A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescenceof 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 toxic ity. The efficacy of a nontoxic TNF-mimetic peptide (TNF70-80) was tested i n mice infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG). In vitro TNF70-80 and recombinant human TNF (hTNF) acted with interferon gamm a (IFN-gamma) to reduce bacterial replication and to induce synthesis of ba ctericidal nitric oxide (NO) in BCG-infected, bone marrow-derived murine ma crophages, The dose-dependent inhibitory effect on bacterial replication wa s blocked by neutralizing anti-IFN-gamma and anti-hTNF mAbs, Further, n-mon o-methyl-L-arginine (n-MMA) and a soluble TNF-receptor I (TNFRI-IgG) blocke d bacterial growth and NO synthesis. Therefore, the peptide acted with IFN- gamma via induction of NO synthase and signaled through TNFRI receptors, Co ncomitant 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 tre ated, T cell-depleted mice and hi chronically infected, intact animals, Thu s, TNF70-80 and hTNF can modulate recrudescent BCG infection in CD4(+) T ce ll-deficient mice.