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IL-17A is the dominant IL-17-family cytokine required for immunity to acute murine oral mucosal candidiasis

Whibley, Natasha and Tritto, Elaine and Traggiai, Elisabetta and Kolbinger, Frank and Moulin, Pierre and Brees, Dominique and Coleman, Bianca M. and Mamo, Anna J. and Garg, Abhishek V. and Jaycox, Jillian R. and Siebenlist, Ulrich and 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

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