A proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis.
Targeting IL-17 in inflammatory disease
The interleukin-17 (IL-17) family cytokines are strong inducers of inflammation and help to protect us against invading pathogens. However, they also have a dark side and contribute to the tissue destruction that occurs in chronic inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis and multiple sclerosis.
The landmark discovery that IL-17-producing T cells were central drivers of these diseases positioned IL-17 as a promising therapeutic target. Several approaches that disrupt signalling by this cytokine family are now being tested in the clinic. Excitingly, real benefits for patients are starting to emerge, particularly for patients with psoriasis.
This collection of Research and Review-type articles highlights the role of the IL-17 pathway in inflammatory diseases, and how our improved understanding of the mechanisms of disease has revealed new opportunities for and potential benefits of IL-17-targeted therapies.
The content for this collection has been chosen by the editors of Nature Reviews Immunology and selected Comment and Review articles have been made freely available for 6 months, thanks to support from Eli Lilly and Company.
In addition, Nature Reviews Drug Discovery presents a Poster that summarizes the key aspects of the IL-17 pathway relevant to its potential as a therapeutic target, and an Animation of the immunopathology of psoriasis that illustrates how agents that target IL-17 signalling are being developed into novel therapies for this disease and other inflammatory conditions.
Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6T17 cells in health and inflammation
Skin-resident IL-17-producing γδT cells have an important role in skin inflammation but their development and trafficking is not well established. Here, Cai et al. unveil differences in the developmental requirements and functional regulation of two subsets of dermal γδT cells.
In mice, it is possible to induce a psoriasis-like condition by applying imiquimod; here, the production of interleukin-23 that is stimulated by such skin inflammation is shown to depend on the interaction of nociceptors expressing the Nav1.8 and TRPV1 channels with skin-resident dendritic cells.
Regulatory T (Treg) cells exhibit substantial phenotypic and functional plasticity. Hiroshi Takayanagi and his colleagues report that in autoimmune arthritis, a subset of Treg cells can lose Foxp3 expression and convert into TH17 cells. This conversion is mediated by synovial fibroblast-derived IL-6, and in vivo, these cells are osteoclastogenic and exacerbate arthritis. These findings suggest that a proportion of pathogenic TH17 cells in autoimmune disease may be derived from Treg cells.
A global view of the genetic networks regulating the differentiation of TH17 cells is presented, based on temporal expression profiling, computational network reconstruction and validation of predicted interactions by nanowire-mediated siRNA perturbation.
Exposure to interleukin 23 (IL-23) is required for the induction of pathogenic TH17 cells. Kuchroo and colleagues show that IL-23-dependent induction of the cytokine TGF-β3 produces a molecular signature characteristic of highly pathogenic TH17 cells.