Allergen immunotherapy increases the concentrations of serum allergen-specific IgG or IgG4 and IgA antibodies (Abs) (
Figure 1) [
26,
27,
28,
29] and transiently increases concentrations of allergen-specific IgE Abs. Several studies have demonstrated the inhibitory capacity of IgG or IgG4 for IgE-dependent immune responses. IgG or IgG4 can compete with IgE for allergen, inhibiting allergen-IgE complex formation [
30]. Thus, it prevents cross-linking of high-affinity IgE receptors (FcεRI) on basophils and mast cells, which suppress histamine release, and blocks binding of allergen-IgE complexes to low-affinity receptors (FcγRIIb) on B cells [
31], which suppress IgE-facilitated antigen presentation to T cells.
Local production of Th2 cytokines, such as IL-4 and IL-5, or the numbers of Th2 cells are decreased by allergen immunotherapy (
Figure 1) [
32,
33,
34]. We found that immunotherapy attenuates HDM-specific production of thymus and activation-regulated chemokine, a potent chemokine activator of Th2 cells, from peripheral blood mononuclear cells (PBMCs) obtained from patients with HDM-sensitized allergic asthma, suggesting that immunotherapy can reduce accumulation of Th2 cells during allergen exposure [
3]. Furthermore, immunotherapy suppresses allergen-induced Th2 cytokines such as IL-5 from PBMCs of allergic patients [
35]. Therefore, immunotherapy can induce systemic immunological changes in response to allergens and provides some clinical benefits in allergic asthma. In addition to the effects on Th2-mediated immune responses, allergen immunotherapy induces regulatory T cells (Tregs) (
Figure 1) [
27,
29,
36,
37,
38]. Tregs are divided into two subsets: natural regulatory T cells (nTregs), which express the transcription factor forkhead box P3 (FOXP3), and inducible regulatory T cells (iTregs), which produce IL-10, IL-35, and TGF-β. For example, allergen immunotherapy increases local FOXP3
+ T cells [
36,
37]. Allergen immunotherapy also increases local IL-10-expressing T cells [
27,
38] and TGF-β+ T cells [
29]. However, the involvement of Tregs in allergen immunotherapy for Th2 suppression is probably regulated by multiple factors, including allergen and time of assessment. Furthermore, the role of regulatory B cells (Bregs), which also produce IL-10 and can suppress immune responses, has also been highlighted [
39,
40]. In bee venom-tolerant patients, IL-10-producing B cells, which express CD25 and CD71 but not CD73, are increased and associated with IgG4 production [
39,
40]. In addition to IL-10, Bregs reveal their suppressive property through TGF-β and IL-35 [
39]. Moreover, allergen immunotherapy increases allergen challenge-induced expression of IL-12 mRNA in the skin [
41]. These findings suggest that allergen immunotherapy suppresses T cell-mediated airway inflammation via downmodulation of Th2 cells and induction of Tregs or Th1 cells. As for type-2 innate lymphoid cells (ILC2), which are also important sources of Th2 cytokines such as IL-5 and IL-13, allergen immunotherapy decreases the number of ILC2 in peripheral blood [
42], although this finding is controversial [
43].
Eosinophilic airway inflammation is an important feature of bronchial asthma. Infiltration of activated eosinophils in the airways is associated with asthma severity. Allergen immunotherapy suppresses airway inflammation, including the numbers of infiltrated eosinophils and concentrations of eosinophil-specific granule proteins (
Figure 1) [
3]. For circulating eosinophils to accumulate in asthmatic airways, they must adhere to and then migrate across vascular endothelial cells. These processes are largely regulated by cytokines/chemokines produced by various cells, including Th2 cells [
44,
45,
46]. Increased adhesion of peripheral blood eosinophils and increased chemotactic activity of eosinophils into the airways are observed during the allergen exposure period in birch pollen asthma, and allergen immunotherapy suppresses increased eosinophil adhesion and chemotactic activity [
3,
32]. We reported that stimulation of PBMCs from HDM-sensitized allergic asthmatics with HDM increases eosinophil adhesion-inducing activity, eosinophil chemotactic activity, and eosinophil transendothelial migration-inducing activity, and the increase in these eosinophil activities was attenuated by allergen immunotherapy [
3,
47]. These findings suggest that the modification of Th2-mediated immune responses to specific allergens by allergen immunotherapy can suppress eosinophil accumulation in the airways.