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.

疱疹病毒感染导致严重的发病率，并且在造血细胞移植后可能是致命的。 移植（HCT）。项目8的目标是探索先天性免疫缺陷早期重建的假设， 抗病毒免疫与适应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）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再活化。异基因HCT患者 将在HCT后30天和90天以及6个月和12个月使用流式细胞术方法进行评价，以评估 NK细胞成熟度、受体库和T细胞依赖性IFN-γ产生以及病毒特异性CD 4和IFN-γ产生。 CDS T细胞频率。为了建立与保护的相关性，将监测患者的临床VZV 和CMV疾病和亚临床感染，通过外周血单核细胞PCR检测 治疗病毒血症免疫重建、病毒感染指标之间关系的统计分析 临床变量将被完成。在具体目标2中，我们将评估VZV感染的先天控制， 在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， VZV感染和未感染的神经元和非神经元细胞中的白细胞介素-15（IL-15）表达。调制 通过用VZV感染DRG来确定外源性IFN-α、IFN-γ或IL-15对VZV感染的影响 rOkaF 62/63 RL，其具有萤火虫荧光素酶报告盒，允许VZV的非侵入性评估 复制的是否过继性转移NK细胞或马槟榔诱导的杀伤细胞限制了VZV的复制， 还将研究DRG。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VZV在感觉神经节内复制的影响 证明先天性应答是否可以限制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应答，沿着监测VZV和CMV 重新激活和疾病将确定抗病毒机制是重要的修改疱疹病毒 HCT后感染外源性干扰素和IL-15是可以被认为是预防性治疗的方式。 HCT接受者的治疗。包括CIK细胞在内的免疫细胞疗法正在评估其杀肿瘤作用。 活性，并可能有控制疱疹病毒感染的增量效益。这些 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- 感染的SCIDhu DRG有可能产生关于抗病毒免疫机制的新见解， 建议新的措施，以尽量减少负担的疱疹病毒相关疾病后HCT。