Review article Immune mechanisms of allergen-specific sublingual immunotherapy Allergen-specific immunotherapy has been used in humans for almost a century with the aim to redirect inappropriate immune responses in atopic patients (1, 2). It has proven to be efficacious to treat type I allergies to a variety of allergens (3–8). While the parenteral (subcuta- neous) route of immunization is still a reference, local routes (e.g. intranasal, oral) have been considered as an alternative with mixed results, both in terms of efficacy and tolerance (9). Of note, a specific form of oral tolerance induction, i.e. sublingual immunotherapy (SLIT) is raising a lot of interest as a noninvasive procedure, as it has been shown to be efficacious, provided that high doses of allergen (i.e. 50–100-fold the subcutaneous dose) are administered (10–25). In a recent meta-analysis, encompassing 22 clinical studies evaluating SLIT in 979 patients with allergic rhinitis to house dust mite, pollens (from grass, parietaria, olive, ragweed, cupressus) and cat dander, it was concluded that SLIT significantly reduces both symptoms and medica- tion requirements (26). Importantly, it is now widely admitted that SLIT is much safer than subcutaneous immunotherapy (SCIT), with no evidence of anaphylactic shock recorded after more than 500 million doses admin- istered to humans (12, 17, 27, 28). Whereas SLIT has been successfully used to treat allergic patients, our understanding of the immunological mechanisms involved has been limited. We review herein recent scientific advances, which provide some clues on effec- tor/regulatory immune mechanisms elicited during suc- cessful allergen-specific immunotherapy in general, and SLIT in particular. Based on such improved biological foundations, we comment on arising opportunities to design second-generation sublingual allergy vaccines relying upon well-characterized recombinant allergens, capable of controlling T-cell polarization following vac- cine-mediated and subsequent natural exposure to the allergen. Immunomodulation during allergen-specific immunotherapy As summarized in Fig. 1, allergen-specific immunothera- py, whether it be SCIT or SLIT, is known to reduce both immediate as well as late-phase allergen-induced symp- toms, by acting both on humoral, as well as on cellular immune mechanisms involved in allergic inflammation (4, 29–33). Schematically, three categories of immunological changes are induced by active immunotherapy, encompas- Sublingual immunotherapy has been shown in some clinical studies to modulate allergen-specific antibody responses [with a decrease in the immunoglobulin E/ immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and acti- vation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-spe- cific T-cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of inter- leukin (IL)-10 and/or transforming growth factor (TGF)-b. We discuss herein immune mechanisms involved during allergen-specific sublingual immuno- therapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans-like dendritic cells expressing high-affinity IgE receptors, producing IL-10 and TGF- b, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well-established safety profile of SLIT. In this context, second-generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans-like cells in the sublingual mucosa, with the aim to induce allergen-specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans. P. Moingeon 1 , T. Batard 1 , R. Fadel 1 , F. Frati 2 , J. Sieber 3 , L. Van Overtvelt 1 1 Stallergnes, Antony, France; 2 Stallergenes Italia S.r.l, Milan, Italy; 3 Stallergenes GmbH & Co. KG Germany, Kamp-Lintfort, Germany Key words: allergy vaccine; Langerhans cells; regulatory T lymphocyte; sublingual immunotherapy. Philippe Moingeon Research and Development Stallergenes 6 rue Alexis de Tocqueville 92160 Antony France Accepted for publication 5 September 2005 Allergy 2006: 61: 151–165 Copyright Ó Blackwell Munksgaard 2006 ALLERGY DOI: 10.1111/j.1398-9995.2006.01002.x 151