In this study, we demonstrate a refined kinetics of serum and cellular changes by omalizumab. The expected ~80% reduction in both basophil surface IgE and FcεRI expression in subjects 10 days after receiving omalizumab followed the expected decline in IgE (> 90% in free IgE by day 3). Of note, significant, but modest reductions in cat allergen induced BHR occurred as early as day 3 at the 0.1 BAU/mL dose (20% decline) and by day 18 at the 1 BAU/mL dose (35% decline) compared to greater reductions in surface bound IgE, which was reduced by 30% and 87% at day 3 and 18, respectively.
We also found that the percentage of cat specific to total IgE <3% was a predictor of a decline in basophil responsiveness to cat allergen by day 30 while patients were receiving omalizumab. In these enrolled subjects with a positive NAC, this percentage <3% was also associated with a less sensitive basophil response to cat allergen in vivo. However, the ratio of cat specific to total IgE was not associated with the magnitude of decline in symptoms score or reduction in SPT wheal/flare size during either the mid-study or final NAC in patients receiving omalizumab. This observation may be explained by the longer time to mid-study NAC in subjects with higher percentages of cat specific to total IgE. By the final NAC, subjects had received omalizumab for a sufficient duration to clearly effect both basophil and tissue mast cell responses. Future studies should more thoroughly examine the impact of allergen specific to total IgE as a predictor of the early and ultimate clinical impact of omalizumab on subject’s symptoms to a particular allergen.
Acute NAC responses (VAS and sneezes) were suppressed ~50% at the time of basophil hyporesponsiveness although a further suppression to ~80% occurred by the end of the treatment period relative to baseline. Nasal lavage PGD2
measurements, a measure of mast cell activation, were not suppressed at the time of basophil hyporesponsiveness to cat allergen. Another measure of mast cell function, SPT wheal and flare response, was also not suppressed at the time of basophil hyporesponsiveness. These findings are striking and suggest that the acute allergic response to cat allergen appears at least partly dependent on the reduction of basophil allergen response given the stable measures of mast cell function (PGD2
) at a time of depressed clinical nasal response to allergen. Alternatively, it is possible that basophil hyporesponsiveness may serve as a surrogate for process leading to a change in the end-organ allergic response or a surrogate for changes in another cellular compartment. Although we did not directly assess nasal mast cell numbers or surface FcεRI density, the measures of PGD2
achieved at mid-study NAC were stable. Shortcomings of this study include limited measures of nasal mast cell biology other than PGD2
levels. It seems less likely this would support either a heightened per mast cell PGD2
production in the case of a marked reduction in nasal mast cell population at the mid-study NAC. These findings also suggest that IgE depletion with omalizumab leads to a change in tissue responsiveness to basophil and mast cell mediators independent of, or in addition to, suppressed mediator release, since a decrease occurred in nasal scores at each dose of nasal allergen challenge. Recently, the critical role of the basophil in both acute and chronic allergic response has been better defined in mouse models.19
Overall, the basophil has emerged as a initiator of certain allergen-dependent responses in the skin and also a key cell in the production of a Th2 response.
More recently, mechanistic studies using the same omalizumab dosing strategy as our present study have been published. Noga et al. demonstrated a 29–96% reduction in BHR to the optimal dose of allergen (dust mite, cat or dog) after 16 weeks of treatment with omalizumab, but no kinetic to this reduction was studied.20
Lin et al.12
demonstrated a reduction in serum free IgE by 96% by day three, a sustained 70% reduction in basophil FcεRIα expression by day 14, and a significant reduction (~30%) in the acute response to intranasal ragweed challenge by day 7–14 and a further decrease by day 35–42 (~60%). However, in contrast to our study, no concomitant mast cell studies were present in that particular study. Hanf et al.14
demonstrated a 90% reduction in nasal symptoms scores to allergen challenge (variety of allergens) after 16 weeks of omalizumab treatment. Similar to Hanf et al., we were not able to measure a consistent rise in nasal lavage histamine or tryptase content (data not shown) following NAC unlike others10
In summary, these findings support the importance of the basophil, either directly being involved in the acute response to allergen during NAC or as a biomarker of the end organ nasal clinical allergic responses. The kinetic of basophil loss of responsiveness to allergen in the setting of omalizumab was also elucidated. The ratio of cat allergen specific to total IgE <3%, a predictor of early basophil hyporesponisveness to allergen, may also be important in predicting the onset of clinical response to omalizumab treatment and is in need of future study.
Reduction in nasal symptom scores occurred when the basophil, but not mast cell, response was reduced on omalizumab, implicating a role for basophils in the acute NAC response.