Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy

Background: Induction of allergen-specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgGassociated inhibitory activity such as inhibition of IgEallergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response. Methods: In an 8-month doseresponse randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ-U, 10 000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG4 titres and IgG-associated inhibitory activity were evaluated. Results: A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollenspecific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptomrescue medication scores (IgE-FAB: r = -0.25, P = 0.0002; IgE-blocking factor: r = -0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG4 levels (r = -0.11, P = 0.12). Conclusions: Functional assays of inhibitory IgG4 and IgE-blocking factor may be more useful surrogates of clinical response than IgG4. Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.