Blocking the Receptor for IL-10 Improves Antimycobacterial Chemotherapy and Vaccination

Abstract

Novel approaches are required for the prevention and therapy of mycobacterial infections since the only vaccine in use, bacillus Calmette-Guérin, is poorly effective and chemotherapy is long and often ineffective in sterilizing the infection. We used a mouse model of Mycobacterium avium infection to address the usefulness of a mAb able to block IL-10R both in treatment of primary infections and in conventional multidrug therapy and subunit vaccination. Treatment of infected mice with this mAb during the entire period of experimental infection had little impact on the course of M. avium infection, with a slight improvement in the resistance of infected mice observed in the liver and spleen at day 30 of infection, which was associated with increased macrophage activation and priming of CD4+ T cells for IFN-γ production. Administration of this mAb later in infection had no effect on its course, but improved the effectiveness of chemotherapy when the latter was started in a chronic phase of infection. Also, the anti-IL-10R mAb acted as an adjuvant in the induction of protective immunity upon vaccination with a mycobacterial subunit preparation.

Gamma Interferon-Induced T-Cell Loss in VirulentMycobacterium aviumInfection

“…This is consistent with prior observations in other models where we found that increasing IFN-␥ secretion by treatment with recombinant IL-12 or blocking of the IL-10 receptor did not increase protection against infection (31)(32)(33). Also, low T-cell numbers appear not to be the reason of the susceptibility to this highly virulent strain of M. avium, since bcl-2 transgenic animals had increased T-cell numbers throughout the course of the infection, namely, those that produce IFN-␥ and yet were as permissive to M. avium 25291 growth as the control mice.…”

IL-10 Underlies Distinct Susceptibility of BALB/c and C57BL/6 Mice to Mycobacterium avium Infection and Influences Efficacy of Antibiotic Therapy

“…The mixture of antibiotics was either administered ad libitum in the drinking water or administered by gavage. The mixture administered in the drinking water contained 0.4 mg/ml rifampicin, 1.94 mg/ml clarithromycin, and 0.25 mg/ml ethambutol on sterile tap water (19). Each mouse drank on average 3 ml/day.…”

“…Whereas transgenic mice overexpressing IL-10 were consistently more susceptible than wild-type mice to infection by Mycobacterium bovis bacillus Calmette-Guérin, Mycobacterium avium, or Mycobacterium tuberculosis (14 -16), depletion studies generated less consistent data. Thus, although the use of IL-10-or IL-10R-blocking Abs led to a reduced multiplication of M. avium (17)(18)(19), the analysis of IL-10 knockout (KO) 3 mice showed that they could be either more resistant to infection or as resistant as wild-type animals (20 -24). Among the possible reasons for the discrepancies observed is the genetic background of the different mouse strains used in the various studies.…”

Peripheral Blood Gamma Interferon Release Assays Predict Lung Responses andMycobacterium tuberculosisDisease Outcome in Mice

“…Furthermore, overexpression of IL-10 on the relatively resistant C57BL/6 background strain led to reduced antigen-specific IFN-␥ secretion and significantly elevated bacterial burdens (53). The exact mechanism through which IL-10 negatively influences chronic M. tuberculosis in-fection is not fully known, but in other mycobacterial infections, blocking IL-10 promoted macrophage activation, proinflammatory cytokine production, and production of reactive nitrogen intermediates, as well as positively influencing vaccination and therapeutic responses (47,52).…”