Clinical Trial: Interferon Responses in Eczema Herpeticum

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: Investigation of Reduced Interferon Responses in Peripheral Blood Mononuclear Cells of Participants With Atopic Dermatitis and a History of Eczema Herpeticum (ADRN-01)

Brief Summary: Atopic dermatitis (AD) is a chronic skin disorder characterized by recurrent viral skin infections. A small subset of patients with AD suffer from disseminated viral infections, e.g., eczema herpeticum (ADEH+), after herpes simplex infection (HSV) or eczema vaccinatum (EV) after smallpox vaccination. Interferon gamma (IFNγ) plays a critical role in the innate and acquired immune responses by activating macrophages, enhancing natural killer cell activation, and promoting T cell differentiation, as well as regulating B cell isotype switching to immunoglobulin (Ig) G2a. Recent studies have demonstrated that IFNγ generation was significantly decreased after stimulation with HSV ex vivo. The purpose of this study is to determine if deficient IFNγ induction leads to susceptibility to HSV infection in ADEH+ patients.

Detailed Summary:

The investigators hypothesize that defective IFNγ responses in peripheral blood mononuclear cells (PBMCs) from ADEH+ patients results from aberrant pattern recognition receptors (PRR) signaling in antigen-presenting cells (APCs) resulting in low level production of IL-12, an essential cytokine for IFNγ generation. This study will compare results from 40 ADEH+, 40 ADEH-, and 40 non-atopic participants.

Study procedures will typically be completed in one visit; however, participants may be asked to return for additional unscheduled visit(s) occurring as frequently as every 3 months for the duration of the study to provide an additional blood sample for further characterization of immune mechanisms leading to reduced IFNγ responses in ADEH+.


Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Current Primary Outcome: Expression of IFNγ and Interleukin-12 (IL-12), in response to stimulation with Herpes Simplex Virus 1 (HSV-1), Vaccinia Virus (VV), and Pattern Recognition Receptors (PRR) agonists [ Time Frame: Day 1 ]

Protein and messenger ribonucleic acid (mRNA) levels of IFNγ, and the IFN-γ promoting cytokine, IL-12, produced by Cluster of Differentiation 14 (CD14+) monocytes in response to stimulation with HSV-1, VV, and various PRR agonists


Original Primary Outcome: Expression of IFN and IL-12, in response to stimulation with HSV-1, VV, and PRR agonists. [ Time Frame: Day 1 ]

Messenger ribonucleic acid (mRNA) levels of IFN, and the IFN promoting cytokine, IL-12, produced by CD14+ monocytes in response to stimulation with HSV-1, VV, and various PRR agonists.


Current Secondary Outcome:

  • Cell surface expression of Major Histocompatibility complex (MHC) class I and class II and co-stimulatory molecules on CD14+ cells in response to IFNγ and Interferon-alpha (IFNα) stimulation [ Time Frame: Day 1 ]
  • Production of IL-18 and IFNα protein and mRNA by CD14+ cells following stimulation with HSV-1, VV, or PRR agonists [ Time Frame: Day 1 ]
  • Production of IFNγ protein by Cluster of Differentiation 8 (CD8+) T cells in response to stimulation with recombinant human cytokines including but not limited to IL-12, IL-18, and IFNα [ Time Frame: Day 1 ]
  • Protein expression of IFNγ receptor and IFNα/β receptor on CD14+ cells [ Time Frame: Day 1 ]
  • Immunodominant HSV-1 peptide repertoires [ Time Frame: Day 1 ]
    Analysis of immunodominant HSV-1 peptide repertoires with related Human Leukocyte Antigen (HLA) in ADEH+, ADEH-, and non-atopic participants
  • High-throughput gene expression profiling to analyze ribonucleic acid (RNA) from HSV-1 stimulated and sham stimulated CD14+ monocytes [ Time Frame: Day 1 ]
    Global transcriptional response of CD14+ monocytes to stimulation with HSV-1 as evaluated by GeneChip Profiling
  • Production of protein and RNA of IFN family members and any related pro- or anti-inflammatory cytokines/chemokines in response to stimulation of PBMCs or purified monocytes [ Time Frame: Day 1 ]
    IFN family members include IFNα, Interferon beta (IFNβ), and IFNγ. Related pro- or anti-inflammatory cytokines/chemokines include, but are not limited to IL-29 and IL-10
  • Expression of MHC and co-stimulatory molecules on CD14+ cells in response to stimulation with HSV-1, VV, or PRR agonists [ Time Frame: Day 1 ]
  • Viral titer of VV as determined by plaque assay following incubation of virus with PBMCs [ Time Frame: Day 1 ]
  • Gene expression profiles and gene variant profiles of PBMCs stimulated with HSV-1 as assayed by RNA-seq [ Time Frame: Day 1 ]


Original Secondary Outcome:

  • Cell surface expression of MHC class I/II and co-stimulatory molecules on CD14+ cells in response to IFN-gamma and IFN-alpha. [ Time Frame: Day 1 ]
    Expression of MHC class I/II and co-stimulatory molecules on CD14+ monocytes in response to IFN-gamma and IFN-alpha stimulation.
  • IL-18 and IFN-α by CD14+ cells following stimulation with HSV-1, VV, and PRR agonists. [ Time Frame: Day 1 ]
    Production of IL-18 and IFN-α and mRNA by CD14+ cells following stimulation with HSV-1, VV, or PRR agonists.
  • IFN-γ production by CD8+ T cells, in response to stimulation with cytokines IL-12, IL-18, and IFN-α. [ Time Frame: Day 1 ]
    Production of IFN-γ by CD8+ T cells in response to stimulation with recombinant human cytokines including but not limited to IL-12, IL-18, and IFN-α.
  • Expression of IFN-γ receptor and IFN- α/β receptor on CD14+ cells. [ Time Frame: Day 1 ]
    Expression of IFN-γ receptor and IFN- α/β receptor on CD14+ cells.
  • Immunodominant HSV-1 peptide repertoires. [ Time Frame: Day 1 ]
    Analysis of immunodominant HSV-1 peptide repertoires with related HLA in ADEH+, ADEH-, and non-atopic participants.
  • High-throughput gene expression profiling to analyze ribonucleic acid (RNA) from HSV-1 stimulated and sham stimulated CD14+ monocytes. [ Time Frame: Day 1 ]
    Global transcriptional response of CD14+ monocytes to stimulation with HSV-1 as evaluated by GeneChip Profiling.


Information By: National Institute of Allergy and Infectious Diseases (NIAID)

Dates:
Date Received: July 19, 2011
Date Started: April 2011
Date Completion:
Last Updated: April 26, 2017
Last Verified: April 2017