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: 4.59). 07/2011; 179(1):289-301. DOI: 10.1016/j.ajpath.2011.03.039
Source: PubMed


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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    • "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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    • "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.
    Full-text · Article · Jul 2013
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    • "Mycobacterium tuberculosis (Mtb) clinical isolate CDC1551 was provided by Dr. Shinnick (CDC, Atlanta, GA, USA). The bacterial inoculum for rabbit infection were prepared by growing Mtb to mid-log phase (OD560 = 0.6-0.8) in Middlebrook 7H9 medium supplemented with 10% oleic acid albumin dextrose catalase mix (Difco BD, Franklin Lakes, NJ) as described earlier [60]. Aliquots of the Mtb culture were stored at -80°C until ready to use. "
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    ABSTRACT: Background Infection of humans with Mycobacterium tuberculosis (Mtb) results in latent tuberculosis infection (LTBI) in 90-95% of immune competent individuals, with no symptoms of active disease. The World Health Organization estimates that 1.5 billion people have LTBI, which can reactivate in the setting of waning host immunity, posing a threat to global TB control. Various animal models have been used to study the pathogenesis of TB. However, besides nonhuman primates, rabbits are the only animal model that fully recapitulates the pathological features of human TB, including progressive disease with necrosis and cavitation or establishment of spontaneous latency. Results We defined the molecular immunological correlates of LTBI establishment in a rabbit model of pulmonary infection with Mtb CDC1551. After aerosol infection, exponential bacterial growth was noted in the lungs for 4 weeks, followed by a significant decline by 12 weeks, resulting in the absence of cultivable bacilli by 24 weeks. We used rabbit whole genome microarrays to profile the lung transcriptome during the course of infection. At 2 weeks post-infection, gene networks involved in natural killer (NK) and dendritic cell (DC) activation and macrophage antimicrobial activities were highly upregulated. This was followed by upregulation of gene networks involved in macrophage and T cell activation and autophagy, peaking at 4 to 8 weeks. Concomitantly, host Th1, but not Th2 or inflammatory, immune response genes were significantly upregulated. Thus, the expression kinetics of genes involved in cross-talk between innate and adaptive immunity over the first 8 weeks post-infection were consistent with early efficient control of infection in the lungs. Interestingly, expression of many genes of the host innate and adaptive immune response pathways was downregulated at 12 weeks, suggesting that immune activation did not persist once bacilli began to clear from the infected lungs. Conclusions Our results suggest that early activation of host innate immunity prior to efficient activation of T cell-mediated adaptive immunity but not inflammation is essential for establishment of LTBI in Mtb CDC1551-infected rabbits. We also show that T cell activation and the host adaptive immune response networks are dampened once bacterial growth is controlled, ultimately resulting in spontaneous LTBI.
    Full-text · Article · Feb 2013 · Cell Communication and Signaling
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