Induction of antibody responses to new B cell epitopes indicates vaccination character of allergen immunotherapy

Abstract

Whether the modulation of antibody responses can contribute to the improvement of clinical symptoms in patients receiving allergen immunotherapy represents a controversial issue. We have used purified [seven recombinant (r) and one natural] timothy grasspollen allergens as well as recombinant B cell epitope‐containing fragments of the major timothy grass pollen allergen, Phl p 1, to investigate humoral immune responses in eight allergic patients receiving grass pollen‐specific immunotherapy. We found that the administration of aluminium hydroxide‐adsorbed grass pollen extract induced complex changes in allergen / epitope‐specific antibody responses: increases in IgG subclass (IgG1, IgG2, IgG4) responses against allergens recognized before the therapy were observed. All eight patients started to mount IgE and IgG4 responses to continuous Phl p 1 epitopes not recognized before the therapy and a de novo induction of IgE antibodies against new allergens was found in one patient. Evidence for a protective role of IgG antibodies specific for continuous Phl p 1 epitopes was provided by the demonstration that preincubation of rPhl p 1 with human serum containing therapy‐induced Phl p 1‐specific IgG inhibited rPhl p 1‐induced histamine release from basophils of a grass pollen‐allergic patient. Our finding that immunotherapy induced antibody responses against previously not recognized B cell epitopes indicates the vaccination character of this treatment. The fact that patients started to mount de novo IgE as well as protective IgG responses against epitopes may explain the unpredictability of specific immunotherapy performed with allergen extracts and emphasizes the need for novel forms of component‐resolved immunotherapy.

The IgE-facilitated allergen binding (FAB) assay: Validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses

“…This suggests a functional role of IgG4 in inhibition of IgE-FAB, which may be due to changes in their specificity and/or affinity. Another role of allergen-specific IgG4 antibodies induced by immunotherapy is their ability to block allergen-induced IgE-dependent histamine release by basophils confirming the functional blocking activity of these antibodies (Ball et al, 1999;Lambin et al, 1993).…”

Vaccination with genetically engineered allergens prevents progression of allergic disease

“…(Table 1). Injection immunotherapy with natural allergen extracts is known to induce mainly Th2-like immune responses (i.e., IgG4) (22,23). However, the allergy vaccines that we developed led to a change of the allergic immune response toward a Th1 phenotype, as shown by the induction of IgG2 Abs in both actively treated groups (Table 1).…”

“…Granulocytes from birch pollen-allergic donors were isolated by dextran sedimentation from heparinized blood samples (21). Different concentrations (0.001, 0.01, 0.1, 1, and 10 g͞ml) of rBet v 1, rAln g 1, and (for control purposes) an immunologically unrelated allergen (i.e., timothy grass pollen allergen, Phl p 1) or anti-IgE Abs were incubated with sera obtained before and after treatment and then exposed to the granulocyte preparation (22)(23)(24). Histamine released into culture supernatants was measured by RIA (Immunotech, Marseille, France).…”

T Cell Epitope-Containing Hypoallergenic Recombinant Fragments of the Major Birch Pollen Allergen, Bet v 1, Induce Blocking Antibodies

“…It has been shown that allergen-specific IgG Abs can inhibit the IgE-mediated release of biological mediators from effector cells and thus may prevent immediate symptoms (37,(51)(52)(53).…”

“…Selection of patients by component-resolved diagnosis will allow component-resolved immunotherapy with the disease-eliciting allergen and thus prevent de novo sensitization against other components present in natural allergen-extracts (15,53). As rBet v 1 fragments exhibited a Ͼ100-fold reduced allergenic activity, we expect fewer side effects and think that higher doses can be administered.…”