Dupilumab, a Monoclonal Antibody for Atopic Dermatitis: A Review of Current Literature

Kim Blakely, BSc, PhD; Melinda Gooderham, MD, MSc, FRCPC; Kim Papp, MD, PhD, FRCPC

Disclosures

Skin Therapy Letter. 2016;21(2) 

In This Article

Immune Dysfunction in AD

Recent research has demonstrated that immune system dysfunction plays a central role in the development and persistence of AD. These cellular and cytokine targets provide potential therapeutic opportunities. AD skin has been shown to harbor increased levels of the TH2 cytokines IL-4, IL-5, IL-10, and IL-13, with a corresponding decrease in the TH1 cytokines interferon-γ and IL-2.[25–30] IL-4 and IL-13 have established roles in B-cell differentiation and class switching, thus providing a plausible link to characteristic elevations of serum IgE levels in AD patients.[4,31] Importantly, these TH2 cytokines have been shown to contribute to AD pathogenesis, as mice genetically engineered to over-express these cytokines develop skin barrier defects and an AD-like disease.[32–35] High levels of the TH2 cytokines IL-4 and IL-13 in AD skin have been shown to act as inhibitors of both epidermal differentiation and production of antimicrobial peptides.[36–38] IL-4 and IL-13 signal through a common receptor, IL-4Rα, to activate the Signal Transducer and Activator of Transcription 6 (STAT6)/Janus kinase 1 (JAK1) signalling cascade, and genetic polymorphisms in IL-4, IL-13 and IL-4Rα have all been associated with the development of AD in speci c populations.[39–44] Mice that have been genetically engineered to over-express a constitutively active STAT6 display decreased expression of epidermal differentiation complex genes, including laggrin, loricrin, and involucrin, and develop an AD- like disease by allowing for enhanced penetration of allergens and pathogens across the skin barrier.[45] Importantly, IL-4 de ciency was shown to be protective against the development of allergic skin in ammation in these mice, as was treatment with immune- modulators targeting either IL-4 or IL-13.[45] Additionally, IL-4 and IL-13 have also been demonstrated to induce expression of genes, such as Î2-defensins and cathelicidin, involved in susceptibility to skin pathogens including Staphylococcus aureus and herpes simplex virus, potentially accounting for the fact that AD patients have an increased propensity for infection by these pathogens.[36–38] Together, this evidence suggests that targeting TH2 polarization in AD, including antagonism of IL-4 and IL-13, could be ef cacious in the treatment of AD.

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