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.
Tuberculosis is the number one cause of death due to infectious disease in the world today. Understanding the dynamics of the immune response is crucial to elaborating differences between individuals who contain infection vs those who suffer active disease. Key cells in an adaptive immune response to intracellular pathogens include CD8+ T cells. Once stimulated, these cells provide a number of different effector functions, each aimed at clearing or containing the pathogen. To explore the role of CD8+ T cells in an integrative way, we synthesize both published and unpublished data to build and test a mathematical model of the immune response to Mycobacterium tuberculosis in the lung. The model is then used to perform a series of simulations mimicking experimental situations. Selective deletion of CD8+ T cell subsets suggests a differential contribution for CD8+ T cell effectors that are cytotoxic as compared with those that produce IFN-γ. We also determined the minimum levels of effector memory cells of each T cell subset (CD4+ and CD8+) in providing effective protection following vaccination.
Background
Mycobacterium tuberculosis (M. tuberculosis) infection in humans results in either latent infection or active tuberculosis (TB). We sought to determine whether a higher frequency of regulatory T cells predispose an individual toward active disease or whether the Tregs develop in response to active disease.
Methods
In cynomolgus macaques infected with a low dose M. tuberculosis approximately 50% develop primary TB and 50% present with latent infection. 41 animals were followed for 6-8 months to correlate the frequency of Foxp3+ cells in peripheral blood and airways with outcome of infection.
Results
In all animals, the frequency of Tregs (CD4+Foxp3+) in peripheral blood rapidly decreased and simultaneously increased in the airways. Latently infected monkeys had a significantly higher frequency of Tregs in peripheral blood prior to infection and during early infection than those that developed active disease. Monkeys with active disease had increased Tregs in PBMC as they developed disease.
Conclusions
Our data suggest that increased Tregs in active disease occur in response to more inflammation, rather than act as a causative factor in progression to active disease.
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