The IL-17–TH17 pathway is a popular target for the treatment of psoriasis and other autoimmune conditions. Bartlett and Million discuss the key agents in the pipeline, several of which are expected to gain approval in the near future.
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.
MDR1 expression distinguishes pathogenic from non-pathogenic TH17 cells in humans.
Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, TH17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than TH17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called γδ T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis.
Immune homeostasis in the skin requires dynamic crosstalk between epithelial, stromal and immune cells, which is influenced by environmental insults and commensal microorganisms. Here, the authors highlight recent studies that provide an insight into the immunoregulatory mechanisms that mediate host defence and prevent chronic inflammation in the skin.
T helper 17 (TH17) cells promote protective immune responses against infection, particularly at barrier sites, but they can also have pathogenic roles in inflammatory diseases. In this Review, the authors describe the factors that control the development and maintenance of TH17 cells, and discuss their diverse functions in both health and disease.
This Review highlights the role of T helper 17 (TH17) cells and interleukin-17 (IL-17) in the pathogenesis of inflammatory diseases, and discusses key advances and challenges in targeting IL-17 in disorders such as psoriasis, rheumatoid arthritis and ankylosing spondylitis.
Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease.
Although advances in therapy of rheumatoid arthritis (RA) have greatly improved disease outcomes, a considerable portion of patients still do not attain clinical remission. Thus, new treatments targeting a range of cytokines and cell types are being explored. This Review outlines these novel approaches to RA therapy.
Interleukin 22 receptor 1 (IL-22R1) activity affects the development and course of disorders including psoriasis, ulcerative colitis, certain infections and tumours, without directly regulating immune cell function. Here, the authors describe the biology of IL-22 and highlight the therapeutic potential of modulating the activity of IL-22 and/or its receptor IL-22R1.