Biologics and immunotherapy
Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab

https://doi.org/10.1016/j.jaci.2017.07.035Get rights and content

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.

Section snippets

Mechanistic study design

In participants from 2 of the 8 sites of the PROSE clinical trial (UT Southwestern Medical Center, Dallas, Texas, and National Jewish Health, Denver, Colorado), blood for ex vivo assays was drawn before randomization and 12 to 16 weeks after initiation of treatment. These assays were designed to measure the effect of IgE cross-linking on virus (rhinovirus and influenza)–induced and TLR7 agonist (gardiquimod)–induced IFN-α in cultures of PBMCs (all participants) and pDCs (in a subset of

Results

IFN-α responses were evaluated in participants receiving omalizumab and placebo treatment (n = 92) at 2 clinical sites. Participants had similar demographic and laboratory characteristics as those in the multisite clinical trial, including low income, predominant Hispanic ethnicity, increased peripheral blood eosinophil counts, and total serum IgE levels (see Table E3 in this article's Online Repository at www.jacionline.org). No significant differences in baseline characteristics were found

Discussion

Overexpression of FcεRIα and cross-linking of this receptor can disrupt virus-induced IFN-α responses,5, 6 and this represents a potential mechanism for more severe viral respiratory illnesses in patients with allergic asthma. We demonstrated previously that omalizumab treatment of urban children with moderate asthma restores ex vivo PBMC IFN-α responses and that these improved responses were related to a lower risk for asthma exacerbation.10 In the present study we extend these findings by

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    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.

    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.

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