ESSENTIAL ROLE FOR NATURAL-KILLER-CELLS IN THE LETHAL LIPOPOLYSACCHARIDE-INDUCED SHWARTZMAN-LIKE REACTION IN MICE

Observations in our laboratory have provided evidence that interferon- gamma (IFN-gamma) is a key regulator of inflammatory responses to bact erial lipopolysaccharide (LPS) (Heremans et al., J. Exp. Med. 1990. 17 1: 1853): treatment of mice with neutralizing monoclonal antibody agai nst IFN-gamma was found to completely prevent lethal shock reactions, in particular the generalized Shwartzman reaction, whereas treatment w ith IFN-gamma sensitized the mice to the development of such reactions . Since activated T cells and natural killer (NK) cells are the main i f not the only potential source of LPS-induced IFN-gamma, we investiga ted the relative importance of these cells in the development of the g eneralized Shwartzman-like reaction in mice by depleting them selectiv ely with relevant monoclonal antibodies. Treatment with antibodies dir ected against the CD4(+) T cell subset was not effective in protecting mice. Anti-CD8 antibody did attenuate the reaction to some extent. Ho wever, markedly reduced mortality was seen in mice which were depleted of NK cells by systemic administration of polyclonal anti-asialo GM1 or monoclonal anti-NK1.1 antibodies. Failure of T cells to promote the Shwartzman reaction was also evidenced by the observation that thymus -less nude mice,which are deficient in T cells, were more rather than less sensitive to the reaction. Approximately 20 times less LPS was ne eded to induce the lethal reaction in these mice than in NMRI mice and 58 times more anti-IFN-gamma antibody was required to block mortality . Nu/nu mice reportedly have an over-active NK cell compartiment. IFN- gamma production by these cells in LPS-treated mice may account for th e augmented sensitivity. Our data suggest that NK cells may be the mos t important source of endogenous IFN-gamma which mediates the LPS-indu ced lethal reactions in mice.