FRI0025 No Reactivation of Dormant Mycobacterium Tuberculosis in Human in Vitro Granuloma Model after anti-IL-17A Treatment, in Contrast To anti-TNFα Treatment
Authors: N. Kapoor, M. Kammüller, P.E. Kolattukudy
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> IL-17A inhibition has shown significant efficacy in the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of innate and adaptive immunity may carry the risk of an increased susceptibility to infections. While <i>Mycobacterium tuberculosis</i> infections can be an important complication of anti-TNFα therapies, the role of the Th17/IL-17 pathway in host resistance to this intracellular pathogen is less clear. A comparison of tool antibodies neutralizing TNFα or IL-17A in an acute murine <i>M. tuberculosis</i> infection model, confirmed the importance of TNFα in host resistance to <i>M. tuberculosis</i>, and highlighted that anti-IL-17A treatment for four weeks <i>in vivo</i> does not impair immunity to this intracellular pathogen<sup>1</sup>. <h3>Objectives</h3> To investigate the effect of adalimumab (anti-TNFα antibody) and secukinumab (anti-IL-17A antibody) on <i>M. tuberculosis</i> dormancy and reactivation, we utilized a novel <i>in vitro</i> human 3D microgranuloma model<sup>2</sup>. <h3>Methods</h3> Human peripheral blood mononuclear cells were infected with <i>M. tuberculosis</i>. Dormant mycobacteria exhibited the following characteristics: (1) loss of acid-fastness, (2) accumulation of lipid bodies, (3) development of rifampicin-tolerance, and (4) gene expression changes<sup>2</sup>. We measured Auramine-O and Nile red staining indicative of <i>M. tuberculosis</i> membrane acid fastness and accumulating lipid bodies, respectively, and also investigated rifampicin resistance. In this <i>in vitro</i> human 3D microgranuloma model we studied the anti-TNFα antibody adalimumab at 10 ng/ml, and the IL-17A antibody secukinumab at 10, 100, and 1000 ng/ml. <h3>Results</h3> <i>M. tuberculosis</i> from granulomas treated with anti-TNFα antibody (adalimumab) showed increased staining for Auramine-O, decreased Nile red staining, and decreased rifampicin resistance, indicating <i>M. tuberculosis</i> reactivation. In contrast, anti-IL-17A antibody (secukinumab) treatment was comparable to control treatment indicating that the drug did not trigger <i>M. tuberculosis</i> reactivation in human microgranuloma <i>in vitro</i>. <h3>Conclusions</h3> Overall, these results confirm the importance of TNFα in host resistance to <i>M. tuberculosis</i> infection, and highlight that anti-IL-17A treatment <i>in vitro</i> does not reverse <i>M. tuberculosis</i> dormancy in this human granuloma model, in accordance with available clinical data<sup>3,4</sup>. <h3>References</h3> Kammüller M, et al. (2013). Effect Of Neutralizing IL-17A and IL-17F Antibodies On Host Resistance To Acute Mycobacterium Tuberculosis Infection In Mice In Comparison With Neutralizing TNF-α Treatment. Arthritis Rheum 65 (Suppl.), Abstract Nr. 931. Kapoor N, et al. (2013). Human Granuloma In Vitro Model, for TB Dormancy and Resuscitation. PLoS ONE 8(1): e53657. Tsai TF, et al. (2014). Evaluation of Infections With Secukinumab in a Pooled Analysis of 10 Clinical Studies of Moderate-to-Severe Plaque Psoriasis. J Invest Dermatol 134: S33. Tsai TF, et al. (2015). Secukinumab Treatment Shows No Evidence for Reactivation of Previous or Latent TB Infection in Subjects with Psoriasis: A Pooled Phase 3 Safety Analysis. Am Acad Dermatology Abstract 607. <h3>Acknowledgement</h3> Funding from Novartis. <h3>Disclosure of Interest</h3> N. Kapoor Grant/research support from: Novartis Institutes for Biomedical Research, M. Kammüller Employee of: Novartis Institutes for Biomedical Research, P. Kolattukudy Grant/research support from: Novartis Institutes for Biomedical Research