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.

疱疹病毒感染可导致严重的发病率，并可在造血细胞死亡后致命 移植（HCT）。项目 8 的目标是探索以下假设：先天性的早期重建 抗病毒免疫与适应性免疫协同作用来控制这些感染。具体目标 1 将 评估自然杀伤 (NK) 细胞的重建与水痘带状疱疹病毒 (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 30 和 90 天以及 6 和 12 个月使用流式细胞术方法进行评估 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，将对患者进行临床 VZV 监测 通过外周血单核细胞 PCR 检测发现 CMV 疾病和亚临床感染 对于病毒血症。免疫重建、病毒感染指标之间关系的统计分析 和临床变量将被完成。在具体目标 2 中，我们将评估背部水痘带状疱疹病毒感染的先天控制 SCIDhu 小鼠模型中的根神经节 (DRG) 异种移植物。将使用以下方法研究先天反应 免疫组织化学评估干扰素 (IFN) 和核因子 K-B (NFicB) 的上调和 VZV 感染和未感染的神经元和非神经元细胞中白细胞介素 15 (IL-15) 的表达。调制 通过用VZV感染DRG来确定外源性IFN-a、IFN-y或IL-15对VZV感染的影响 rOkaF62/63RL，具有萤火虫荧光素酶报告基因盒，可对 VZV 进行非侵入性评估 复制。 NK 细胞或细胞因子诱导的杀伤细胞的过继转移是否限制 VZV 复制 DRG 也将被调查。 SCIDhu DRG 模型提供了评估抗病毒药物的独特机会 细胞因子和细胞免疫治疗对体内感觉神经节 VZV 复制的影响，应该 证明先天反应是否可以限制 VZV 在模拟同种异体 HCT 的系统中的复制。 分析 HCT 患者的先天性和适应性免疫反应以及 VZV 和 CMV 监测 再激活和疾病将确定对于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 可以被视为辅助疗法 HCT 接受者的治疗。包括 CIK 细胞在内的过继细胞疗法正在评估其杀肿瘤作用 HCT 接受者的活性，可能会带来控制疱疹病毒感染的增量益处。这些 针对 VZV 和 CMV 的先天性和适应性免疫的前瞻性临床研究以及 VZV 实验 感染的 SCIDhu DRG 有可能产生关于抗病毒免疫机制的新见解并 建议采取新措施，尽量减少 HCT 后疱疹病毒相关疾病的负担。