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.

Inhibition of IL‐17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections

“…Whereas, elevated M. tuberculosis infection rates have been reported in association with anti‐TNFα therapies in subjects with psoriasis and rheumatoid conditions, 9 , 10 , 11 , 12 , 13 the low risk for TB reactivation upon secukinumab treatment in subjects with a medical history of TB or LTBI is further supported experimentally by the in vitro findings in a novel M. tuberculosis H37Rv three‐dimensional microgranuloma model comparing adalimumab and secukinumab side by side. Moreover, in vivo mouse M. tuberculosis H37Rv infection studies directly comparing anti‐IL‐17A, anti‐IL‐17F and anti‐TNFα antibody treatments provide further experimental support of the low clinical risk of mycobacterial infection under anti‐IL‐17A therapy 37 …”

“…Moreover, in vivo mouse M. tuberculosis H37Rv infection studies directly comparing anti-IL-17A, anti-IL-17F and anti-TNFα antibody treatments provide further experimental support of the low clinical risk of mycobacterial infection under anti-IL-17A therapy. 37 Investigating the complex dynamic interplay between the host and the intracellular pathogen M. tuberculosis has proven to be challenging. Understanding the host-pathogen interaction during latency and defining the conditions leading to M. tuberculosis reactivation has been the subject of numerous studies in various animal species and humans.…”

“…[9][10][11][12][13] In a recent investigation we compared side by side the effects of anti-IL-17A, anti-IL-17F or TNFα-neutralizing surrogate antibodies in a murine M. tuberculosis H37Rv infection model, and confirmed the importance of TNFα in immunity to M. tuberculosis infection, in contrast to the anti-IL-17 pathway. 37 To further explore any associations of secukinumab with reactivation of LTBIs, we have retrospectively re-evaluated pooled phase 3 clinical trials in subjects with moderate to severe plaque psoriasis, who had a history of pulmonary TB or tested positive for latent TB at screening, and received secukinumab for 1 year. In addition, to more directly study the effect of secukinumab on dormant mycobacteria in comparison with an anti-TNFα antibody treatment, we utilized a novel in vitro human M. tuberculosis H37Rv three-dimensional microgranuloma model.…”

Interleukin‐17 family cytokines in protective immunity against infections: role of hematopoietic cell‐derived and non‐hematopoietic cell‐derived interleukin‐17s

“…IL‐17A‐deficient mice infected with a laboratory strain of M. tuberculosis showed normal bacterial burdens; however, the same study showed that infection with a clinically isolated virulent M. tuberculosis strain resulted in increased bacterial burdens in IL‐17A‐deficient mice . Furthermore, bacterial burdens in anti‐IL‐17A antibody‐treated mice are similar to those of control antibody‐treated mice after M. tuberculosis lung infection . IL‐17RA‐deficient mice also show normal protective responses to M. tuberculosis infection .…”

“…Furthermore, bacterial burdens in anti‐IL‐17A antibody‐treated mice are similar to those of control antibody‐treated mice after M. tuberculosis lung infection . IL‐17RA‐deficient mice also show normal protective responses to M. tuberculosis infection . The reason for these discrepancies in the role of IL‐17A in M. tuberculosis infections requires further clarification.…”