The use of TNF-mutants that are selective agonists of the TNF-R55 is one strategy that is being explored to broaden the therapeutic margin of TNF. Several problems still have to be overcome before they can be used in clinical trials. Regarding the sensitizing effect of some infections and some tumours, we identified IFN-gamma as a mediator in BCG- but not in tumour-induced sensitization. In both models, the vessel wall is most probably the key tissue as alpha-LFA-1 antibodies could protect against lethality. Studies in primates showed that an unexpected feature, namely, the longer half-life of such mutants, might interfere with this strategy. Recent observations also indicate that the mechanism of tolerance-induction, another way to separate antitumour and toxic effects of TNF, might reside in the functional ablation of the TNF-R75. Using IL-60/0 knockout mice, we could not find any causal role for IL-6 in TNF-mediated lethality, this in contrast to results obtained previously with neutralizing antibodies. Finally, we identified the acute phase protein alpha 1-acid glycoprotein as a protein with protective properties towards TNF-induced lethality and liver damage.