Allergen-Specific Tolerance Induction: Of Mice and Men

gen tolerance. In this regard, animal models represent very helpful tools to analyze the immune effects of AIT in more detail since they allow investigators to focus on certain aspects when evaluating the immune mechanisms of tolerance induction, and can thus close a gap between in vitro analysis and immunological studies in humans [10] . A variety of mouse models have been developed to study the immune alterations of tolerance induction and one has to keep in mind that no model completely mimics the clinical and immunological features of the human situation [11, 12] . Important parameters affecting the outcome are: (i) the mouse strain, (ii) the allergen (ovalbumin as an obligatory IgE-inducing allergen or clinically relevant antigens, like house dust mite or birch pollen allergen), (iii) the route of its administration (intraperitoneal, intranasal, intratracheal, subcutaneous, oral), (iv) the dosing regimen (low dose, high dose, escalating doses), (v) the type of adjuvants (alum, endotoxins, other or none) and (vi) the duration of treatment (e.g. rapid, gradual or intermediate desensitization protocols can result in very different immune alterations, albeit with similar clinical responses [13] ). Furthermore, clinical and immunological relevance of the animal model has to be interpreted differently depending on the type of model, i.e. if it represents a prophylactic model preventing either allergen sensitization or the elicitation of allergic reactions in sensitized animals, or if it really induces allergen tolerance in sensitized mice which already have become allergic after subsequent allergen challenge [11] . While IgE-mediated respiratory allergies are among the most prevalent diseases in the Western world with about 25% of the European population suffering from allergic rhinoconjunctivitis and around 5% affected by bronchial asthma [1] . While symptomatic therapies like nasal and inhalative corticosteroids or oral antihistamines show only temporal relief, allergen-specific immunotherapy (AIT) carries the potential of persistently reversing the natural course of these diseases. The first successful application dates back more than 100 years when patients suffering from hay fever showed substantial improvement of their allergic symptoms after receiving repeated subcutaneous injections of grass pollen extract [2] . Since then, many clinical studies with different allergens and forms of their application (e.g. subcutaneous or sublingual, ultra rush, slowly increasing or cluster dosing regimens) have proven the efficacy of AIT, both for treatment of allergic rhinoconjunctivitis [3, 4] and bronchial asthma [5] , and in 1998 the WHO approved AIT as the only causative therapy for IgE-dependent allergies [6] . While the clinical effectiveness of AIT is well established, the immunological changes underlying the induction of allergen tolerance remain incompletely understood. Potential mechanisms encompass a switch from a Th2 to a Th1 cell-dominated immune reaction, the induction of regulatory T (Treg) cells, a simple loss of allergen-specific T cell responses and the production of IgG antibodies, which are able to block allergen binding by IgE [7–9] . However, it is still debated to what extent the different factors contribute to the development of allerPublished online: March 10, 2015