ROLE OF GAMMA-INTERFERON AND TUMOR-NECROSIS-FACTOR-ALPHA DURING T-CELL-INDEPENDENT AND T-CELL-DEPENDENT PHASES OF MYCOBACTERIUM-AVIUM INFECTION

To design an effective immunotherapy for Mycobacterium avium infection s, the protective host response to the infection must be known. Here w e analyzed the role of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF alpha) in the innate and acquired responses to M. a vium infections in mice. T-cell depletion studies showed that CD4(+) T cells were required for control of the infection. CD4(+)-depleted mic e showed enhanced bacterial proliferation and at the same time showed a reduction in the level of expression of both IFN-gamma and TNF-alpha mRNAs in spleen cells. In contrast, M. bovis BCG immunization restric ted M. avium proliferation and at the same time promoted expression of the mRNAs for the two cytokines. In vivo depletion studies using spec ific monoclonal antibodies showed that both IFN-gamma and TNF-alpha ar e involved in an early protection possibly involving NK cells, and fur thermore, IFN-gamma is involved in the later T-cell-protective respons e to infection. In vivo neutralization of IFN-gamma during M. avium in fection also blocked the priming for enhanced TNF-ol secretion trigger ed by endotoxin. Both cytokines were found to be involved in the resis tance expressed in BCG immunized animals and exhibited additive bacter iostatic effects in vitro on bone marrow-derived macrophages infected with different strains of M. avium. These data suggest that both cytok ines act in an additive or synergistic fashion in the induction of bac teriostasis and that IFN-gamma is also involved in priming TNF-alpha s ecretion.