Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model

Abstract

Objective. An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor ␣ (TNF␣)-neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model.Methods. Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6-8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF-neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55-TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison.Results. Administration of TNF-neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin-12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria-induced interferon-␥ production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes.

Mycobacterial diseases developed during anti-tumour necrosis factor-α therapy

“…Extrapulmonary manifestation was higher in patients receiving anti-TNF-a therapy than in the general population, which has also been shown in previous studies [6,9,10]. These findings may be explained by systemic spreading of mycobacteria due to inhibition of TNF-a by anti-TNF-a therapy in TB patients [28,29].…”

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

“…Bacterial numbers were very low in both groups of treated animals after prophylactic treatment. Although bacterial numbers were also low in the latent (untreated) group, 80% of untreated animals in this study reactivated the infection after TNF neutralization, similar to our previously reported data (22). Thus, short-term drug treatment reduced bacterial load or altered granuloma structure and prevented reactivation, even without sterilizing all of the animals.…”

“…In macaques, bacterial numbers are generally quite low during latent infection and only increase upon reactivation (19,22). Thus, we assumed that simply comparing bacterial numbers in latent monkeys with and without drug treatment would not provide sufficient sensitivity for identifying an efficacious drug against bacilli present in latent animals.…”

“…Thus, we assumed that simply comparing bacterial numbers in latent monkeys with and without drug treatment would not provide sufficient sensitivity for identifying an efficacious drug against bacilli present in latent animals. Short-term (4-8 wk) anti-TNF antibody treatment caused reactivation in at least 70% of macaques with latent infection (22). Our strategy was to test effectiveness of a drug in preventing TNF neutralization-induced reactivation (Fig.…”

Insights from animal models on the immunogenetics of leprosy: a review

“…TNF knockout mice -TNF is an important mediator in both innate and adaptive immunity and plays a pivotal role in inflammatory phenomena that culminate in either pathogenesis or resistance in mycobacterial disease (Adams et al 1995, Flynn et al 1995, Bean et al 1999, Kaneko et al 1999, Lin et al 2010). Recently, the association of SNP TNF-308A with protection against leprosy was confirmed (Cardoso et al 2011a).…”