LOCAL SUPPRESSION OF IFN-GAMMA IN HEPATIC GRANULOMAS CORRELATES WITH TISSUE-SPECIFIC REPLICATION OF LEISHMANIA-CHAGASI

BALB/c mice are susceptible to infection with the visceralizing specie s of Leishmania, Leishmania chagasi. The parasite load initially rises in the liver and spontaneously subsides, whereas parasite multiplicat ion begins later and remains lower in the spleen. To investigate wheth er this organ-specific multiplication of L. chagasi correlates with lo calized immune responses, we compared cytokine production by splenic v s hepatic immune cells. Livers from infected mice contained granulomas harboring intracellular L. chagasi amastigotes, whereas few amastigot es were present in the spleen. FACS analysis of isolated granuloma cel ls showed granuloma lymphocytes expressed a memory/effector phenotype, Granuloma cells cultured in vitro produced IL-10 and IL-6 but no dete ctable lFN-gamma, IL-4, or IL-5, In contrast, splenocytes from the sam e animals secreted lFN-gamma, IL-4, IL-6, and IL-10. T cells were depl eted from granuloma cells by immune lysis, and the results indicated t hat IL-10 and IL-6 were derived at least in part from a non-T cell com partment. Paradoxically, FACS-purified Thy-1(+) granuloma lymphocytes were able to produce IFN-gamma in the absence of other granuloma cells , suggesting IFN-gamma production might usually be inhibited by a gran uloma-associated non-T cell element. Coculture of splenocytes with eit her granuloma cells or supernatants from granuloma cultures inhibited the usual splenocyte production of IFN-gamma and IL-4 but not IL-10, T hus, there may be a unique granuloma-associated suppressive factor acc ounting for the absence of IFN-gamma in hepatic granuloma cultures. It may be the absence of lFN-gamma in the liver and presence in the sple en that allows or inhibits parasite survival, respectively, in these d ifferent locations.