Regulation of allergic sensitization and oral tolerance to peanut

Abstract

The usual response to harmless gut antigens is the induction oral tolerance. Lack of oral tolerance due to absence of optimal immunoregulation may be involved in causing food allergy. Allergic reactions to food components can cause serious illness and sometimes life-threatening anaphylactic reactions. The underlying mechanisms that control oral tolerance versus oral sensitization remain to be elucidated. Revealing the mechanisms of sensitization to food proteins may contribute to the development of new treatment methods for food allergies. In the present thesis, animal models were used to explore different immunoregulatory mechanisms. Our results and previous studies describe the mechanisms for an increased allergic response as an imbalance of Th1/Th2 cells, a failure in appropriate activation of innate effector cells and signalling molecules or a reduced activation of Treg cells. More specifically, it was observed that NK cells are important regulators of the allergic response and are involved in the induction of oral tolerance. The results indicate that NK cells, probably by IFN-γ production, are able to control an initiation of oral sensitization by favouring a Th1 response. Furthermore, we show that although nTreg cells have an unequivocal role in homeostasis, they are unable to transfer oral tolerance to PE following PE plus CT sensitization. Comparing depletion of CD25 cells with neutralization of IL-10 and TGF-β indicates that both regulatory cytokines are important for general modulation of immune responses, but that TGF-β is particularly involved in modulating the Th2-biased PE-specific response. In real-life, virus and bacterial infections may be important factors regulating the above mentioned features leading to allergic responses. Therefore, the capacity of a Th1-promoting mucosal virus infection (reovirus) to regulate the allergic response to PE in an animal model of allergy and infection was studied. We found that the robust Th1 responses to reovirus modulate PE-specific immune responses in mice, although it did not result in modulation of the peanut allergic response. These experiments provide evidence for a role of enteric viruses in regulating allergic immune responses. Similarly, an apparent decline in microbial exposure during early life is proposed as a possible cause for the increase incidence of allergic diseases over the past few decades. Probiotics, live bacteria exhibiting health-promoting activities, may be considered for treatment of allergic individuals on the basis of their immune modulatory properties. We have used a translational strategy to assess the allergy-modulating capacity of probiotics. Selected probiotics appeared to have a moderate effect on peanut sensitization, despite the fact that they appeared to profoundly stimulate cytokine production in vitro. However, combined neutralization studies indicated that the probiotic strain LP256 does not have the capacity to modulate peanut allergic responses. Our study shows that careful strain selection is difficult. The translational approach presented here, using human PBMC, mouse splenocytes as well as animal models, and including means of exploring existing regulatory mechanisms, may be helpful in selecting and characterizing immunomodulatory probiotics.