Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab - 04/05/18
, Andrew H. Liu, MD c, Agustin Calatroni, MA, MS d, Rebecca Z. Krouse, MS d, Baomei Shao, PhD b, Allison Schiltz, BA c, James E. Gern, MD f, Alkis Togias, MD e, William W. Busse, MD fAbstract |
Background |
Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-α responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma.
Objective |
We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-α responses in inner-city children with asthma.
Methods |
PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-α levels were measured in supernatants, and mRNA expression of IFN-α pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. FcεRIα protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations.
Results |
Omalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-α responses in the presence of IgE cross-linking and reduced pDC surface FcεRIα expression. Omalizumab-induced reductions in pDC FcεRIα levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-α responses. PBMC FcεRIα mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction.
Conclusions |
These findings indicate that omalizumab treatment augments pDC IFN-α responses and attenuates pDC FcεRIα protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations.
Le texte complet de cet article est disponible en PDF.Key words : Plasmacytoid dendritic cells, rhinovirus, IFN-α, asthma, IgE, omalizumab, FcεRα
Abbreviations used : IRF, pDC, PROSE, RIG-I, TLR
Plan
| Supported in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services, under contract and grant numbers NIH NIAID 5R01AI098077, HHSN272200900052C, HHSN272201000052I, 1UM1AI114271-01, and UM2AI117870. Additional support was provided by the National Center for Research Resources and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, under grants NCATS/NIH UL1TR000150, NCRR/NCAT/NIH UL1TR000077-04, UL1TR000451, UL1TR001105, UL1TR000040, UM1AI109565, UL1TR000075, 1UL1RR025780, UL1TR000154, and UL1TR001082. The following were donated: omalizumab and matching placebo by Novartis and fluticasone and matching placebo by GlaxoSmithKline under a clinical trial agreement with the University of Wisconsin-Madison; EpiPens by Mylan; and Ayr nasal rinse by B.F. Ascher & Company. |
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| Disclosure of potential conflict of interest: M. A. Gill's institution received a grant from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID), consulting fees and support for travel from the American Academy of Allergy, Asthma & Immunology (AAAAI) for this work and received lecture fees from the American Academy of Pediatrics (AAP) for other works. A. H. Liu received a grant from the NIH/NIAID for this work; served on the Data Safety Monitoring Board for GlaxoSmithKline; and received speakers' fees from Merck Sharp & Dohme for other works. A. Calatroni received a grant from the NIH/NIAID for this work. R. Z. Krouse's, B. Shao's, and A. Schiltz's institutions received grants from the NIH/NIAID for this work. J. E. Gern's institution received a grant from the NIH/NIAID for this work and personally received consultancy fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer Ingelheim. W. W. Busse received a grant from the NIH/NIAID for this work; board membership from Boston Scientific and ICON; and consultancy fees from Novartis, Glaxo SmithKline, Genentech, Roche, Boehringer Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, Knopp Bio, and Elsevier. A. Togias declares no relevant conflicts of interest. |
Vol 141 - N° 5
P. 1735 - mai 2018 Retour au numéro
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