The immune system tolerates to the protein through the oral routes and this phenomenon is called oral tolerance. The underlying mechanism of oral tolerance is sophisticated and has been studied for decades. Many patients have allergy to the house dust mites and which have more than 20 groups of allergens. Therefore, we tried to investigate the effect of oral tolerance induced by single protein on the animals had allergy to 2 or more proteins. The mice were sensitized with the conjugated proteins to mimic the patients that have allergy to the complicated allergens. We found that the single protein induced oral tolerogenic response inhibited the immune response to the other protein. These could be observed in the animal model of allergic asthma and also in vitro cell culture system. These results suggested that the non-antigen-specific regulation of oral tolerance could be clearly detected under certain circumstances. On the other hand, we have utilized the B cells induced regulatory T cells (also called Treg-of-B cells) in several aspects. The B cell-deficient mice showed a defect in cytokine production after oral treatment. We found that the antigen-presenting B cells modulated splenocytes proliferative response to the antigen ex vivo. Then, we further analyzed the role of the Treg-of-B cells in the mechanism. We found that there were several similarities between oral treated antigen-activated Treg cells and the Treg-of-B cells, including the marker expressions, cytokine productions, and suppressive functions in vitro as well as in vivo. Our data suggested that Treg-of-B cells might have a role in the sophisticated mechanism of oral tolerance (Figure). We are the few reports that studied the non-antigen-specific regulation of oral tolerance and the role of Treg cells induced by B cells. Our finding might provide information that could be used for future therapeutic treatment for multiple allergen-induced allergic diseases. Legend: Antigen derived from oral route presented by B cells and induced Treg-of-B cells generation. Treg-of-B cells expressed regulatory molecules and cytokines to suppress antigen-specific and non-antigen-specific effector T cells responses. Reference 1. Chien, C.H., Yu, H.H. & Chiang, B.L. Single allergen-induced oral tolerance inhibits airway inflammation in conjugated allergen immunized mice. J Allergy Clin Immunol. 136(4): 1110-3.e4 (2015). Reference Chien-Hui Chien, Hsin-Hui Yu & Bor-Luen Chiang. Single allergeninduced oral tolerance inhibits airway inflammation in conjugated allergen immunized mice. J Allergy Clin Immunol. 136(4): 1110-3.e4 (2015). DOI: 10.1016/ j.jaci.2015.04.018. Professor Bor-Luen Chiang Graduate Institute of Immunology gicmbor@ntu.edu.tw