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A review of imiquimod 5% cream for the treatment of various dermatological conditions

New therapies, or therapies that exert their effects via different mechanisms and pathways, are exciting for the practising clinician. It is always the hope that such therapies will result in better patient management. Imiquimod, an immune response modifier (IRM) is one such therapy. It is the first commercially available member of a new class of therapeutic compounds that exert their effects by modifying local immune responses. Imiquimod is a novel synthetic molecule, which enhances both the innate and cell-mediated immune pathways. This is achieved by stimulation of immune cells, such as monocytes, macrophages and dendritic cells, to produce specific cytokines. Imiquimod is believed to be capable of increasing the synthesis and release of various cytokines, including interferon (IFN)-a, interleukins 1, 6, 8, 10, and 12 and tumour necrosis factor (TNF)-a. Induction of these cytokines by imiquimod has been observed in both human and animal studies. For example, topical application of imiquimod to hairless mice resulted in increased levels of IFN-a and IFN-c, which was not observed in the untreated skin. As well as stimulation of innate immunity, imiquimod also indirectly activates the T-helper (Th)-1 pathway of cellmediated immunity via IFN-a. The stimulation of the innate and cell-mediated immune response is thought to mediate the antiviral, antitumour, and other antiproliferative effects of imiquimod. In addition, chemokines, such as interleukin (IL)-8, macrophage inflammatory protein-1a and -1b and macrophage chemotactic protein-1 are also induced in imiquimod-responsive cells. Induction of these chemokines in the skin results in the attraction of immune cells to their site of production, resulting in a localized immune response at the site of the lesion. Imiquimod also stimulates natural killer cells, proliferation of B cells and the activation and migration of Langerhans cells to the regional lymph node, potentially enhancing antigen presentation to T cells. Current literature suggests that IRMs, including imiquimod, activate the immune response via specific cell-surface receptors called Toll-like receptors (TLRs). TLRs are a type of pattern-recognition receptor in the innate immune system that recognize specific pathogenassociated molecular patterns, resulting in the initiation of the host defence response. Activation of TLRs results in activation of signalling events that induce the expression of effector molecules, such as cytokines, chemokines and costimulatory molecules, which subsequently control the activation of an antigen-specific adaptive immune response. The family of immune response modifiers activate a specific subset of TLRs (TLR 7 and ⁄ or 8), which are expressed mainly in cell types involved in the first line of defence such as dendritic cells, macrophages, neutrophils and dermal endothelial cells. Hemmi et al. have shown that in the presence of IRMs, wildtype macrophages produced large amounts of TNF-a and IL-12, whereas macrophages deficient in MyD88, a key protein in the TLR signalling cascade, produced no detectable amounts of these cytokines. It has also been shown that expression of TLR7 and TLR8 confers IRM responsiveness in studies where human embryonic kidney (HEK) 293 cells were transiently transfected with a range of TLR expression vectors. IRMs can also elicit an in vivo response through TLR7. Intraperitoneal injection of wild-type mice with a member of the IRM family (R-848) resulted in increased serum concentrations of IFN-a, TNF-a and IL-12, whereas TLR7and MyD88-deficient mice were both completely unresponsive to R-848. The role of specific immune cells in the response to imiquimod has been investigated and dendritic cells appear to have an important role. The paper in this supplement by Quatresooz and Pierard addresses this issue, especially regarding the responsiveness of basal cell carcinomas (BCCs) to imiquimod therapy. Correspondence: S. Salasche, Clinical Professor of Medicine, Department of Medicine, Section of Dermatology, University of Arizona Health Sciences Center, Arizona, USA.