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FRI0025 No Reactivation of Dormant Mycobacterium Tuberculosis in Human in Vitro Granuloma Model after anti-IL-17A Treatment, in Contrast To anti-TNFα Treatment
  1. N. Kapoor1,
  2. M. Kammüller2,
  3. P.E. Kolattukudy1
  1. 1Burnett School of Biomedical Sciences - University of Central Florida, Orlando - Florida, United States
  2. 2Novartis Institutes of Biomedical Research, Basel, Switzerland

Abstract

Background 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 Mycobacterium tuberculosis 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 M. tuberculosis infection model, confirmed the importance of TNFα in host resistance to M. tuberculosis, and highlighted that anti-IL-17A treatment for four weeks in vivo does not impair immunity to this intracellular pathogen1.

Objectives To investigate the effect of adalimumab (anti-TNFα antibody) and secukinumab (anti-IL-17A antibody) on M. tuberculosis dormancy and reactivation, we utilized a novel in vitro human 3D microgranuloma model2.

Methods Human peripheral blood mononuclear cells were infected with M. tuberculosis. 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 changes2. We measured Auramine-O and Nile red staining indicative of M. tuberculosis membrane acid fastness and accumulating lipid bodies, respectively, and also investigated rifampicin resistance. In this in vitro 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.

Results M. tuberculosis from granulomas treated with anti-TNFα antibody (adalimumab) showed increased staining for Auramine-O, decreased Nile red staining, and decreased rifampicin resistance, indicating M. tuberculosis reactivation. In contrast, anti-IL-17A antibody (secukinumab) treatment was comparable to control treatment indicating that the drug did not trigger M. tuberculosis reactivation in human microgranuloma in vitro.

Conclusions Overall, these results confirm the importance of TNFα in host resistance to M. tuberculosis infection, and highlight that anti-IL-17A treatment in vitro does not reverse M. tuberculosis dormancy in this human granuloma model, in accordance with available clinical data3,4.

  1. 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.

  2. Kapoor N, et al. (2013). Human Granuloma In Vitro Model, for TB Dormancy and Resuscitation. PLoS ONE 8(1): e53657.

  3. 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.

  4. 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.

Acknowledgement Funding from Novartis.

Disclosure of Interest 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

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