cell and ig responses in mice by allergen immunotherapy is

Download Cell and Ig Responses in Mice by Allergen Immunotherapy Is

Post on 03-Jan-2017




0 download

Embed Size (px)


  • of April 4, 2011This information is current as

    http://www.jimmunol.org/content/185/7/3857doi:10.4049/jimmunol.0903909August 2010;

    2010;185;3857-3865; Prepublished online 27J Immunol van Oosterhout and Martijn C. NawijnSamsom, J. Sjef Verbeek, Bart N. Lambrecht, Antoon J. M.Betty C. A. M. van Esch, Paul A. J. Henricks, Janneke N. Soheila Shirinbak, Yousef A. Taher, Hadi Maazi, Rene Gras, Cell and Ig Responses in Miceby Allergen Immunotherapy Is Independent of B Suppression of Th2-Driven Airway Inflammation

    References http://www.jimmunol.org/content/185/7/3857.full.html#ref-list-1

    , 21 of which can be accessed free at:cites 53 articlesThis article

    Subscriptions http://www.jimmunol.org/subscriptions

    is online atThe Journal of ImmunologyInformation about subscribing to

    Permissions http://www.aai.org/ji/copyright.html

    Submit copyright permission requests at

    Email Alerts http://www.jimmunol.org/etoc/subscriptions.shtml/

    Receive free email-alerts when new articles cite this article. Sign up at

    Print ISSN: 0022-1767 Online ISSN: 1550-6606.Immunologists, Inc. All rights reserved.

    by The American Association ofCopyright 2010 9650 Rockville Pike, Bethesda, MD 20814-3994.The American Association of Immunologists, Inc.,

    is published twice each month byThe Journal of Immunology

    on April 4, 2011





    nloaded from


  • The Journal of Immunology

    Suppression of Th2-Driven Airway Inflammation by AllergenImmunotherapy Is Independent of B Cell and Ig Responsesin Mice

    Soheila Shirinbak,*,1 Yousef A. Taher,,1 Hadi Maazi,* Renee Gras,* Betty C. A. M. van Esch,

    Paul A. J. Henricks, Janneke N. Samsom, J. Sjef Verbeek,x Bart N. Lambrecht,{

    Antoon J. M. van Oosterhout,*,2 and Martijn C. Nawijn*,2

    Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated

    serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical

    for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling

    through FcgRIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase

    allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcgRIIB or FcgRI/FcgRIII signaling.

    We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of

    FcgRIIB and FcgRI/FcgRIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses

    and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the

    secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are

    in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-

    specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed

    by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase

    allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment. The Journal of

    Immunology, 2010, 185: 38573865.

    Allergen exposure in sensitized individuals results in cross-linking of IgE bound to FcRI on the mast cell surfaceand induces the immediate type I hypersensitivity re-

    sponse, which is driven by inflammatory mediators released fromthe mast cells (1). This immediate-phase allergic response is strictlyIgE dependent and is treated by pharmacotherapy aimed at blockingmast cell effector molecules, such as histamine. The late response to

    allergen exposure is characterized by an influx of eosinophils, neu-trophils, basophils, and activated CD4+ T cells and is sensitive to im-munosuppressive drugs, such as steroids (1). Allergen-specific immu-notherapy (IT) is the only disease-modifying treatment for allergicdisorders and consists of a series of s.c. injections with increasingdoses of allergen, which induces long-term desensitization andrelief of symptoms (2, 3). IT is commonly used for the treatment ofallergic rhinitis and insect venom hypersensitivity, yet its efficacyin allergic asthma is controversial. The main drawbacks of IT arethe long-term treatment protocols and the risk for eliciting anaphy-lactic reactions (2). Improvement of safety and efficacy can only beachieved by characterizing the immunological mechanisms that con-tribute to IT-induced suppression of allergic inflammation in moredetail.Although the critical mechanisms by which IT suppresses al-

    lergic symptoms have not been fully identified, several potentialmechanisms have been postulated to contribute to IT, convergingon the modulation of Tand B cell responses to the allergen (4).Withregard to the T cell responses, IT was postulated to divert theallergen-specific Th2 response into Th1 responses and induce regu-latory T cell activity (5). With regard to the B cell responses, ITwasshown to induce an IgG1 and IgG4-dominated Ab response to theallergen with a mild increase in IgA levels, whereas the serumlevels of allergen-specific IgE showed an early increase followedby a long-term gradual decline (1). However, the relationship be-tween the efficacy of IT and induction of allergen-specific IgG re-mains controversial, with serum concentrations of allergen-specificIgG not consistently correlating with clinical improvement (1, 6, 7).The increase in IgG serum levels, and especially IgG4, following

    IT treatment led to the formulation of the blocking Ab hypothesis,which states that the IgG Abs compete with IgE for binding to the

    *Laboratory of Allergology and Pulmonary Diseases, Department of Pathology andMedical Biology, Groningen Research Institute for Asthma and COPD Research, Uni-versity Medical Center Groningen, University of Groningen, Groningen; Divisionof Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University,Utrecht; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, ErasmusUniversity Medical Center, Erasmus University, Rotterdam; xDepartment of HumanGenetics, Leiden University Medical Center, Leiden University, Leiden, The Nether-lands; and {Laboratory of Immunoregulation and Mucosal Immunology, Departmentof Respiratory Diseases, University of Ghent, Ghent, Belgium

    1S.S. and Y.A.T. contributed equally to this work.

    2A.J.M.v.O. and M.C.N. share senior authorship.

    Received for publication December 10, 2009. Accepted for publication July 20, 2010.

    This work was supported by the Stichting Astmabestrijding Project No. 2007/032 (toA.J.M.v.O.), by funding under the Sixth Research Framework Programme of theEuropean Union, Project MUGEN LSHG-CT-2005-005203 (to M.C.N.), and Re-search Grant 1575.1370 from Al-Fateh Medical University, Tripoli, Libya (toY.A.T.).

    Address correspondence and reprint requests to Prof. Antoon J.M. van Oosterhout,Laboratory ofAllergology and PulmonaryDiseases, Department of Pathology andMed-ical Biology, University Medical Center Groningen, Groningen University, Hanzeplein1, NL-9713-GZ, Groningen, The Netherlands. E-mail address: a.j.m.van.oosterhout@path.umcg.nl

    Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bron-choalveolar lavage; Fel d1, Felis domesticus allergen 1; IT, immunotherapy; pIgR,polymeric IgR.

    Copyright 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00


    on April 4, 2011





    nloaded from


View more >