The IL23/Th17 Pathway as a Therapeutic Target in Chronic Inflammatory Diseases

Eric      Toussirot

Abstract

IL-23 is a pro-inflammatory cytokine belonging to the IL-12 cytokine family. IL-23 is essential for the differentiation of Th17 lymphocytes, a subtype of T lymphocyte implicated in chronic inflammatory/autoimmune mediated diseases. IL-23 and Th17 correspond to a new axis that drives immune activation and chronic inflammation through the differentiation and activation of Th17 cells. Animal models of chronic inflammatory diseases such as chronic joint diseases, inflammatory bowel diseases and demyelinating diseases strongly suggest the involvement of this cytokine pathway. Thus, IL-23/Th17 is considered as a relevant therapeutic target in autoimmune driven diseases, and biological agents blocking IL-23 or IL-17 are currently being developed. Ustekinumab is a monoclonal antibody targeting the common p40 subunit of IL-12 and IL-23. This treatment has demonstrated its efficacy over placebo in randomized placebo controlled trials and is currently licensed for the treatment of psoriasis. It has also demonstrated its efficacy in psoriatic arthritis. Results for Crohns disease were less evident, while ustekinumab was ineffective in multiple sclerosis. Secukinumab is an IL-17A monoclonal antibody that is under development and preliminary results have suggested its efficacy in inflammatory mediated diseases such as psoriasis and ankylosing spondylitis. Several other IL-23 or IL-17 neutralizing agents are being evaluated in clinical trials. The biological properties of the IL-23/Th17/IL-17 axis and the clinical applications of the drugs that aim to block its functions are reviewed here. Targeting the IL-23/Th17 axis seems to be a relevant and realistic therapeutic approach and these new agents pave the way for additive and alternative treatments to currently available biologics in chronic inflammatory diseases.

Keywords: Autoimmune diseases, briakinumab, interleukin-12, interleukin-17, interleukin-23, secukinumab, Th17, cytokine pathway, inflammatory mediated diseases, Chronic inflammatory disease, ustekinumab, <, kwd, >