279 : Experimental analysis of acute murine oral candidiasis after in vivo Anti-IL-17A/ IL-17F treatment and in knockout mice

Abstract

Inhibitors targeting IL-17A or one of its receptor chains (IL-17RA) are now in clinical trials for the treatment of autoimmune diseases, with promising results. However, potential side effects associated with anti-IL-17 pathway therapy, in particular the potential for increased susceptibility to infections, are poorly understood. A number of genetic diseases with increased chronic mucocutaneous candidiasis (CMC) in humans have implicated the Th17/ IL-17 pathway in immune protection against Candida albicans infections. However, the individual roles of IL-17A or IL-17F regarding mucosal candidiasis have not been well defined. To further examine the potential role of the IL-17 pathway in fighting mucosal candidiasis, we took advantage of a murine model of acute oropharyngeal candidiasis (OPC) in which wild type mice clear infection by day 4. Following oral C. albicans exposure, C57BL/6 (wild type) mice were treated with isotype control Abs or neutralizing anti-IL-17A or anti-IL-17F Abs and disease symptoms, fungal burden in the tongue and body weight change were assessed. IL-17A blockade resulted in delayed clearance of OPC with anti-IL-17A-treated mice failing to clear infection by day 4, but with clearance by day 7 onwards in contrast to isotype-treated or untreated mice which cleared infection by day 4. This susceptibility was associated with reduced mucosal expression of specific IL-17-associated genes, such as lipocalin-2 and CXCL5. In contrast, anti-IL-17F treatment did not impair clearance. Additionally, IL-17A −/− mice fully cleared infection by day 4 akin to wild type mice, but IL-17RA −/− and Act1 −/− mice failed to clear infection by day 14 (end of study). Overall, these results highlight differences between cytokine blockade in vivo versus constitutive genetic ablation of individual IL-17 cytokines, receptors and key signaling components, and implicate a role for both IL-17A and alternative mechanisms in resistance to OPC. Funding from Novartis and NIH Grant DEO22550.