Whibley, Natasha, Tritto, Elaine, Traggiai, Elisabetta, Kolbinger, Frank, Moulin, Pierre, Brees, Dominique, Coleman, Bianca M., Mamo, Anna J., Garg, Abhishek V., Jaycox, Jillian R., Siebenlist, Ulrich, Kammueller, Michael and Gaffen, Sarah L. (2016) IL-17A is the dominant IL-17-family cytokine required for immunity to acute murine oral mucosal candidiasis. Journal of Leukocyte Biology, 99 (?). ?.

Abstract

Antibodies targeting IL-17A or IL-17RA show unprecedented efficacy in treating psoriasis. However, IL-17RA signaling is critical for immunity to mucosal Candida albicans infections. IL-17A, IL-17F and IL-17AF bind a receptor composed of IL-17RA and IL-17RC and deliver qualitatively similar signals through Act1. This study aimed to determine the impact of blocking IL-17 family cytokines on oropharyngeal candidiasis (OPC) and evaluate their relative contributions to antifungal immunity. Accordingly, C57BL/6 (WT) mice were treated with Abs targeting IL-17A, IL-17F and IL-17AF. Susceptibility to acute OPC was compared to IL-17A-/-, IL-17F-/- and Act1-/- mice. Anti-IL-17A Abs, which neutralize IL-17A and IL-17AF, caused elevated fungal loads in immunocompetent WT mice, whereas anti-IL-17AF and anti-IL-17F Abs did not increase susceptibility. Blocking IL-17A, IL-17AF and IL-17F together led to increased OPC compared to anti-IL-17A treatment alone. Termination of anti-IL-17A treatment was associated with Candida clearance. IL-17A-/- mice also displayed OPC, but to a lesser degree than anti-IL-17A-treated mice. IL-17F-/- mice were fully resistant. Act1-/- mice were much more susceptible to OPC than anti-IL-17A Ab-treated mice, yet anti-IL-17A and anti-IL-17RA Ab treatment caused equivalent susceptibilities. Only a limited number of immune genes attributable to epithelial and myelo-monocytic cells associated with OPC susceptibility based on microarray analyses. We therefore conclude that IL-17A, not IL-17F or IL-17AF, is the main mediator of immunity in murine OPC. However, a cooperative relationship between IL-17A and IL-17F appears to exist in vivo. Susceptibility displays the following hierarchy: IL-17RA-/- or Act1-/- > anti-IL-17A + anti-IL-17F Abs > anti-IL-17A or anti-IL-17RA Abs > IL-17A-/-.

Item Type:	Article
Date Deposited:	04 Feb 2016 00:45
Last Modified:	04 Feb 2016 00:45
URI:	https://oak.novartis.com/id/eprint/26660