Early increase in serum specific IgG2 upon allergen immunotherapy with a 300 IR sublingual house dust mite tablet

Allergen immunotherapy (AIT) is the only approach recognized as an etiologic treatment of allergy with long-lasting effects.1 Numerous studies have shown that AIT is accompanied by changes in cellular (e.g., ILC2, Th2A, B and Treg, Tfh) and humoral (e.g., IgE, IgG4, and IgA) parameters.2 However, no biomarkers have been established to date that either predict or associate with the outcome of AIT.3 Recent studies focusing on IgG2 antibodies showed an increase in grass pollen or house dust mite (HDM) allergen-specific IgG2 in the course of AIT with sublingual tablets.4, 5 Particularly, coordinated IgG2 and IgE responses have been observed after 1 year of AIT in European allergic individuals, but only in those exhibiting high clinical benefit (high responders), when compared to low responders.5 The present study aimed to confirm those results with a cohort of HDM-allergic Japanese individuals, and to assess HDM specific-IgG2 responses as early as 4 months after AIT initiation. Briefly, 76 patients receiving placebo and 75 patients treated with a 300-IR HDM tablet were selected, as previously described,6 from a randomized, double-blind, placebo-controlled clinical trial performed in HDM-allergic Japanese patients7 (see details of the trial in Appendix S1, demographics of the studied patients in Table S1, and their serum specific IgE levels before and after AIT in Figure S1). This trial demonstrated that 1 year of daily treatment with the 300-IR tablet was effective without major safety concerns.7 Among the patients treated with the 300-IR HDM tablet, 25 were stratified as high responders and 25 as low responders on the basis of their relative changes (RC) from baseline of the average adjusted symptom score (AASS) in the last 8 weeks of treatment (see details in Ref.7 and Appendix S1). Sera were obtained from all study participants before (visit V2), and 4 months (V8) and 12 months (V17) after initiation of the 1-year treatment. Humoral (i.e., serum specific IgG2 and IgE) responses were analyzed as described previously5 (see details in Appendix S1). As expected, no significant changes in serum levels of Dermatophagoides farinae (Der f)- or Dermatophagoides pteronyssinus (Der p)-specific IgG2 were observed in individuals receiving placebo (Figures 1A and 2A). By contrast, statistically significant increases in serum levels of Der f- and Der p-specific IgG2 were observed after 1 year of AIT in all patients treated with the 300-IR tablet (Figures 1A and 2A). These increases were more significant in high responders (p < .01) than in low responders (p < .05 or not significant) (Figures 1A and 2A). Strikingly, this increase occurred during the first 4 months, but only when patients were considered as a whole (p < .0001 and p < .001 for Der f and Der p, respectively; Figures 1A and 2A). Coordinated specific IgG2 and IgE responses were not observed in the whole population receiving the 300-IR tablet, except for Der f-specific responses between the start (V2) and the end (V17) of AIT (p < .05; Figure S2). Such coordinated specific IgG2 and IgE responses were not observed in low responders, but were observed in high responders, for both the Der f- (p < .01; Figure 1B,C) and the Der p-specific responses (p < .05; Figure 2B,C). Of note, in high responders this correlation was observed as early as after 4 months of AIT for the responses to Der f (p < .05; Figure 1D,E), but not to Der p (not significant; Figure 2D,E). The changes in either Der f- or Der p-specific IgG2 serum levels were not correlated to the RC of AASS between baseline (V2) and the end of AIT (V17) for patients receiving the 300-IR tablet, whether patients were considered as a whole, as high responders or as low responders (Figure S3). In a previous study performed in European patients, a correlation was observed specifically in high responders between the RC from baseline of the clinical score at the end of AIT and both the changes in Der f- and Der p-specific IgG2 serum levels.5 The fact that this correlation is not confirmed here might be explained by the difference in the study population. Altogether, the significant increases in Der f- and Der p-specific IgG2 previously observed after 1 year of AIT to HDM5 occur as early as 4 months after the initiation of AIT. Our data, therefore, support the interest in IgG2 as an emerging biomarker of long-term memory responses by previously formed memory B cells, as previously described.4, 5, 8 We also confirm a differential behaviour in humoral responses in subjects undergoing AIT, as recently published,5, 9 particularly with IgG2 and IgE coordinated responses occurring mostly in high responders to AIT.5 Our findings pave the way for follow-up tools monitoring the onset of efficacy during AIT and support the need of personalized AIT to address the differential behaviour of patients' immune responses. MCvZ and ROH are supported by NHMRC Ideas grant 2000773. Co-authors (NB, VBLF, TB and LM) are employees at Stallergenes Greer. GWC reports having received in the last 3 years research grants as well as lecture or advisory board fees from Alk-Abello, Allergy Therapeutics, Anallergo, Hal Allergy, and Stallergenes Greer. Figure S1 Figure S2 Figure S3 Table S1 Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.