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Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity

https://doi.org/10.1016/j.jaci.2008.01.072Get rights and content

Background

Grass pollen immunotherapy is an effective treatment for seasonal allergic rhinitis that provides the opportunity to study the induction and maintenance of allergen-specific immune tolerance.

Objectives

We investigated the relationship between clinical responsiveness, regulatory cytokine production, and antibody responses to allergen during 1 year of immunotherapy.

Methods

Eighteen subjects with severe seasonal allergic rhinitis were randomized double-blind to receive active or placebo injections of an alum-adsorbed grass pollen vaccine (Alutard SQ). Subjects underwent repeated testing of early- and late-phase skin responses to intradermal allergen, and cellular responses to grass pollen allergen were tested. Sera were tested for allergen-specific IgG4, IgA, and inhibitory activity in biologic assays of IgE responses.

Results

Grass pollen immunotherapy was effective in reducing overall symptom scores (P < .05) and conjunctival reactivity (P < .05). In the active group significant IL-10 production occurred early at low allergen doses and at a similar time as inhibition of late skin responses at 2 to 4 weeks. Serum allergen-specific IgG4, IgA, and inhibitory antibody activity for basophil histamine release and IgE-facilitated allergen binding to B cells occurred later, at 6 to 12 weeks, at higher allergen doses and preceded inhibition of early skin responses.

Conclusion

IL-10 responses occur early but at immunotherapy doses that are not clinically effective. Later induction of inhibitory antibodies, including IgG4 and IgA, might be required for efficacy through modulation of IgE-mediated events.

Section snippets

Patient selection

Patients with seasonal allergic rhinitis were selected on the basis of a history of moderate/severe seasonal allergic rhinitis and poor symptom control in previous years despite pharmacotherapy (see the Methods section in the Online Repository at www.jacionline.org for further details). Participants had a positive skin prick test response (wheal >5 mm) to timothy grass pollen extract (Soluprick SQ; ALK-Abelló, Hørsholm, Denmark). Patients were excluded if they were polysensitized with perennial

Overall clinical and immunologic changes during allergen immunotherapy

Subjects who received grass pollen immunotherapy during 2003 had a significant clinical response to treatment, with reduced symptoms and responsiveness to grass pollen allergen compared with those seen in the placebo group. After 1 year's treatment, patients receiving immunotherapy had significantly better mean (±SE) overall assessment scores (2.42 ± 0.22) compared with patients receiving placebo (1.50 ± 0.34, P < .05; Fig 1, A). Patients receiving immunotherapy also required significantly

Discussion

In this study we have examined in detail the time course of clinical desensitization in relation to cellular and humoral immunologic changes during grass pollen immunotherapy. First, immunotherapy resulted in a striking early induction of peripheral IL-10 responses that accompanied suppression of cutaneous allergen–induced late responses. These events were detected as early as 2 to 4 weeks after the first allergen injection, corresponding to a cumulative allergen dose of only 0.9% to 5.4% of

References (36)

  • Y.E. Ong et al.

    Anti-IgE (omalizumab) inhibits late-phase reactions and inflammatory cells after repeat skin allergen challenge

    J Allergy Clin Immunol

    (2005)
  • U. Muller et al.

    Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom

    J Allergy Clin Immunol

    (1998)
  • C.L. Kepley et al.

    Negative regulation of FcepsilonRI signaling by FcgammaRII costimulation in human blood basophils

    J Allergy Clin Immunol

    (2000)
  • P.S. Creticos et al.

    Dose response of IgE and IgG antibodies during ragweed immunotherapy

    J Allergy Clin Immunol

    (1984)
  • A. Nanda et al.

    Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract

    J Allergy Clin Immunol

    (2004)
  • V. Bauchau et al.

    Epidemiological characterization of the intermittent and persistent types of allergic rhinitis

    Allergy

    (2005)
  • M. Plaut et al.

    Clinical practice. Allergic rhinitis

    N Engl J Med

    (2005)
  • P. White et al.

    Symptom control in patients with hay fever in UK general practice: how well are we doing and is there a need for allergen immunotherapy?

    Clin Exp Allergy

    (1998)
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    Supported by grants from the Immune Tolerance Network, National Institutes of Health; Asthma UK; and GlaxoSmithKline in partnership with Imperial College Trust (academic Drug Discovery Initiative) and ALK-Abelló, Hørsholm, Denmark. S.J.T. is the recipient of a Clinician Scientist Fellowship supported by the Health Foundation.

    Disclosure of potential conflict of interest: M. A. Calderon has consulting arrangements with ALK-Abelló, MSD, and Schering-Plough and has received research support from ALK-Abelló. S. R. Durham has consulting arrangements with ALK-Abelló and GlaxoSmithKline, has received research support from ALK-Abelló and GlaxoSmithKline, and has served as a member of the Immune Tolerance Network and the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest.

    These authors contributed equally to this work.

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