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Sublingual immunotherapy: the quest for innovative adjuvants

The delivery of antigens through mucosal routes has been established in several experimental models as an efficient means to induce immunological tolerance. Our better knowledge of the unique characteristics of the mucosal immune system has recently shed light on the mechanistic basis of mucosally induced tolerance. Indeed, the dendritic cells (DC), which handle antigens in mucosal sites, appear to promote the emergence of regulatory T lymphocytes with potent suppressive properties. So far, sublingual immunotherapy (SLIT) for allergic rhinitis is the only therapeutic strategy based on this concept, which has reached clinical practice. There is a large consensus – primarily based on meta-analysis studies – that SLIT is an effective treatment in adults [1–3]. As a whole, about 35–40% of adult patients undergoing SLIT experienced a reduction in clinical symptoms with a decreased need for anti-allergic drugs. However, the optimal doses and schedules of administration to be used have not been defined so that the cost/benefit of SLIT is not demonstrated [1]. Furthermore, its efficiency is not as firmly established in children as in adults [4]. SLIT has not yet been approved by the U.S. Food and Drug Administration. Several factors limit the widespread acceptance of SLIT as standard of care for allergic rhinitis, among which the mode of preparation of the allergens is an important one, because aqueous allergen extracts are difficult to standardize [5]. Therefore, increased attention is paid to allergens obtained through recombinant technology. Recombinant allergens are less potent stimulators of the immune systems than allergen extracts, so that recombinant SLIT products will have to include adjuvant-like molecules favouring differentiation of antigen-specific regulatory T lymphocytes. Cholera toxin B is an example of such adjuvants as it was shown to induce FOXP3CD4 regulatory T cells when administered with antigen via the sublingual route [6]. The study of Lombardi et al. [7] published in this issue indicates that agonists of Toll-like receptor (TLR) 2 should also be considered as potential SLIT enhancers. Ligands of the TLR are currently considered as the most attractive adjuvant candidates for novel vaccines, because they stimulate DC to mature and migrate in draining lymph nodes where they induce immune responses through their interactions with T lymphocytes. In humans, 10 functional TLRs were identified so far. They differ in their pattern of expression and the signalling pathways they are associated with. Expressed on the membrane of myeloid DC, TLR2 and TLR4 are coupled to the adaptor protein named myeloid differentiation primary-response protein 88 (MyD88) which initiates activation of mitogenactivated protein (MAP) kinases and nuclear translocation of the transcription factor NF-kB, resulting in transcription of genes controlling synthesis of key inflammatory cytokines such as interleukin-6 (IL-6) but also IL-10, a master anti-inflammatory mediator. TLR4 is also coupled to TIR domain – containing adaptor protein-inducing interferon (IFN)-b (TRIF). The TRIF pathway downstream of TLR3 and TLR4 is critically involved in the activation of genes controlled by IFN regulatory factors (IRF) 3 and 7, which include the genes encoding type I interferons and the p35chain of IL-12 in humans [8]. There is a complex cross-regulation between MyD88 and TRIF-dependent signalling pathways so that the patterns of cytokines produced by DC in response to TLR2 and TLR4 are distinct. A hallmark of DC responses to TLR2 agonists is the release of high levels IL-10 [9], a finding which was confirmed by Lombardi et al. [7] as far as Pam3CSK4 is concerned. Conflict of interest disclosure: The Institute for Medical Immunology is sponsored by GSKBiologicals (Rixensart, Belgium) and Michel Goldman serves as consultant for GSKBiologicals and OM-Pharma (Meyrin, Switzerland). Correspondence: Michel Goldman, Institute for Medical Immunology, Université Libre de Bruxelles 8, Rue Adrienne Bolland, B-6041 Charleroi, Belgium. E-mail: mgoldman@ulb.ac.be Cite this as: M. Goldman, Clinical and experimental Allergy, 2008 (38) 1705–1706. Clinical and Experimental Allergy, 38, 1705–1706 doi: 10.1111/j.1365-2222.2008.03090.x