Allergen immunotherapy (AIT) is an effective treatment for
allergic rhinitis, inducing long-term clinical tolerance to the sensitizing
allergen. Clinical tolerance induction can be achieved when AIT is administered for at least 3 years. AIT is associated with the modulation of innate and adaptive immune systems. This comprises inhibition of
IgE-dependent activation of mast cells and basophils in the local target organ, suppression of TH2 cells, immune deviation toward TH1 cells, induction of T and B regulatory cells, and production of
allergen-
neutralizing antibodies. However, recent developments in their underpinning mechanisms have revealed that AIT, administered subcutaneously or sublingually, induces immune regulation through novel cell targets and molecular mechanisms. This comprehensive review discusses how immune tolerance driven by subcutaneous
immunotherapy and sublingual immunotherapy is associated with the induction of a novel regulatory subset of innate lymphoid cells and suppression of proinflammatory TH2,
allergen-specific TH2 (TH2A), and T follicular helper cells. Moreover, they are associated with exhaustion of TH2A cells and differential expression of nasal and systemic
IgA antibodies. Uncovering the underpinning mechanisms of a successful AIT and immune tolerance induction will allow the development of targeted
therapeutics for
allergic rhinitis with and without
asthma.