Early Specific Host Response Associated with Starting Effective Tuberculosis Treatment in an Infection Controlled Placebo Controlled Mouse Study

Abstract

Recently we proposed exploring the potential of treatment stimulated testing as diagnostic method for tuberculosis (TB). An infection controlled placebo controlled mouse study was performed to investigate whether serum cytokine levels changed measurably during the early phase of TB chemotherapy. Serum was collected prior to and during the first 3 weeks of isoniazid (INH) and rifampicin (RIF) chemotherapy, and levels of 23 selected cytokines/chemokines were measured using a liquid bead array. The serum levels of IFNγ, IP-10, MIG, MCP-1, IL-17 and IL-6 were elevated in the TB infected mice compared to non-infected mice at least at 1 time point measured. In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo. Treatment of non-infected mice in the absence of tuberculosis infection had no effect on these cytokines. IL-17 and IL-6 had decreased to baseline in all infected mice prior to the initiation of treatment. This study demonstrates that systemic levels of some cytokines, more specifically IFNγ, IP-10, MIG and MCP-1, rapidly and specifically change upon starting TB chemotherapy only in the presence of infection in a mouse model. Thus, IFNγ, IP-10, MIG and MCP-1 are promising ‘Treat-to-Test’ targets for the diagnosis of TB and deserve further investigation in a study on human TB suspects.

Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of activeMycobacterium tuberculosisinfection

“…Reductions in the frequencies of Mtb antigen-specific total and single IFN-γ-producing CD4 + and CD8 + T cells, already significant after 2 weeks, were overall the best markers associated with successful therapy. We found support in both human studies [25][26][27] and animal TB models [28,29], where reductions in the proinflammatory cytokines IFN-γ and TNF-α were described after few weeks of treatment. Day et al observed a decline in PPD-specific TNF-α + and IFN-γ + single-positive T cells in a cohort of pulmonary TB patients during 6 months of anti-TB treatment with a concomitant increase in the polyfunctional T cells [27].…”

“…Reductions in the frequencies of Mtb antigen‐specific total and single IFN‐γ‐producing CD4 + and CD8 + T cells, already significant after 2 weeks, were overall the best markers associated with successful therapy. We found support in both human studies and animal TB models , where reductions in the proinflammatory cytokines IFN‐γ and TNF‐α were described after few weeks of treatment. Day et al .…”

Individualizing management of extensively drug-resistant tuberculosis: diagnostics, treatment, and biomarkers

“…Early evidence suggests that these responses will be informative before culture or microscopic conversion is currently detected [78,79,89,90]. Thus, as measuring the response of host biomarker kinetics has the potential to be both simple and rapid [91], measuring biomarkers deserve attention.…”

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

“…Vaccination studies with Mycobacterium bovis (bacille Calmette‐Guérin) show increased IL‐17A responses, 23 , 24 , 25 however T‐cell frequencies and cytokine expression profiles did not correlate with protection against TB after bacille Calmette‐Guérin vaccination 25 . M. tuberculosis infections have been associated with increased IL‐17A levels in patients with acute TB, 26 in in vivo mouse models, 27 , 28 , 29 , 30 , 31 , 32 as well as in in vitro human peripheral blood mononuclear cell (PBMC) cultures 33 , 34 , 35 . Early granuloma formation may be dependent on IL‐17A, 28 but IL‐17A‐induced neutrophil recruitment may also increase pathological lesions and bacterial burden in chronic pulmonary infections 36 .…”