Can Allergen Immunotherapy Improve Antiviral Immunity in Patients with Allergic Asthma?

Allergen exposure and respiratory virus infections are the key triggers for acute asthma exacerbations (1). The susceptibility to virus infections and asthma exacerbations is often attributed to deficient IFN synthesis in the airway mucosa because virus-infected bronchial epithelial cells (BECs) from people with asthma seem to produce less innate antiviral IFNs in vitro relative to BECs from healthy people (2). Understanding whether altered IFN production is an intrinsic property of BECs in asthma or arises secondary to immune-mediated inflammation has important implications for developing therapies for viral infections and asthma exacerbations. It is known experimentally that allergic inflammation can impair IFN production via alarmins such as IL-33 (3), T2 cytokines such as IL-4 and IL-13 (4), and allergen–IgE interactions (5), prompting researchers to determine if inhibiting allergic pathways in patients with asthma enhances antiviral IFN production and protects against viral infections.

Evidence that allergen immunotherapy (AIT) is beneficial in allergic diseases has accumulated in recent decades (6). AIT induces immunological tolerance, reduces asthma exacerbations, and probably has a disease-modifying effect, with some improvements persisting long after treatment concludes (6). The beneficial effects of AIT involve direct effects on mast cells and basophils and induction of regulatory cells, cytokines, and IgE-blocking antibodies. AIT is associated with fewer lower respiratory tract infections in people with allergic asthma (7), though the mechanisms involved and whether there is protection against viral or bacterial infections are not clear.

In this issue of the Journal, Woehlk and colleagues (pp. 1161–1170) report the findings of their randomized, double-blind, placebo-controlled trial of house dust mite sublingual allergen immunotherapy (HDM-SLIT) to determine if this intervention enhances BEC antiviral responses in allergic asthma (8). The study recruited 39 people with HDM sensitization and suboptimal asthma control despite maintenance inhaled corticosteroids, to which HDM-SLIT or placebo was added for 24 weeks. BECs (collected by bronchoscopy at baseline and at Week 24) were activated in vitro with the viral nucleic acid mimic polyinosinic:polycytidylic acid (poly I:C). The primary outcome measure was IFN-β and IFN-λ gene expression in BECs and the extent to which this changed between baseline and Week 24. Recruited patients had asthma of varying severity, and the placebo and HDM-SLIT groups were generally well matched.

The key findings were as follows. At baseline, there were no between-group differences in poly I:C–induced IFN-β and IFN-λ expression. At Week 24, poly I:C–induced IFN-β mRNA and protein were higher than at baseline in BECs from the HDM-SLIT–treated group but not the placebo-treated group. IFN-λ expression followed a similar pattern, with an increase in the HDM-SLIT–treated group but not the placebo group (8). Reductions were seen in IL-33 mRNA and protein release by BECs in the HDM-SLIT–treated group; diminished IL-33 was significantly associated with enhanced IFN-β mRNA expression. Epithelial cell T2 cytokine expression did not change, though greater IL-6 expression was observed in the HDM-SLIT treatment group. Asthma symptom scores, quality-of-life measures, and airway obstruction improved over 24 weeks in both groups (8), but no differences between treatment groups were observed. These clinical improvements were probably a consequence of study participation per se rather than the intervention itself.

The authors interpret these findings as evidence that HDM-SLIT can improve innate airway epithelial responses to viral infection, thereby providing a mechanism by which HDM-SLIT might reduce asthma exacerbations and respiratory viral infections (8). One intriguing aspect of this study is the concept that controlled allergen delivery to the oral mucosa can have a distant, beneficial effect on BEC innate immune function. How might this occur? Microaspiration of allergens into the lower airway is possible but unlikely. The key immunological processes are much more likely to be occurring in the oral mucosa and draining lymph nodes, followed by delivery of a “regulatory signal” to the airway mucosa. The nature of this regulatory signal is unclear but is likely to involve induction of multiple components of adaptive immunity, including regulatory T and B cells, regulatory cytokines, and blocking antibodies. Such “long-distance regulation” has precedence in the ability of systemic anti-IgE therapy to enhance type I IFN synthesis in vitro (9) and to reduce virus-associated asthma exacerbations (10).

Before proceeding further, it is important to raise questions about the desirability of enhancing antiviral IFN production capacity in asthma. The recent observation that AIT is associated with reductions in lower respiratory tract infection risk in allergic asthma supports this hypothesis (7) but will ultimately require longer studies of AIT to provide evidence that augmenting IFN synthesis is responsible for fewer viral infections. The notion that antiviral IFN deficiency is characteristic of asthma is controversial. Deficient IFN synthesis in vitro may be confined to a minority inflammatory phenotype among those with poorly controlled asthma (11) rather than being a universal trait, whereas some in vivo studies of viral infections actually report that IFN release is higher in those with asthma than in those without asthma (12, 13). If IFN release during a viral infection is already high, is further augmenting IFN release a desirable goal? Unfortunately, the benefits of inhaled IFN for viral infections in asthma have been underwhelming in recent clinical trials (14, 15). More evidence is needed to advance the field.

The authors acknowledge the limitations of their present study (8). BEC function was assessed at 24 weeks, well before clinical improvements usually become apparent, whereas standard courses of AIT usually last for 3 years. The study was underpowered for some outcomes, and it will be important to design longer and larger studies of AIT that examine the extent to which changes in BEC function, specifically IFN-β, IFN-λ, and IL-33 release, antedate prevention of respiratory viral infections. The present report provides a solid foundation on which to design such future studies.