NEUTRALIZATION OF IL-12 DECREASES RESISTANCE TO LISTERIA IN SCID AND C.B-17 MICE - REVERSAL BY IFN-GAMMA

Interleukin-12 (IL-12) is necessary for the production of IFN-gamma by NK cells during the generation of innate immunity and by T cells for the development of the Th1 response during specific cell-mediated immu nity. Here we demonstrate that the endogenous production of IL-12 is c ritical to the survival of both immunocompromised SCID mice and normal C.B-17 control mice during a primary infection with Listeria monocyto genes. When IL-12 is neutralized in vivo, both strains of mice die at a normally sublethal dose of Listeria. Anti-IL-12 antibody-treated mic e showed a decrease in macrophage I-A(d) expression and an increased L isteria burden in the spleen. Furthermore, as has been demonstrated in vitro, these effects of IL-12 in vivo were predominantly regulated th rough the production of IFN-gamma. Administration of IFN-gamma simulta neously with neutralizing antibodies to IL-12 restored macrophage I-A( d) expression, limited the spread of the infection, and resulted in th e survival of SCID mice. Thus, IL-12 is critical for resistance to inf ection with Listeria monocytogenes, and this resistance is mediated th rough stimulation by IL-12 of IFN-gamma production. Concomitant experi ments confirmed that anti-TNF antibodies also resulted in uncontrolled infection and a decrease in macrophage I-A(d) expression. However, ad ministration of IFN-gamma restored the levels of I-A(d) in macrophages but did not limit Listeria growth.