Pretreatment IgE sensitization patterns determine the molecular profile of the IgG4 response during updosing of subcutaneous immunotherapy with timothy grass pollen extract

Abstract

Allergen immunotherapy is an effective treatment of allergic rhinoconjunctivitis. Clinical efficacy is associated with improvement of basophil sensitivity and an increase in allergen-specific immunoglobulin concentration. We sought to determine whether changes in allergen component-specific serum IgE and IgG4 levels during the updosing phase of subcutaneous immunotherapy (SCIT) are biomarkers of the immunologic changes that can lead to treatment efficacy. Twenty-four subjects with grass pollen-induced allergic rhinoconjunctivitis were randomized 3:1 to receive SCIT (Alutard SQ) or to an open control group. IgE and IgG4 concentrations were determined for the major allergens Phl p 1 or Phl p 5 by using ImmunoCAP and for 8 grass pollen molecules by using Immuno Solid-phase Allergy Chip (ISAC) before treatment and after updosing. Levels of specific IgE against the dominant major allergens Phl p 1 and Phl p 5 increased from a mean of 23.0 to 48.8 kU/L (P=.01, n=18) during the updosing phase in ImmunoCAP measurements but decreased from a median of 4.6 ISAC specific units (ISU) to 2.14 ISU (P<.0001, n=102) when measured by using ISAC against 8 grass allergen components. The updosing phase induced a specific IgG4 level increase from a median of 0 ISU before treatment to 0.83 ISU after 12weeks (P<.0001, n=102) but only for allergen molecules to which pretreatment-specific IgE antibodies were detected (Spearman σ=0.72, P<.0001, n=102). Pretreatment allergen component-specific IgE appears to determine the induction of IgG4 in the updosing phase. Induced IgG4 seems to suppress IgE levels on ISAC, resulting in a marked decrease in ISAC-measured specific IgE levels after updosing of SCIT. Thus this decrease in ISAC IgE levels can be used to monitor the blocking effect of allergen-specific immunotherapy-induced non-IgE antibodies.