Effects of modulating TGF-beta;1 on immune responses to mycobacterial infection in guinea pigs

Setting: TGF-β1 has been implicated as an important mediator of immuno-suppression in clinical tuberculosis.

Objective: The objective was to determine the role of TGF-β1 in experimental pulmonary tuberculosis in the guinea pig.

Design: Groups of guinea pigs, maintained on either a low protein (LP) diet or an isocaloric high protein (HP) diet. were challenged via the respiratory route with virulent Mycobacterium tuberculosis H37Rv. Ten days post-infection, guinea pigs were given daily intraperitoneal injections of recombinant human TGF-β1 (rhTGF-β1 τ for 10 consecutive days). Following the treatment, guinea pigs were euthanized, and PPD-induced proliferation of peripheral blood mononuclear cells (PBMCs) was assessed and disease resistance measured by recovery of mycobacteria from the lungs and spleens. In a second set of experiments, groups of HP and LP guinea pigs were vaccinated with attenuated M. tuberculosis H37Ra. Six weeks later, the effects of rhTGF-β1 on lymphoproliferation and cytokine production were determined.

Results: Protein deficiency significantly impaired host anti-tuberculosis resistance, as expected. Treatment with rhTGF-β1 significantly increased mycobacterial loads in the tissues of guinea pigs and decreased the PPD-induced proliferation of PBMCs from both LP and HP guinea pigs. PPD-driven lymphoproliferation, TNF-a and IFN production were significantly suppressed in vaccinated, protein-deficient guinea pigs, and rhTGF-β1 further inhibited lymphoproliferation and cytokine production.

Conclusion: Both in vivo and in vitro results indicate that TGF-β1 exerts immunosuppressive activity and exacerbates the progression of experimental pulmonary tuberculosis in both normally nourished and protein-deficient guinea pigs.