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* Laboratory of Experimental Immunology, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium;
Department of Otorhinolaryngology-Head and Neck Surgery, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium;
Laboratory for Experimental Medicine and Endocrinology, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium;
Department of Internal Medicine, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium;
¶ Rega Institute, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Belgium; and
|| Pangenetics, Amsterdam, The Netherlands
Interaction between CD154 (CD40 ligand) on activated T lymphocytes and its receptor CD40 has been shown to be critically involved in the generation of cell-mediated as well as humoral immunity. CD40 triggering activates dendritic cells (DC), enhances their cytokine production, up-regulates the expression of costimulatory molecules, and induces their maturation. It is unknown how stimulation of CD40 during sensitization to an airborne allergen may affect the outcome of allergic airway inflammation. We took advantage of a mouse model of allergic asthma and a stimulatory mAb to CD40 (FGK45) to study the effects of CD40-mediated DC activation on sensitization to OVA and subsequent development of OVA-induced airway inflammation. Agonistic anti-CD40 mAb (FGK45) injected during sensitization with OVA abrogated the development of allergic airway inflammation upon repeated airway challenges with OVA. Inhibition of bronchial eosinophilia corresponded with reduced Th2 cytokine production and was independent of IL-12, as evidenced by a similar down-regulatory effect of anti-CD40 mAb in IL-12 p40-deficient mice. In addition, FGK45 equally down-regulated allergic airway inflammation in IL-10-deficient mice, indicating an IL-10-independent mechanism of action of FGK45. In conclusion, our results show that CD40 signaling during sensitization shifts the immune response away from Th2 cytokine production and suppresses allergic airway inflammation in an IL-12- and IL-10-independent way, presumably resulting from enhanced DC activation during sensitization.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants (G.0227.01) from the Fund for Scientific Research-Vlaanderen and Grant OT from the Research Council of the Catholic University of Leuven. P.W.H. is the recipient of a research fellowship of the Fund for Scientific Research-Vlaanderen.
2 Address correspondence and reprint requests to Dr. Peter W. Hellings, Laboratory of Experimental Immunology, Onderwijs en Navorsing, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail address: Peter.Hellings{at}med.kuleuven.be
3 Abbreviations used in this paper: CD40L, CD40 ligand; BAL, bronchoalveolar lavage; DC, dendritic cell; EU, experimental unit; KO, knockout; MGG, May-Grünwald-Giemsa; PBLN, peribronchial lymph node; SN, supernatant; WT, wild type.
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