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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 proliferation of spleen T cells.Spleen cells from CDC1551-infected mice treated with CC-3052 or untreated were harvested at 42 days post-infection, labeled with CFSE and stimulated in culture for 6 days with heat-killed CDC1551 (black), ConA (5 µg/ml) (blue), or left unstimulated (red). Cells were stained with anti-CD4 and anti-CD8 antibodies. Proliferation was measured as a reduction in CFSE fluorescence intensity. (A) Proliferating lymphocytes are displayed as histograms. One representative mouse per group is shown. (B) The percent of CD4+ and CD8+ proliferating cells from 3 mice per group are presented as a mean ± SD.
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pone-0017091-g004: Effect of CC-3052 on proliferation of spleen T cells.Spleen cells from CDC1551-infected mice treated with CC-3052 or untreated were harvested at 42 days post-infection, labeled with CFSE and stimulated in culture for 6 days with heat-killed CDC1551 (black), ConA (5 µg/ml) (blue), or left unstimulated (red). Cells were stained with anti-CD4 and anti-CD8 antibodies. Proliferation was measured as a reduction in CFSE fluorescence intensity. (A) Proliferating lymphocytes are displayed as histograms. One representative mouse per group is shown. (B) The percent of CD4+ and CD8+ proliferating cells from 3 mice per group are presented as a mean ± SD.

Mentions: The impact of CC-3052 on Mtb-specific activation of CD4+ and CD8+ T cells in chronically infected mice (42 days), at the time when acquired immunity is fully established, was evaluated. Single cell suspensions prepared from spleen were stimulated ex vivo with ConA or Mtb CDC1551 for 6 days, and T cell proliferation was measured by the carboxyfluorescein succinimidyl ester (CFSE) flow cytometry assay. The capacity of CD4+ and CD8+ T cell to proliferate in response to ConA or CDC1551 stimulation was similar in spleen cells from the infected mice with or without CC-3052 treatment (Figure 4). Our observations suggest that CC-3052 does not interfere with T cell activation, consistent with published reports [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 proliferation of spleen T cells.Spleen cells from CDC1551-infected mice treated with CC-3052 or untreated were harvested at 42 days post-infection, labeled with CFSE and stimulated in culture for 6 days with heat-killed CDC1551 (black), ConA (5 µg/ml) (blue), or left unstimulated (red). Cells were stained with anti-CD4 and anti-CD8 antibodies. Proliferation was measured as a reduction in CFSE fluorescence intensity. (A) Proliferating lymphocytes are displayed as histograms. One representative mouse per group is shown. (B) The percent of CD4+ and CD8+ proliferating cells from 3 mice per group are presented as a mean ± SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045423&req=5

pone-0017091-g004: Effect of CC-3052 on proliferation of spleen T cells.Spleen cells from CDC1551-infected mice treated with CC-3052 or untreated were harvested at 42 days post-infection, labeled with CFSE and stimulated in culture for 6 days with heat-killed CDC1551 (black), ConA (5 µg/ml) (blue), or left unstimulated (red). Cells were stained with anti-CD4 and anti-CD8 antibodies. Proliferation was measured as a reduction in CFSE fluorescence intensity. (A) Proliferating lymphocytes are displayed as histograms. One representative mouse per group is shown. (B) The percent of CD4+ and CD8+ proliferating cells from 3 mice per group are presented as a mean ± SD.
Mentions: The impact of CC-3052 on Mtb-specific activation of CD4+ and CD8+ T cells in chronically infected mice (42 days), at the time when acquired immunity is fully established, was evaluated. Single cell suspensions prepared from spleen were stimulated ex vivo with ConA or Mtb CDC1551 for 6 days, and T cell proliferation was measured by the carboxyfluorescein succinimidyl ester (CFSE) flow cytometry assay. The capacity of CD4+ and CD8+ T cell to proliferate in response to ConA or CDC1551 stimulation was similar in spleen cells from the infected mice with or without CC-3052 treatment (Figure 4). Our observations suggest that CC-3052 does not interfere with T cell activation, consistent with published reports [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