title: Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization.
abstract: Antibodies targeting IL-17A or its receptor IL-17RA show unprecedented efficacy in the treatment of autoimmune diseases such as psoriasis. These therapies, by neutralizing critical mediators of immunity, may increase susceptibility to infections. Here, we compared the effect of antibodies neutralizing IL-17A, IL-17F or TNFα on murine host responses to Mycobacterium tuberculosis infection by evaluating lung transcriptomic, microbiological and histological analyses. Coinciding with a significant increase of mycobacterial burden and pathological changes following TNFα blockade, gene array analyses of infected lungs revealed major changes of inflammatory and immune gene expression signatures 4 weeks post-infection. Specifically, gene expression associated with host-pathogen interactions, macrophage recruitment, activation and polarization, host-antimycobacterial activities, immunomodulatory responses, as well as extracellular matrix metallopeptidases, were markedly modulated by TNFα blockade. IL-17A or IL-17F neutralization elicited only mild changes of few genes without impaired host resistance four weeks after M. tuberculosis infection. Further, the absence of both IL-17RA and IL-22 pathways in genetically deficient mice did not profoundly compromise host control of M. tuberculosis over a 6-months period, ruling out potential compensation between these two pathways, while TNFα-deficient mice succumbed rapidly. These data provide experimental confirmation of the low clinical risk of mycobacterial infection under anti-IL-17A therapy, in contrast to anti-TNFα treatment.
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Noria
authors.initials: N
authors.lastname: Segueni
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bourigault
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rose
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: François
authors.initials: F
authors.lastname: Erard
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bert
authors.affiliation: Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, South Africa.|National Health Laboratory Service, Cape Town, South Africa.
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stiehl
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Brees
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.|Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, South Africa.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Kammüller
authors.affiliation: CNRS, UMR7355, Orleans, France.|University of Orleans, INEM, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D007109:Immunity / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D020381:Interleukin-17; D007378:Interleukins; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22