Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute at the University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
American Journal Of Pathology (Impact Factor: 4.6). 07/2011; 179(1):289-301. DOI: 10.1016/j.ajpath.2011.03.039
Source: PubMed

ABSTRACT Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-α and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment.

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    • "An alternative for intervention discussed recently consisted in modification of host immune responses that could potentially alter M. tuberculosis transition from a dormant state, as found within granulomatous lesions, to a resuscitation or replicating state that may allow better drug accessibility [9]. This hypothesis was tested using an inhibitor of macrophage responses combined to Isoniazid (INH) resulting in reduced lung pathology and better bacillary clearance compared to INH therapy alone [10] [11]. These studies suggest that modification of host immune system may affect bacillus elimination by chemotherapy. "
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    ABSTRACT: Tuberculosis (TB) is a major health problem requiring sustained immunity to inhibit Mycobacterium tuberculosis growth and appropriate antimicrobial therapy to prevent dissemination and drug resistance. Cell-mediated immune responses to M. tuberculosis involve the activation of cytokines such as Tumor Necrosis Factor (TNF) which is critical for granuloma formation and host resistance against TB. TNF inhibition, used as therapy for the treatment of inflammatory diseases, disrupts granuloma allowing replication of mycobacteria which may increase the efficacy of TB chemotherapy. To test this hypothesis mice infected with M. tuberculosis were treated with isoniazid (INH) and rifampicin (RMP) in the presence or absence of Enbrel, a soluble TNF receptor antagonist during three phases of M. tuberculosis infection. Inhibition of TNF with Enbrel augmented the efficacy of TB chemotherapy as shown by enhanced mycobacterial clearance from the lung of acute and established infection as well as in chronically infected mice. Furthermore, TNF inhibition significantly reduced lung pathology as compared to TB chemotherapy alone. Therefore, the experimental data suggest that TB chemotherapy may be more effective in the presence of a TNF inhibitor, which may be relevant to eradicate mycobacteria during chronic M. tuberculosis infection or reactivation.
    01/2013; 2(1):124-34.
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    • "Recently, an inhibitory effect of CC-3052, an inhibitor of phosphodiesterase-4, on TNF- production was shown. Co-treatment of Mtb infected rabbits and mice with isoniazid plus CC-3052 significantly reduced the level of TNF- expression and the extent of disease (Koo et al., 2011; Subbian et al., 2011). As mentioned above, simultaneous blocking of IL-1 and TNF- significantly prolonged survival of Tir-8-/-mice, and neutralization of G-CSF or depletion of neutrophils decreased disease severity in CARD9-/-mice (Garlanda et al., 2007; Dorhoi et al., 2010). "
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    ABSTRACT: The role of type I interferons (IFNs) in the host response to bacterial infections is controversial. Here, we examined the role of IFN-alpha/beta in the murine response to infection with Mycobacterium tuberculosis, using wildtype mice, mice with impaired signaling through the type I IFN receptor (IFNAR), and mice treated to reduce levels of type I IFNs. In this study, we used virulent clinical isolates of M. tuberculosis, including HN878, W4, and CDC1551. Our results indicate that higher levels of type I IFNs are induced by the HN878 and W4 strains. Induction of type I IFNs was associated with lower levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin- 12 (IL-12) and reduced T cell activation, and associated with decreased survival of the mice infected with HN878 or W4 relative to infection with CDC1551. Infection of mice with HN878 and W4 was also associated with relatively higher levels of mRNA for a number of negative regulators of the Jak-Stat signaling pathway, such as suppressors of cytokine signaling (SOCS) 1, 4, and 5, CD45, protein inhibitor of activated Stat1 (PIAS1), protein tyrosine phosphatase nonreceptor type 1 (Ptpn1), and protein tyrosine phosphatase nonreceptor type substrate 1 (Ptpns1). Taken together, these results suggest that increased type I IFNs may be deleterious for survival of M. tuberculosis-infected mice in association with reduced Th1 immunity.
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