Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis

Abstract

Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency.

Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

“…Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions [53, 54]. We found that intravitreal treatment with anti-IL-17A-neutralizing mAb alleviated DR-like pathology, including retinal Müller cell activation and dysfunction, BRB breakdown, and retinal ganglion cell apoptosis.…”

Candida albicans–epithelial interactions and induction of mucosal innate immunity

“…This may simply mean that blockade is incomplete, due either to dose effects or access of anti-IL-17 antibodies to the oral mucosal tissue. Alternatively, these biologics spare IL-17F, which has been shown to cooperate with IL-17A in promoting resistance to OPC [63,78]. Cumulatively, these findings all support a central role for IL-17 receptor signal transduction in mucosal host defense, at both innate and adaptive levels.…”

Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

“…IL-17A is dominant in the requirement for control of C. albicans OPC infection in mice, although IL-17F and IL-17AF may also contribute to protection [113]. Notably, a mutation in the IL17F gene was recently reported in a family with CMC [114].…”