Abstract
Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling and airway hyperresponsiveness (AHR). CD4+ T-cells, in particular T-helper type 2 (Th2) cells, play a critical role in orchestrating the disease process through the release of cytokines like IL-4, IL-5 and IL-13. Allergen-specific immunotherapy (IT) is currently the
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only disease-modifying treatment with long-term suppression of allergen-induced complaints. However, although IT is effective in allergic rhinitis and insect venom allergy, in allergic asthma it seldom results in complete alleviation of symptoms, and bears the risk of inducting severe systemic reactions. There is a strong need to improve IT, however, the mechanism of action is still incompletely understood. Previously we developed a mouse model of IT for allergic asthma which inhibits development of AHR and eosinophilic airway inflammation associated with suppression of Th2-type cytokines. Moreover, we have shown that IT induces IL-10 dependent long-lasting immune tolerance, pointing to a role for T-regulatory type 1 (Tr1) cells. In this thesis, the immunoregulatory mechanisms underlying the beneficial effects of IT were further investigated in an ovalbumin (OVA)-induced mouse model of allergic asthma with the ultimate aim to improve its treatment efficacy. We addressed the following questions: • Do IgG Fcgamma receptors play a role in tolerance induction by IT (chapter 2)? • Is the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase, (IDO) expressed in dendritic cells, involved in immune suppression and/or tolerance induction by IT (chapter 3)? • Does the induction of immune tolerance by IT require the suppressive activity of natural regulatory T (nTreg) cells (chapter 4)? • Does the inhibition of NF-kappa B by the active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3, potentiate the suppressive effects of IT?, and are the immunoregulatory cytokines IL-10 and TGF-beta involved in the effector phase (chapter 5)? Using Fcgamma RI & III and Fcgamma RIIB deficient mice, it is clearly demonstrated that Fcgamma receptors have no role in the effects of IT on asthma manifestations in this mouse model. Interestingly, our findings indicate that nTreg cells partially contribute to the induction of tolerance by IT. Functional inactivation of these nTreg cells through GITR activation or blockade of CTLA-4 reduces the efficacy of IT, in particular the suppression of AHR. Moreover, we show that inhibition of IDO by treatment with the inhibitor 1-methyl-tryptophan, reverses the suppressive effects of IT on AHR, bronchoalveolar lavage eosinophilia and Th2 cytokine levels. In addition, the tryptophan metabolites generated via IDO, kynurenine, 3-hydroxy-kynurenine and xanthurenic acid, but not tryptophan depletion, are involved in the induction of tolerance by IT. Interestingly, nTreg cells can trigger the induction of IDO in dendritic cells by engagement of B7 through CTLA-4 and also by GITR:GITRL interaction. Taken together, our data suggest that tolerance induction by IT is partially mediated by a nTreg-IDO pathway leading to the generation of adaptive Treg cells that suppress Th2 cell activation and development allergen-induced asthma manifestations. In order to improve IT, we examined whether the induction of IL-10 and/or TGF-beta producing adaptive Treg cells could be potentiated by suppression of dendritic cell maturation using 1alpha,25-dihydroxyvitamin D3. It is shown that coadministration of the active form of vitamin D3 with IT augments the suppressive effects on Th2-driven asthma manifestations when compared to IT alone. Moreover, these suppressive effects are reversed by blocking of the regulatory cytokines IL-10 and TGF-beta. These findings have increased our knowledge of the mechanisms of action of IT and may be translated to IT in allergic and asthmatic patients and ultimately guide the design of novel strategies to improve the efficacy of IT.
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