**9. Oral tolerance**

The mechanism of action of the allergen-specific immunotherapy is very complicated and still remained unexplained. For an easier understanding of the mechanism of action of ASIT, we divided the immune response to early and late immunological response. In the early phase of immunotherapy (induction phase) there is a decrease in the number of tissue mast cells, eosinophils and basophils followed by a decrease in the release of their cell mediators [105]. Reduction of the number of basophils induced by the oral regulation of the H2 receptor leads to the inhibition of FcεRI-mediated histamine suppression and other mediators. In the first phase of the immune response, the synthesis of IgG4 and IgA is increased [106]. IgG4 blocks the interaction of IgE and allergens as well as the presentation of allergen to T cells. In the late phase, after one to several months, the immune response from Th2 to Th1 is reoriented, as well as the increase in the number and function of both types of T-regulatory cells (T-reg): natural (nT-reg) and inducible (iT-reg) [107]. iT-reg originated from naive CD4<sup>+</sup> T lymphocytes and they are the most important source of IL-10, which is an important factor in peripheral tolerance [108, 109], because it inhibits IgE production from one, and on the other hand stimulates IgG4 secretion and in this way directly inhibits the activity of allergen-specific T lymphocytes [110]. The nT-reg cells (CD4<sup>+</sup> , CD25<sup>+</sup> and FOXP3<sup>+</sup> (Forkhead box protein 3)) are thymus origin and exhibit synergistic effects with iT-reg cells [111] exposing high levels of IL-10 and TGF-beta [112]. T-reg stimulates the proliferation and differentiation of IL-10-secreting dendritic cells, which have a crucial role in the activation and differentiation of different subtypes of T cells. Reducing the number of cell mastocytes, eosinophils, and basophils, increasing IgG4 and IgA synthesis, re-orientation from Th2 to Th1, increasing the number, and function of IL-10 producing T-reg cells play a significant role in the development of immune tolerance and long-lasting immunotherapy effect on the overall immune function and on the immune response to allergens [113–116].
