ACTIVATION OF RESIDENT TISSUE-SPECIFIC MACROPHAGES BY SWAINSONINE

The induction of macrophage tumoricidal activity by swainsonine (8a be ta-indolizidine-1 alpha, 2 alpha, 8 beta-tri-ol), an indolizidine alka loid, has been implicated as possibly an important immune effector mec hanism involved in the suppression of tumor growth and metastasis in v ital organs such as the lung, liver and spleen (Olden, K. et al. The p otential importance of swainsonine in therapy for cancers and immunolo gy. Pharmacol. Ther. 50:285-290; 1991). The present study further expl ores this possibility by determining whether resident tissue-specific macrophages of several mouse strains can be rendered tumoricidal by sy stemic administration of swainsonine. We found that systemically admin istered swainsonine could increase the tumoricidal activity of both al veolar (lung) and splenic macrophages. The activity was enhanced as mu ch as 3- to 4-fold over that obtained with macrophages from organs of control animals and was both dose- and time-dependent. The level and e xtent of activation by swainsonine was comparable to that achieved wit h traditional macrophage-activating agents, such as lipopolysaccharide and interferon-gamma. The fact that swainsonine activated highly puri fied (>95%) cultures of macrophages from the various sources suggests a direct mechanism of activation. Furthermore, the in vivo activation of macrophages in immune-compromised animals (SCID and nude) lends cre dence to this suggestion. These findings provide a plausible explanati on for the observations that systemically administered swainsonine inh ibits organ colonization of metastatic cells and growth of SC tumor xe nografts, whereas the growth of tumor cells is not inhibited by swains onine in culture.