Allergen immunotherapy is effective in patients with IgEdependent
allergic rhinitis and asthma. When immunotherapy
is given continuously for 3 years, there is persistent clinical
benefit for several years after its discontinuation. This diseasemodifying
effect is both antigen-specific and antigen-driven.
Clinical improvement is accompanied by decreases in numbers
of effector cells in target organs, including mast cells, basophils,
eosinophils, and type 2 innate lymphoid cells. Immunotherapy
results in the production of blocking IgG/IgG4 antibodies that
can inhibit IgE-dependent activation mediated through both
high-affinity IgE receptors (FcεRI) on mast cells and basophils
and low-affinity IgE receptors (FcεRII) on B cells. Suppression
of TH2 immunity can occur as a consequence of either deletion
or anergy of antigen-specific T cells; induction of antigenspecific
regulatory T cells; or immune deviation in favor of TH1
responses. It is not clear whether the altered long-term memory
resides within the T-cell or the B-cell compartment. Recent data
highlight the role of IL-10–producing regulatory B cells and
‘‘protective’’ antibodies that likely contribute to long-term
tolerance. Understanding mechanisms underlying induction and
persistence of tolerance should identify predictive biomarkers of
clinical response and discover novel and more effective
strategies for immunotherapy.