**11. Conclusion**

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

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

and FOXP3<sup>+</sup>

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 func-

As it mentioned above clinical efficacy of immunotherapy has been proven in a great number of clinical studies but there are still some issues to be discussed. Recent studies are more focused on the usage of recombinant allergen-based immunotherapy that will possible makes allergy vaccines more safe, convenient, and effective. Recombinant-allergen vaccines also contain defined amounts of the allergen components, and the composition can be tailored according to patient's sensitizations. Both recombinant allergen-diagnostic tests and immunotherapy lead to more personalized and stratified treatment of different allergic entities. Recombinant allergen-based vaccines have been developed and successfully evaluated for several respiratory allergen sources including food allergies [117–120]. The second approach for minimizing side effects and improves compliance is the usage of peptide immunotherapy that has been proven in many studies as effective in treating patients with different respiratory allergies [121]. Data from the studies showed that this kind of immunotherapy is clinical effective for months to years after a short course of treatment. Some studies also investigate new routes of administration such as intralymphatic and epicutaneous. Although it is proven as safe and efficacy, both routes require further clinical investigation [122, 123]. Recently, scientists have exploited the immune system to produce antibodies from single B cell clones, heralding the era of monoclonal antibodies. Biological agents (biologicals or biologics) bring revolution in the treatment of many rheumatic and immunological disorders and are currently being assessed for allergic disorders. Better understanding the endotypes and phenotypes of allergic disease may lead

T lymphocytes and they are the most

(Forkhead box protein 3)) are thymus

(iT-reg) [107]. iT-reg originated from naive CD4<sup>+</sup>

, CD25<sup>+</sup>

tion and on the immune response to allergens [113–116].

[110]. The nT-reg cells (CD4<sup>+</sup>

110 Allergen

**10. Future perspectives**

According to a great number of clinical studies, allergen-specific immunotherapy in combination with asthma and anti-allergic medication is clinically effective in treating children with respiratory allergies. Respecting the newest data, SLIT can be used not only in children with stable asthma, but also in those with uncontrolled asthma but then in combination with anti-IgE-omalizubam treatment. AIT in children can even bring more benefits. At first, data suggested that SLIT reduced the usage of corticosteroids that can have deep negative impact on child development. The second benefit is the possibility of AIT to change the natural course of allergic diseases in terms of asthma prevention in children with allergic rhinitis. The problem of SLIT, especially in the young population of children and adolescents, is compliance that can be possibly overcome with the introduction of ultra-rush and rush protocols. Investigating the various effects of immunotherapy based on the developmental stage of children and adolescents can help to identify the optimal dose, frequency, treatment duration, and age for starting to treatment. Better selection of well responders based on endotypedriven approach is expected to increase both efficacy and safety.
