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(Journal of Leukocyte Biology. 2000;68:538-544.)
© 2000 by Society for Leukocyte Biology

A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescence of Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in CD4⁺ T cell-depleted mice

Helen Briscoe^*,, Daniel R. Roach^*,, Natalie Meadows^*, Deborah Rathjen and Warwick J. Britton^*,

^* Department of Medicine, University of Sydney, NSW 2006, Australia;
Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, NSW 2042, Australia; and
Peptech Ltd. North Ryde, New South Wales 2113, Australia

Correspondence: Dr. Helen Briscoe, Department of Medicine, Blackburn Building DO6, University of Sydney, NSW 2006, Australia. E-mail: hbriscoe{at}med.usyd.edu.au

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 (TNF_70–80) was tested in mice infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG). In vitro TNF_70–80 and recombinant human TNF (hTNF) acted with interferon gamma (IFN-) 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- 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- via induction of NO synthase and signaled through TNFRI receptors. Concomitant in vivo treatment with TNF_70–80 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, TNF_70–80 and hTNF can modulate recrudescent BCG infection in CD4⁺ T cell-deficient mice.

Key Words: mycobacteria • cytokine • nitric oxide • granuloma • macrophages