title: 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.
authors.affiliation: Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
authors.forename: Natasha
authors.initials: N
authors.lastname: Whibley
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Kolbinger
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Brees
authors.affiliation: Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Coleman
authors.affiliation: Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Mamo
authors.affiliation: Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
authors.forename: Abhishek V
authors.initials: AV
authors.lastname: Garg
authors.affiliation: Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Jaycox
authors.affiliation: National Institute of Allergy and Infectious Disease, Laboratory of Molecular Immunology, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; and michael.kammueller@novartis.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Kammüller
authors.affiliation: Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; sarah.gaffen@pitt.edu.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D000208:Acute Disease; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000908:Antibodies, Fungal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D002180:Candidiasis, Oral / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D018928:Immunity, Mucosal / Q000187:drug effects*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009061:Mouth Mucosa / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*
chemical_list: D019138:Antibodies, Blocking; D000908:Antibodies, Fungal; D057134:Antibodies, Neutralizing; D020381:Interleukin-17
keywords: IL-17R; Th17; anticytokine therapy; fungal; psoriasis