Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

Abstract

Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human in vitro experiments and in vivo in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.

Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls

“…Nevertheless, it is known that tolerance induction during AIT is supported by dendritic cells influencing naïve T-cells with a cocktail of IL-10, IL-12, and IL-27 to either provoke Th1 deviation or induction of regulatory T-cells (Tregs)- both promoting a Th1 dominant milieu. 24 …”

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance

“…In this review, we describe and discuss the current knowledge and latest results on CpG-ODN as immune adjuvant for AIT and asthma treatment. Indeed, although other adjuvants, especially TLR ligands, have shown immune-regulatory properties ( 123 ), CpG-ODN has been predominantly described for its capacity to induce immune tolerance in comparison to other adjuvants that are also used in the context of AIT ( Table 1 ). Our review of the literature, which is based on searches in PubMed “(CpG ODN OR CpG oligodeoxynucleotides) AND (allergy OR allergic disease)”, “(CpG ODN OR CpG oligodeoxynucleotides) AND (immune tolerance OR tolerance induction)” and “(CpG ODN OR CpG oligodeoxynucleotides) AND (safety)” points to CpG-ODN as an adjuvant with previously unrecognized potential for AIT that is able to effectively induce immune tolerance to allergens when used at appropriate higher concentrations, which are still safe in humans.…”

Der f 38 Is a Novel TLR4-Binding Allergen Related to Allergy Pathogenesis from Dermatophagoides farinae

“…Toll-like receptors (TLRs), protease-activated receptors (PARs), and NOD-like receptors (NORs) can be activated by HDM allergens, thus promoting allergic inflammation and immune deviation [8]. In particular, TLR4 is an essential receptor in HDM-mediated allergy [9]. TLR4 activation leads to the formation of the MyD88 complex.…”