Herpesvirus infections cause serious morbidity and can be fatal after hematopoietic celltransplantation (HCT). The goal of Project 8 is to explore the hypothesis that early reconstitution of innateantiviral immunity acts in concert with adaptive immunity to control these infections.
Specific Aim 1 willassess 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 patientswill be evaluated at 30 and 90 days and 6 and 12 months after HCT using flow cytometry methods to assessNK cell maturity, receptor repertoire and T cell-dependent IFN^y production and for virus-specific CD4 andCDS T cell frequencies. To establish correlations with protection, patients will be monitored for clinical VZVand CMV disease and subclinical infections, detected by PCR testing of peripheral blood mononuclear cellsfor viremia. Statistical analyses of relationships among measures of immune reconstitution, viral infectionand clinical variables will be done.
In Specific Aim 2, we will evaluate innate control of VZV infection in dorsalroot ganglia (DRG) xenografts in the SCIDhu mouse model. Innate responses will be investigated usingimmunohistochemistry to assess interferon (IFN) and Nuclear Factor K-B (NFicB) up-regulation andinterleukin-15 (IL-15) expression in VZV-infected and uninfected neurons and non-neuronal cells. Modulationof VZV infection by exogenous IFN-a, IFN-y or IL-15 will be determined by infecting DRG with VZVrOkaF62/63RL, which has a firefly luciferase reporter cassette allowing non-invasive assessment of VZVreplication. Whether adoptive transfer of NK cells or cytokine-induced killer cells limits VZV replication inDRG will also be investigated. The SCIDhu DRG model offers a unique opportunity to assess the antiviraleffects of cytokines and cellular immunotherapy on VZV replication in sensory ganglia in vivo and shoulddemonstrate 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 CMVreactivation and disease will identify antiviral mechanisms that are important for modifying herpesvirusinfections after HCT. Exogenous IFNs and IL-15 are modalities that can be considered as adjunctivetherapies in HCT recipients. Adoptive cell therapies, including CIK cells are being evaluated for tumoricidalactivity in HCT recipients and could have the incremental benefit of controlling herpesvirus infections. Theseprospective 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 tosuggest new measures for minimizing the burden of herpesvirus-related disease after HCT.
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