IL-17 (IL-17A) was discovered in 1993 originally as a rodent T cell cDNA transcript, cytotoxic T lymphocyte-associated antigen 8 (CTLA8). Human IL-17 was subsequently identified. To date, five additional members of the IL-17 family have been identified and termed IL-17B, C, D, E, and F. IL-17F is most closely related to IL-17, and can form a heterodimer with IL-17, while IL-17E, also named IL-25, is instead classified as a Th2 cytokine. There are five receptors for the IL-17 family of cytokines, ie, IL-17RA, RB, RC, RD, and RE, of which IL-17RA and RC mediate the biologic activity of IL-17. While IL-17 is produced mainly by T cells, its receptor is expressed ubiquitously on various cell types, including myeloid cells, epithelial cells, and fibroblasts. Therefore, IL-17 exerts various biologic functions in vivo, which might be involved in the pathogenesis of a wide range of inflammatory disorders, as well as infectious conditions.
IL-17 mRNA was expressed in inflamed colonic tissue from Crohn's disease or ulcerative colitis. Expression of IL-17 in the intestine of Crohn's disease and ulcerative colitis was also demonstrated by immunohistochemistry, in which highest levels of expression were detected in the active Crohn's disease lesion.
Expression of IL-17 mRNA was detected in biopsies from lesional psoriatic skin. Serum levels of IL-17 correlated with disease severity.
There have been numerous studies examining IL-17 production in human RA. The first report by Chabaud et al detected bioactive IL-17 in the culture supernatants of synovial cells. Immunohistochemical analysis demonstrated IL-17-positive cells in Rheumatoid arthritis synovium, which accounted for about 1% of T cells.
Clinical data on agents that directly target IL-17 or its receptor are now available. Secukinumab (AIN457), a highly selective, fully human immunoglobulin G1k (IgG1k) mAb directed against the IL-17 cytokine, has been evaluated in multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, psoriatic arthritis, Rheumatoid arthritis and autoimmune uveitis. In January 2015, the FDA approved the use of secukinumab (trade name Cosentyx), an IL-17 inhibiting monoclonal antibody, for the treatment of moderate to severe plaque psoriasis. Ixekizumab, a humanised IgG4 anti-IL-17 mAb, and brodalumab, a fully human IgG2 anti-IL-17RA mAb, are also in clinical development and have shown efficacy in autoimmune disease.
In conjunction with studies using the humanised anti-IL-17 monoclonal antibody (mAb) ixekizumab (LY2439821) and the fully human anti-IL-17RA mAb brodalumab (AMG 827), the findings on secukinumab provide evidence for the role of IL-17 in the pathophysiology of autoimmune disease and suggest the potential value of targeting this cytokine.
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