Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies

James, Louisa K. PhD
Shamji, Mohamed H. PhD
Walker, Samantha M. PhD, RGN
Wilson, Duncan R. MD, FRCP
Wachholz, Petra A. PhD
Francis, James N. PhD
Jacobson, Mikila R. PhD
Kimber, Ian PhD
Till, Stephen J. PhD, MRCP
Durham, Stephen R. MD, FRCP

^aAllergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, part of the Medical Research Council and Asthma UK Centre for Allergic Mechanisms of Asthma, London, United Kingdom
^bFaculty of Life Sciences, University of Manchester, Manchester, United Kingdom

^∗Reprint requests: Stephen R. Durham, MD, FRCP, Allergy and Clinical Immunology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, United Kingdom. E-mail: [email protected].

These authors contributed equally to this work.

Supported by grants from the Immune Tolerance Network (S.R.D.), Asthma UK (S.R.D. and S.J.T.), the Health Foundation (S.J.T.), and the London Law Trust (L.K.J.), and a Biotechnology and Biological Sciences Research Council (BBSRC) studentship case award (M.H.S.).

Disclosure of potential conflict of interest: S. M. Walker has received consulting fees and research support from ALK-Abelló. S. R. Durham has received lecture fees and research support from ALK-Abelló and has consulted for ALK-Abelló, Circassia, and Greer Laboratories. The rest of the authors have declared that they have no conflict of interest.

Received for publication August 18, 2010; revised December 17, 2010; accepted for publication December 17, 2010.

Journal of Allergy & Clinical Immunology 127(2):p 509-516e5, February 2011.

Background:

Grass pollen immunotherapy for allergic rhinitis is a disease-modifying treatment that results in long-term clinical tolerance lasting years after treatment discontinuation. Active treatment is associated with generation of inhibitory grass pollen–specific IgG antibodies capable of blocking allergen-IgE interactions.

Objectives:

We sought to investigate the involvement of IgG-associated inhibitory antibodies with long-term clinical tolerance after discontinuation of grass pollen immunotherapy.

Methods:

We conducted a 4-year study in which patients who had moderate-to-severe allergic rhinitis underwent a randomized, double-blind, placebo-controlled discontinuation of subcutaneous grass pollen immunotherapy. All subjects received grass pollen immunotherapy injections for 2 years (n = 13), followed by a further 2 years of either active (n = 7) or placebo (n = 6) injections. Clinical outcomes included seasonal symptoms and use of rescue medication. Serum specimens were collected at baseline and after 2 and 4 years for quantification of allergen-specific IgG antibodies. Sera were also tested for IgG-dependent inhibitory bioactivity against IgE-allergen binding in cellular assays by using flow cytometry and confocal microscopy to detect binding of IgE–grass pollen allergen complexes to B cells.

Results:

Clinical improvement was maintained after 2 years of discontinuation. Although immunotherapy-induced grass pollen–specific IgG1 and IgG4 levels decreased to near-preimmunotherapy levels during discontinuation, inhibitory bioactivity of allergen-specific IgG antibodies was maintained unchanged.

Conclusion:

Grass pollen immunotherapy induces a subpopulation of allergen-specific IgG antibodies with potent inhibitory activity against IgE that persists after treatment discontinuation and that could account for long-term clinical tolerance.