Interferon Responses in Eczema Herpeticum (ADRN-01)
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.
Herpes Simplex Infections
|Study Design:||Time Perspective: Prospective|
|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)|
- 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 ] [ Designated as safety issue: No ]Protein and messenger ribonucleic acid (mRNA) levels of IFNγ, and the IFN-γ promoting cytokine, IL-12, produced by CD14+ monocytes in response to stimulation with HSV-1, VV, and various PRR agonists
- 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 IFNα stimulation [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- Production of IFNγ protein by 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 ] [ Designated as safety issue: No ]
- Protein expression of IFNγ receptor and IFNα/β receptor on CD14+ cells [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
- Immunodominant HSV-1 peptide repertoires [ Time Frame: Day 1 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]IFN family members include IFNα, 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 ] [ Designated as safety issue: No ]
- Viral titer of VV as determined by plaque assay following incubation of virus with PBMCs [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
- Gene expression profiles and gene variant profiles of PBMCs stimulated with HSV-1 as assayed by RNA-seq [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples With DNA
Blood samples, RNA, serum, protein and cells will be retained.
|Study Start Date:||April 2011|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Subjects classified as Atopic Dermatitis (AD) and history of previous Eczema Herpeticum (EH) as defined by the ADRN Standard Diagnostic Criteria
Subjects classified as AD without a history of EH as defined by the ADRN Standard Diagnostic Criteria
Subjects classified as "Non-Atopic controls" as defined by the ADRN Standard Diagnostic Criteria
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+.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01429311
|United States, Colorado|
|National Jewish Health||Recruiting|
|Denver, Colorado, United States, 80206|
|Contact: Judy Lairsmith 303-270-2413 lairsmithj@NJHealth.org|
|Contact: Gayle Spears, NP (303) 398-1852 firstname.lastname@example.org|
|Principal Investigator:||Donald Leung, PhD, M.D||National Jewish Health|