的前瞻性临床研究及VZV的实验研究 被感染的SCIDhu DRG有可能对抗病毒免疫机制产生新的见解，并 建议新的措施，以最大限度地减少HCT后疱疹病毒相关疾病的负担。