TLR4 agonists as emerging adjuvants for sublingual allergen immunotherapy: Preclinical evidence and future...

Sublingual immunotherapy (SLIT) is a safe and convenient treatment for allergic diseases, but it usually requires several years to achieve sufficient clinical benefit. Therefore, effective adjuvants are needed to enhance its efficacy and shorten the time required to achieve a therapeutic response. In this review, we summarize the rationale for using Toll-like receptor 4 (TLR4) agonists as adjuvants for SLIT and describe our recent preclinical findings with synthetic TLR4 agonist derivatives. We established a mouse model of sublingual administration using a small administration volume and a defined retention period after administration. Several TLR4 agonist derivatives enhanced allergen-specific serum IgG responses when administered with allergen. The adjuvant activity of one derivative was abolished in TLR4-knockout mice, indicating that its activity was dependent on TLR4 signaling. A selected derivative was further evaluated in combination with Japanese cedar pollen (JCP) extract. Co-administration of the derivative with JCP extract increased Cry j 1-specific IgG and IgA levels in serum and IgA levels in nasal lavage fluid. It also enhanced allergen-induced IL-10 production without substantially increasing IFN-γ or IL-4 production. Moreover, IgG from mice treated with the derivative and JCP extract more effectively inhibited allergen-induced mast cell degranulation than IgG from mice treated with JCP extract alone. These findings suggest that synthetic TLR4 agonists may enhance SLIT by promoting functional allergen-specific antibody responses. Further studies are needed to confirm their safety and clinical efficacy in humans.