A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescence of Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in CD4+ T cell-depleted mice.
Tumor necrosis factor (TNF) is required to control mycobacterial infections, but its therapeutic value is limited by its in vivo instability and toxicity. The efficacy of a nontoxic TNF-mimetic peptide (TNF70-80) was tested in mice infected with Mycobacterium bovis bacillus Callette-Guerin (BCG). In vitro TNF70-80 and recombinant human TNF (hTNF) acted with interferon gamma (IFN-gamma) to reduce bacterial replication and to induce synthesis of bactericidal nitric oxide (NO) in BCG-infected, bone marrow-derived murine macrophages. The dose-dependent inhibitory effect on bacterial replication was blocked by neutralizing anti-IFN-gamma and anti-hTNF mAbs. Further, n-monomethyl-L-arginine (n-MMA) and a soluble TNF-receptor I (TNFRI-IgG) blocked bacterial growth and NO synthesis. Therefore, the peptide acted with IFN-gamma via induction of NO synthase and signaled through TNFRI receptors. Concomitant in vivo treatment with TNF70-80 or hTNF prevented reactivation of chronic BCG infection in mice depleted of CD4+ T cells by injecting anti-CD4 antibodies. Granuloma number and bacterial load were comparable in treated, T cell-depleted mice and in chronically infected, intact animals. Thus, TNF70-80 and hTNF can modulate recrudescent BCG infection in CD4+ T cell-deficient mice.
Briscoe
H
H
Department of Medicine, University of Sydney, NSW, Australia. hbriscoe@med.usyd.edu.au
Roach
D R
DR
Meadows
N
N
Rathjen
D
D
Britton
W J
WJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000472:pathogenicity*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000494:pharmacology; D012008:Recurrence; D013047:Specific Pathogen-Free Organisms; D014375:Tuberculoma / Q000517:prevention & control; D014376:Tuberculosis / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C112561:tumor necrosis factor alpha (70-80); D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse