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Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.

Koo MS, Manca C, Yang G, O'Brien P, Sung N, Tsenova L, Subbian S, Fallows D, Muller G, Ehrt S, Kaplan G - PLoS ONE (2011)

Bottom Line: We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment.Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone.This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute Center at the University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.

ABSTRACT
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

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Effect of CC-3052 on intracellular TNF-α in spleen cells.(A) Percent of CD14+ spleen cells producing intracellular TNF-α at 21 days post-infection after in vitro stimulation with PPD (P = 0.05), LPS (P = 0.04), or None (unstimulated). Data shown are the mean ± SD of three mice per time point. Untreated mice (open columns) and CC-3052-treated mice (closed columns). * Represents a statistically significant difference (P<0.05) between untreated controls (UN) and CC-3052 (CC) treated mice. P values were calculated using the unpaired t test. (B) Representative contour density plot for PPD stimulated cells.
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pone-0017091-g005: Effect of CC-3052 on intracellular TNF-α in spleen cells.(A) Percent of CD14+ spleen cells producing intracellular TNF-α at 21 days post-infection after in vitro stimulation with PPD (P = 0.05), LPS (P = 0.04), or None (unstimulated). Data shown are the mean ± SD of three mice per time point. Untreated mice (open columns) and CC-3052-treated mice (closed columns). * Represents a statistically significant difference (P<0.05) between untreated controls (UN) and CC-3052 (CC) treated mice. P values were calculated using the unpaired t test. (B) Representative contour density plot for PPD stimulated cells.

Mentions: To evaluate the impact of CC-3052 on monocyte/macrophage activation, the ability of CD14+ cells to produce TNF-α in response to ex vivo stimulation was assessed by flow cytometry. Single cell suspensions from spleens of untreated and CC-3052-treated mice were collected at 21 days post-infection and stimulated ex vivo for 6 h by PPD or LPS. The percentage of CD14+ cells producing TNF-α was significantly lower in spleens from CC-3052 treated mice than those from untreated infected control mice following ex vivo stimulation with PPD (P = 0.05) or LPS (P = 0.04) (Figure 5A and B). These data confirm that CC-3052 targets monocyte/macrophage function and support the results of the gene expression profiling, indicating that treatment of Mtb-infected mice with the PDE4i causes modulation of innate immunity. Taken together, the results of the ex vivo stimulation experiments suggest that CC-3052 modulates the innate immune response, without affecting T cell activation, indicating that the drug is not generally immune suppressive, as previously described [25], [26].


Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.

Koo MS, Manca C, Yang G, O'Brien P, Sung N, Tsenova L, Subbian S, Fallows D, Muller G, Ehrt S, Kaplan G - PLoS ONE (2011)

Effect of CC-3052 on intracellular TNF-α in spleen cells.(A) Percent of CD14+ spleen cells producing intracellular TNF-α at 21 days post-infection after in vitro stimulation with PPD (P = 0.05), LPS (P = 0.04), or None (unstimulated). Data shown are the mean ± SD of three mice per time point. Untreated mice (open columns) and CC-3052-treated mice (closed columns). * Represents a statistically significant difference (P<0.05) between untreated controls (UN) and CC-3052 (CC) treated mice. P values were calculated using the unpaired t test. (B) Representative contour density plot for PPD stimulated cells.
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Related In: Results  -  Collection

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pone-0017091-g005: Effect of CC-3052 on intracellular TNF-α in spleen cells.(A) Percent of CD14+ spleen cells producing intracellular TNF-α at 21 days post-infection after in vitro stimulation with PPD (P = 0.05), LPS (P = 0.04), or None (unstimulated). Data shown are the mean ± SD of three mice per time point. Untreated mice (open columns) and CC-3052-treated mice (closed columns). * Represents a statistically significant difference (P<0.05) between untreated controls (UN) and CC-3052 (CC) treated mice. P values were calculated using the unpaired t test. (B) Representative contour density plot for PPD stimulated cells.
Mentions: To evaluate the impact of CC-3052 on monocyte/macrophage activation, the ability of CD14+ cells to produce TNF-α in response to ex vivo stimulation was assessed by flow cytometry. Single cell suspensions from spleens of untreated and CC-3052-treated mice were collected at 21 days post-infection and stimulated ex vivo for 6 h by PPD or LPS. The percentage of CD14+ cells producing TNF-α was significantly lower in spleens from CC-3052 treated mice than those from untreated infected control mice following ex vivo stimulation with PPD (P = 0.05) or LPS (P = 0.04) (Figure 5A and B). These data confirm that CC-3052 targets monocyte/macrophage function and support the results of the gene expression profiling, indicating that treatment of Mtb-infected mice with the PDE4i causes modulation of innate immunity. Taken together, the results of the ex vivo stimulation experiments suggest that CC-3052 modulates the innate immune response, without affecting T cell activation, indicating that the drug is not generally immune suppressive, as previously described [25], [26].

Bottom Line: We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment.Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone.This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute Center at the University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.

ABSTRACT
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

Show MeSH
Related in: MedlinePlus