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Lower influenza-specific cell-mediated immune responses in individuals with atopic dermatitis compared with healthy controls.

ABSTRACT: In a sub-study of a clinical trial (NCT01737710) investigating the immunogenicity of trivalent inactivated influenza vaccine (IIV3) administered intradermally or intramuscularly to individuals with atopic dermatitis (AD), we assessed T cell and antigen-presenting cell (APC) responses to influenza B in AD and Non-AD controls. The comparison of IFN-γ ELISpot in 58 AD and 31 Non-AD showed lower responses in AD pre-vaccination. Pre-vaccination, AD also had lower Th2 responses and less inflammatory cytokine production by APC measured by flow cytometry and cytokine levels in culture supernatants. AD also had lower Th1 and Th2 responses to nonspecific anti-CD3/anti-CD28-stimulation, but these were not significantly correlated with the influenza-specific responses, suggesting a primary role for the APC in the decreased influenza-specific T cell responses. Multivariate modeling of influenza-specific responses pre-vaccination with influenza-specific antibody titers and IFN-γ ELISpot as outcome measures identified several T cell and APC subsets that negatively or positively predicted protective responses to the vaccine. However, none of the functional differences between AD and Non-AD had high predictive value on adaptive responses to influenza vaccine, which was in agreement with the overall similar responses to the vaccine in the parent clinical trial.

SUBMITTER: Jalbert E

PROVIDER: S-EPMC7734037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an "allergic"/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects.We sought to define whether both variants share a common pathogenesis.We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry.A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin).Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.

Project description:Background and objectiveAbrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure.MethodsAbrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed. Simulations of abrocitinib dose proportionality and steady-state accumulation of maximal plasma drug concentration (Cmax) and area under the curve (AUC) were conducted using the final model.ResultsA two-compartment model with parallel zero- and first-order absorption, time-dependent bioavailability, and time- and dose-dependent clearance best described abrocitinib pharmacokinetics. Abrocitinib coadministration with rifampin resulted in lower exposure, whereas Asian/other race coadministration with fluconazole and fluvoxamine, inflammatory skin conditions (psoriasis/AD), and hepatic impairment resulted in higher exposure. After differences in body weight are accounted for, Asian participants demonstrated a 1.43- and 1.48-fold increase in Cmax and AUC, respectively. The overall distribution of exposures (Cmax and AUC) was similar in adolescents and adults after accounting for differences in total body weight.ConclusionsA population pharmacokinetics model was developed for abrocitinib that can be used to predict abrocitinib steady-state exposure in the presence of drug-drug interaction effects or intrinsic patient factors. Key covariates in the study population accounting for variability in abrocitinib exposures are Asian race and adolescent age, although these factors are not clinically meaningful.Clinical trial numbersNCT01835197, NCT02163161, NCT02201524, NCT02780167, NCT03349060, NCT03575871, NCT03634345, NCT03637790, NCT03626415, NCT03386279, NCT03937258.

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Lower influenza-specific cell-mediated immune responses in individuals with atopic dermatitis compared with healthy controls.

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