RT Journal Article
SR Electronic
T1 Dual Inhibition of Interleukin-23 and Interleukin-17 Offers Superior Efficacy in Mouse Models of Autoimmunity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 152
OP 165
DO 10.1124/jpet.115.224246
VO 354
IS 2
A1 Paul R. Mangan
A1 Linhui Julie Su
A1 Victoria Jenny
A1 Andrea L. Tatum
A1 Caryn Picarillo
A1 Stacey Skala
A1 Noah Ditto
A1 Zheng Lin
A1 XiaoXia Yang
A1 Pete Z. Cotter
A1 David J. Shuster
A1 Yunling Song
A1 Virna Borowski
A1 Rochelle L. Thomas
A1 Elizabeth M. Heimrich
A1 Brigitte Devaux
A1 Ruchira Das Gupta
A1 Irvith Carvajal
A1 Kim W. McIntyre
A1 Jenny Xie
A1 Qihong Zhao
A1 Mary Struthers
A1 Luisa M. Salter-Cid
YR 2015
UL http://jpet.aspetjournals.org/content/354/2/152.abstract
AB Therapies targeting either interleukin (IL)-23 or IL-17 have shown promise in treating T helper 17 (Th17)–driven autoimmune diseases. Although IL-23 is a critical driver of IL-17, recognition of nonredundant and independent functions of IL-23 and IL-17 has prompted the notion that dual inhibition of both IL-23 and IL-17 could offer even greater efficacy for treating autoimmune diseases relative to targeting either cytokine alone. To test this hypothesis, we generated selective inhibitors of IL-23 and IL-17 and tested the effect of either treatment alone compared with their combination in vitro and in vivo. In vitro, using a novel culture system of murine Th17 cells and NIH/3T3 fibroblasts, we showed that inhibition of both IL-23 and IL-17 completely suppressed IL-23–dependent IL-22 production from Th17 cells and cooperatively blocked IL-17–dependent IL-6 secretion from the NIH/3T3 cells to levels below either inhibitor alone. In vivo, in the imiquimod induced skin inflammation model, and in the myelin oligodendrocyte glycoprotein peptide–induced experimental autoimmune encephalomyelitis model, we demonstrated that dual inhibition of IL-17 and IL-23 was more efficacious in reducing disease than targeting either cytokine alone. Together, these data support the hypothesis that neutralization of both IL-23 and IL-17 may provide enhanced benefit against Th17 mediated autoimmunity and provide a basis for a therapeutic strategy aimed at dual targeting IL-23 and IL-17.