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Controlled acute M. tuberculosis infection in mice under treatment with IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Segueni, Noria and Tritto, Elaine and Bourigault, Marie-Laure and Rose, Stephanie and Erard, Francois and Le Bert, Marc and Jacobs, Muazzam and Di Padova, Franco E. and Moulin, Pierre and Brees, Dominique and Chibout, Salah-Dine and Ryffel, Bernhard and Kammueller, Michael and Quesniaux, Valerie (2016) Controlled acute M. tuberculosis infection in mice under treatment with IL-17A or IL-17F antibodies, in contrast to TNFα neutralization. Scientific reports, 6 (36923). pp. 1-17. ISSN 2045-2322

Official URL: hWp://rdcu.be/mJt2

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 and Mycobacterium tuberculosis reactivation. The effect of antibodies neutralizing IL-17A, IL-17F or TNFα- on host response to M. tuberculosis infection was evaluated by lung transcriptomic, microbiological and histological analyses. 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, immunomodularory responses, as well as extracellular matrix metallopeptidases, were markedly modulated by TNFα blockade. This coincided with a significant increase of mycobacterial burden, whereas, IL-17A or IL-17F blockade had no major effect on gene expression nor on host resistance to acute TB 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.

Item Type: Article
Date Deposited: 07 Jan 2017 00:45
Last Modified: 07 Jan 2017 00:45
URI: https://oak.novartis.com/id/eprint/29729

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