Defective tumoricidal capacity of macrophages from P/J mice: tumoricidal defect involves abnormalities in lymphokine-derived activation stimuli and in mononuclear phagocyte responsiveness.

At least two macrophage-activation stimuli can be detected in active lymphokine supernatants: macro¬phages respond to priming stimuli to become noncyto-toxic intermediate cells, which can, in turn, respond to or be triggered by another lymphokine stimulus to de¬velop full cytotoxic activity. Antigen- or mitogen-in-duced lymphokines from spleen cell cultures of the P/J mouse strain did not induce tumoricidal activity in mac¬rophages from responsive mouse strains; macrophage chemotactic activity in these same supernatants, how¬ever, was normal. Analysis of activation stimuli in P/J lymphokines showed a 10- to 15-fold decrease in activity of priming signals for macrophage activation; triggering signals in the same supernatants were normal. Respon¬siveness of P/J macrophages to activation stimuli was also defective: macrophages from P/J mice did not de¬velop cytotoxic activity after treatment in vitro with either lymphokines or LPS alone over a broad range of concentrations and times of treatment. However, P/J macrophages from sterile inflammatory exudates could develop tumoricidal activity after treatment with mul¬tiple activation stimuli: P/J cells treated with lympho¬kines and LPS (0.1 ng/ml) were fully cytotoxic. In con¬trast, macrophages from BCG or C. parvum-induced ex¬udates in P/J mice were not cytotoxic and could not develop cytotoxic activity after further exposure to lym¬phokines and LPS, alone or in combination. These data demonstrate that the macrophage tumoricidal defect of P/J mice involves abnormalities both in lymphokine-derived activation stimuli and in mononuclear phago¬cyte responsiveness.