Effects of modulating TGF-beta 1 on immune responses to mycobacterial infection in guinea pigs.
METHODS
TGF-beta 1 has been implicated as an important mediator of immuno-suppression in clinical tuberculosis.


OBJECTIVE
The objective was to determine the role of TGF-beta 1 in experimental pulmonary tuberculosis in the guinea pig.


METHODS
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-beta 1 (rhTGF-beta 1 tau 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-beta 1 on lymphoproliferation and cytokine production were determined.


RESULTS
Protein deficiency significantly impaired host anti-tuberculosis resistance, as expected. Treatment with rhTGF-beta 1 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-alpha and IFN production were significantly suppressed in vaccinated, protein-deficient guinea pigs, and rhTGF-beta 1 further inhibited lymphoproliferation and cytokine production.


CONCLUSIONS
Both in vivo and in vitro results indicate that TGF-beta 1 exerts immunosuppressive activity and exacerbates the progression of experimental pulmonary tuberculosis in both normally nourished and protein-deficient guinea pigs.
Dai
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Department of Medical Microbiology and Immunology, College of Medicine, Texas A&M University System Health Science Center 77843-1114, USA.
McMurray
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DN
D000818:Animals; D016207:Cytokines / Q000276:immunology; D004044:Dietary Proteins / Q000008:administration & dosage; D006168:Guinea Pigs; D006801:Humans; D007165:Immunosuppression Therapy; D011488:Protein Deficiency / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
D016207:Cytokines; D004044:Dietary Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta