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Early specific host response associated with starting effective tuberculosis treatment in an infection controlled placebo controlled mouse study.

den Hertog AL, de Vos AF, Klatser PR, Anthony RM - PLoS ONE (2013)

Bottom Line: 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.In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo.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.

View Article: PubMed Central - PubMed

Affiliation: Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands.

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.

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TB associated cytokines after 4 and 6 weeks of infection.IL-17 (A) and IL-6 (B) are significantly increased in the infected mice (open symbols) compared with uninfected mice (black symbols) at 4 weeks after infection. At 6 weeks post infection levels in all infected and non-infected mice were similar and around the detection limit for both cytokines. IFNγ (C), IP-10 (D)and MIG (E) are increased both at 4 and 6 weeks after infection compared to non-infected mice. As MIG levels were higher in all infected mice than in all uninfected mice except 1, at 6 weeks significance was not reached (p = 0.08). Levels of MCP-1 (F) were increased in infected mice at 4 weeks post infection compared to uninfected mice. At both 4 and 6 weeks post infection the range of MCP-1 levels was quite wide between both infected and uninfected mice and levels at 6 weeks were very similar between infected and uninfected mice. * p<0.05, ** p<0.01, *** p<0.001
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pone-0057997-g002: TB associated cytokines after 4 and 6 weeks of infection.IL-17 (A) and IL-6 (B) are significantly increased in the infected mice (open symbols) compared with uninfected mice (black symbols) at 4 weeks after infection. At 6 weeks post infection levels in all infected and non-infected mice were similar and around the detection limit for both cytokines. IFNγ (C), IP-10 (D)and MIG (E) are increased both at 4 and 6 weeks after infection compared to non-infected mice. As MIG levels were higher in all infected mice than in all uninfected mice except 1, at 6 weeks significance was not reached (p = 0.08). Levels of MCP-1 (F) were increased in infected mice at 4 weeks post infection compared to uninfected mice. At both 4 and 6 weeks post infection the range of MCP-1 levels was quite wide between both infected and uninfected mice and levels at 6 weeks were very similar between infected and uninfected mice. * p<0.05, ** p<0.01, *** p<0.001

Mentions: At 4 weeks post infection, IFNγ, IP-10, MIG, MCP-1, IL-17 and IL-6 were elevated in infected mice compared to the uninfected mice. However, before the start of treatment (6 weeks after infection) IL-17 and IL-6 levels were below 2.2 pg/ml (or undetectable) in all samples (Figure 2A, 2B). IFNγ, IP-10 and MIG levels also showed a significant decrease in levels between 4 and 6 weeks although IFNγ and IP-10 remained significantly increased compared to the uninfected groups (Figure 2C-E). At 6 weeks, MIG levels were higher in all infected mice than in all uninfected mice except 1 (p = 0.08). The levels of MCP-1 varied greatly between mice (both uninfected and infected) and were similar between both groups at 6 weeks post infection (Figure 2F).


Early specific host response associated with starting effective tuberculosis treatment in an infection controlled placebo controlled mouse study.

den Hertog AL, de Vos AF, Klatser PR, Anthony RM - PLoS ONE (2013)

TB associated cytokines after 4 and 6 weeks of infection.IL-17 (A) and IL-6 (B) are significantly increased in the infected mice (open symbols) compared with uninfected mice (black symbols) at 4 weeks after infection. At 6 weeks post infection levels in all infected and non-infected mice were similar and around the detection limit for both cytokines. IFNγ (C), IP-10 (D)and MIG (E) are increased both at 4 and 6 weeks after infection compared to non-infected mice. As MIG levels were higher in all infected mice than in all uninfected mice except 1, at 6 weeks significance was not reached (p = 0.08). Levels of MCP-1 (F) were increased in infected mice at 4 weeks post infection compared to uninfected mice. At both 4 and 6 weeks post infection the range of MCP-1 levels was quite wide between both infected and uninfected mice and levels at 6 weeks were very similar between infected and uninfected mice. * p<0.05, ** p<0.01, *** p<0.001
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585278&req=5

pone-0057997-g002: TB associated cytokines after 4 and 6 weeks of infection.IL-17 (A) and IL-6 (B) are significantly increased in the infected mice (open symbols) compared with uninfected mice (black symbols) at 4 weeks after infection. At 6 weeks post infection levels in all infected and non-infected mice were similar and around the detection limit for both cytokines. IFNγ (C), IP-10 (D)and MIG (E) are increased both at 4 and 6 weeks after infection compared to non-infected mice. As MIG levels were higher in all infected mice than in all uninfected mice except 1, at 6 weeks significance was not reached (p = 0.08). Levels of MCP-1 (F) were increased in infected mice at 4 weeks post infection compared to uninfected mice. At both 4 and 6 weeks post infection the range of MCP-1 levels was quite wide between both infected and uninfected mice and levels at 6 weeks were very similar between infected and uninfected mice. * p<0.05, ** p<0.01, *** p<0.001
Mentions: At 4 weeks post infection, IFNγ, IP-10, MIG, MCP-1, IL-17 and IL-6 were elevated in infected mice compared to the uninfected mice. However, before the start of treatment (6 weeks after infection) IL-17 and IL-6 levels were below 2.2 pg/ml (or undetectable) in all samples (Figure 2A, 2B). IFNγ, IP-10 and MIG levels also showed a significant decrease in levels between 4 and 6 weeks although IFNγ and IP-10 remained significantly increased compared to the uninfected groups (Figure 2C-E). At 6 weeks, MIG levels were higher in all infected mice than in all uninfected mice except 1 (p = 0.08). The levels of MCP-1 varied greatly between mice (both uninfected and infected) and were similar between both groups at 6 weeks post infection (Figure 2F).

Bottom Line: 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.In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo.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.

View Article: PubMed Central - PubMed

Affiliation: Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus