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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, TN3-19.12, or INH on histopathology of lungs from CDC1551-infected mice.Treatment with IgG1, monoclonal anti-TNF-α antibody (TN3-19.12), CC-3052 and/or INH was initiated at 14 days post-infection and lungs were harvested at 35 days post-infection and histologic analysis was done. (A–C) IgG1-treated (control); (D–F) CC-3052-treated; (G–I) TN3-19.12 treated; (J–L) TN3-19.12+INH treated. Left panel, H&E ×4; Middle panel, H&E ×40; Right panel; ZN ×40. Arrows indicate granulomas (left panel), macrophages (middle panel) and AFB (right panel).
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pone-0017091-g007: Effect of CC-3052, TN3-19.12, or INH on histopathology of lungs from CDC1551-infected mice.Treatment with IgG1, monoclonal anti-TNF-α antibody (TN3-19.12), CC-3052 and/or INH was initiated at 14 days post-infection and lungs were harvested at 35 days post-infection and histologic analysis was done. (A–C) IgG1-treated (control); (D–F) CC-3052-treated; (G–I) TN3-19.12 treated; (J–L) TN3-19.12+INH treated. Left panel, H&E ×4; Middle panel, H&E ×40; Right panel; ZN ×40. Arrows indicate granulomas (left panel), macrophages (middle panel) and AFB (right panel).

Mentions: Histopathologic evaluation of lungs at 35 days post-infection in both control and CC-3052-treated mice revealed similar, well organized granulomas, with small clusters of AFB clearly visible (Figure 7A, C, D and F). The granulomas of CC-3052 treated mice were somewhat less compact, with many macrophages and more evenly distributed lymphocytes than those in control animals (Figure 7B and E). In contrast, mice treated with TN3-19.12 had large granulomas with many polymorphonuclear neutrophils (PMNs) (Figure 7G) and extensive necrosis (Figure 7H). Extremely high numbers of AFB were detected in the granulomas of these mice (Figure 7I). By comparison, co-treatment with TN3-19.12 plus INH resulted in smaller, well-organized lung granulomas, with higher numbers of lymphocytes and few to no AFB (Figure 7J, K, and L).


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, TN3-19.12, or INH on histopathology of lungs from CDC1551-infected mice.Treatment with IgG1, monoclonal anti-TNF-α antibody (TN3-19.12), CC-3052 and/or INH was initiated at 14 days post-infection and lungs were harvested at 35 days post-infection and histologic analysis was done. (A–C) IgG1-treated (control); (D–F) CC-3052-treated; (G–I) TN3-19.12 treated; (J–L) TN3-19.12+INH treated. Left panel, H&E ×4; Middle panel, H&E ×40; Right panel; ZN ×40. Arrows indicate granulomas (left panel), macrophages (middle panel) and AFB (right panel).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017091-g007: Effect of CC-3052, TN3-19.12, or INH on histopathology of lungs from CDC1551-infected mice.Treatment with IgG1, monoclonal anti-TNF-α antibody (TN3-19.12), CC-3052 and/or INH was initiated at 14 days post-infection and lungs were harvested at 35 days post-infection and histologic analysis was done. (A–C) IgG1-treated (control); (D–F) CC-3052-treated; (G–I) TN3-19.12 treated; (J–L) TN3-19.12+INH treated. Left panel, H&E ×4; Middle panel, H&E ×40; Right panel; ZN ×40. Arrows indicate granulomas (left panel), macrophages (middle panel) and AFB (right panel).
Mentions: Histopathologic evaluation of lungs at 35 days post-infection in both control and CC-3052-treated mice revealed similar, well organized granulomas, with small clusters of AFB clearly visible (Figure 7A, C, D and F). The granulomas of CC-3052 treated mice were somewhat less compact, with many macrophages and more evenly distributed lymphocytes than those in control animals (Figure 7B and E). In contrast, mice treated with TN3-19.12 had large granulomas with many polymorphonuclear neutrophils (PMNs) (Figure 7G) and extensive necrosis (Figure 7H). Extremely high numbers of AFB were detected in the granulomas of these mice (Figure 7I). By comparison, co-treatment with TN3-19.12 plus INH resulted in smaller, well-organized lung granulomas, with higher numbers of lymphocytes and few to no AFB (Figure 7J, K, and L).

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