Mechanisms of allergen-specific desensitization.
BACKGROUND
Allergen-specific desensitization (SIT) is the most effective therapy for allergies. Although allergen-specific antibodies have an important role in the process, mechanisms of IgG-mediated inhibition of allergic reactions are not well defined.


OBJECTIVE
We investigated mechanisms by which SIT-induced allergen-specific IgGs inhibit allergic reactions.


METHODS
We generated mAbs that recognize 3 nonoverlapping epitopes of the major cat allergen Fel d 1. Each of the mAbs was produced as an IgE and different IgG isotype.


RESULTS
IgEs against 2 nonoverlapping epitopes on Fel d 1 are necessary and sufficient to sensitize mast cells for maximal FcepsilonRI signaling and degranulation on exposure to monomeric Fel d 1. IgE antibodies of a third specificity did not further increase mast cell degranulation, indicating that formation of large FcepsilonRI clusters are not required to induce maximal activation of mast cells. A single IgG that was specific for an epitope different from those recognized by the IgEs was a potent inhibitor of Fel d 1-mediated mast cell activation in vitro and in vivo. This inhibition required Fcgamma receptor-IIB. In human beings, IgGs of a single specificity were able to block degranulation of basophils from individuals with cat allergy. The inhibitory potential of these antibodies increased when larger allergen-IgG complexes were formed.


CONCLUSIONS
These data reconcile conflicting theories in the literature and might explain the reason IgE levels do not necessarily decrease during therapy, despite clinical efficacy. These findings have important implications for vaccine design.
Uermösi
Christina
C
Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
Beerli
Roger R
RR
Bauer
Monika
M
Manolova
Vania
V
Dietmeier
Klaus
K
Buser
Regula B
RB
Kündig
Thomas M
TM
Saudan
Philippe
P
Bachmann
Martin F
MF
D000485:Allergens / Q000276:immunology* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D003888:Desensitization, Immunologic; D000939:Epitopes / Q000276:immunology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D014612:Vaccines / Q000235:genetics / Q000276:immunology
D000485:Allergens; D000911:Antibodies, Monoclonal; D000939:Epitopes; D006023:Glycoproteins; D007074:Immunoglobulin G; D017455:Receptors, IgE; D017452:Receptors, IgG; D014612:Vaccines; D007073:Immunoglobulin E; C059296:Fel d 1 protein, Felis domesticus