Immune mechanisms of allergen‐specific sublingual immunotherapy

Abstract

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 activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-specific 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 interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We discuss herein immune mechanisms involved during allergen-specific sublingual immunotherapy (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-beta, 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.

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

“…Trp, when administered during SIT, does not inhibit the efficacy of immunotherapy. Further, inhibition of IDO with 1-MT does not impair allergic inflammation during the challenge (46). Thus, IDO activation seems to be relevant during immunotherapy in order to generate trp metabolites, which then cause tolerance to the induction of allergic airway inflammation (47); especially, the metabolite 3-OH-KYN, as well as KYN and xanthurenic acid (XA), contributed to tolerance induction regarding T H 2-dependent allergic airway inflammation and suppression of eosinophilia (Fig.…”

“…Most studies have been performed in mice; however, there is good evidence that increased trp degradation occurs during systemic allergen immunotherapy (SIT) also in humans (45). IDO seems to play a role in the efficacy of allergen immunotherapy: Tolerance induction against allergens is partially mediated by IDO activation during SIT (46,47). Formation of trp metabolites rather than trp deprivation itself seems to establish tolerance toward allergens (46).…”

“…IDO seems to play a role in the efficacy of allergen immunotherapy: Tolerance induction against allergens is partially mediated by IDO activation during SIT (46,47). Formation of trp metabolites rather than trp deprivation itself seems to establish tolerance toward allergens (46). Trp, when administered during SIT, does not inhibit the efficacy of immunotherapy.…”

Inflammation in Respiratory Allergy Treated by Sublingual Immunotherapy

“…1). Despite its much more recent introduction, literature on SLIT also consists of a bulk of data on its effectiveness in modifying the immune response to the administered allergen (20).…”

“…was the induction of synthesis of allergen specific IgG antibodies acting as "blocking antibodies", because of their ability to prevent the interaction between the causative allergen and specific IgE and thus the release of mediators from mast cells and basophils (2). Today, we know that the effects of IT on antibody synthesis depend upon the modifications of the pattern of cytokines and chemokines induced by the interaction between antigen-presenting cells and T cells (19)(20). In early studies with SLIT, it seemed apparent that such a route of administration was unable to stimulate IgG synthesis, but in those studies low doses of allergen extracts were used.…”