SUPPRESSOR MACROPHAGES IN AFRICAN TRYPANOSOMIASIS INHIBIT T-CELL PROLIFERATIVE RESPONSES BY NITRIC-OXIDE AND PROSTAGLANDINS

Suppression of host T cell responses is one of the hallmarks of infect ion with the African trypanosomes. The cellular basis for immunosuppre ssion includes the generation of suppressor macrophages that down-regu late T cell proliferative but not necessarily cytokine responses to bo th mitogen and trypanosome Ag. Since macrophages from infected animals display activation characteristics, we have asked whether products of activated cells specifically nitric oxide (NO) and PG, may mediate th e suppressor cell effects and immunosuppression observed. We demonstra te that cells isolated from B10.BR mice infected with Trypanosoma bruc ei rhodesiense exhibited transcriptional up-regulation of inducible NO synthase and released significant amounts of NO. The levels of NO rel eased were elevated further after stimulation of cells with T cell mit ogens or specific parasite Ag; antibody blocking experiments demonstra ted that this up-regulation of NO synthesis was at least partially dep endent upon IFN-gamma and TNF-alpha. The addition of inducible NO synt hase substrate analogues such as N(G)-monomethyl-L-arginine to cell cu ltures inhibited NO release and also partially reversed the suppressor cell activity and immunosuppression displayed by such cultures. PG le vels also were elevated in cell cultures from infected mice, but the P G inhibitor indomethacin had no effect on suppressor cells or suppress ion when added alone to the cultures. However, the concurrent inhibiti on of NO and PG synthesis by the addition of both N(G)-monomethyl-L-ar ginine and indomethacin completely blocked suppressor cell activity as sociated with infected macrophages and also resulted in further recove ry of infected cells from immunosuppression, thus revealing an epistat ic effect between these two mediators. We conclude that macrophage act ivation in trypanosomiasis induces the release of reactive nitrogen in termediates and PG, which down-regulate proliferative responses by T c ells during infection.