REGULATION OF T-HELPER CELL RESPONSES IN EXPERIMENTAL MURINE SCHISTOSOMIASIS BY IL-10 - EFFECT ON EXPRESSION OF B7 AND B7-2 COSTIMULATORY MOLECULES BY MACROPHAGES

Granulomatous inflammation in schistosomiasis is a manifestation of ce ll-mediated hypersensitivity to parasite egg Ags that is predictably r educed in size over the course of the disease. This down-regulation ma y reflect a state of anergy in the T cells mediating granuloma formati on after interaction with accessory cells incapable of providing full stimulation. The present studies were conducted to investigate this me chanism at the molecular level. We found that granuloma macrophages (C M) strongly inhibit the ability of splenic APC to stimulate egg Ag-spe cific Th1 responses. This property was shown to be dependent on their secretion of IL-10. Moreover, activated CM in culture were found to ex press little or no costimulatory Ags B7 or B7-2. However, when their a utocrine secretion of IL-10 was neutralized with specific mAb, GM disp layed an up-regulation of costimulatory molecules as well as of MHC cl ass II Ags. Most importantly, GM cultured in the presence of anti-IL-1 0 mAb, acquired the ability to stimulate egg Ag-specific T cells. By i ndependently blocking each of the induced costimulatory Ags, it appear ed that B7-2 molecules provided stronger costimulation than B7. In sep arate experiments, culture supernatants from GM exerted a powerful inh ibition of costimulatory Ag expression on Con-A-stimulated peritoneal exudate cells in vivo, which could similarly be attributed to IL-10. O ur results demonstrate that IL-10 can play a critical role in the gene ration of accessory cells that, by virtue of down-regulation of costim ulatory molecules, may be capable of inducing anergy in T cells mediat ing the vigorous granulomatous response of acute stage schistosomiasis . Our studies lend support to the contention that a state of unrespons iveness in pathogenic T cells may precipitate the down-regulation of g ranuloma formation and provide a molecular basis for the underlying me chanisms.