Macrophages from schistosomal egg granulomas induce unresponsiveness in specific cloned Th-1 lymphocytes in vitro and down-regulate schistosomal granulomatous disease in vivo.

Abstract

We previously have proposed that accessory cells from individuals infected with schistosomiasis induce unresponsiveness in specific Th-1 lymphocytes resulting in the immunologic down-regulation of egg-induced granulomatous inflammation characteristically seen in this disease. We now show that macrophages isolated from schistosomal egg granulomas (GM) fail to serve as stimulatory APC for cloned, murine schistosomal egg Ag (SEA)-specific, CD4+, Th-1-type lymphocytes, while being able to stimulate Th-2-type responses. Instead, GM render Th-1 cells unresponsive to restimulation. Based on these findings, we tested two approaches to down-regulate the granulomatous inflammation associated with a schistosomal challenge infection. First, active ectopic granuloma induction in response to Schistosoma mansoni eggs, but not to Ascaris lumbricoides eggs, resulted in a significant reduction of granulomatous disease in vivo, as well as in the inhibition of specific proliferation of mesenteric lymph node cells in vitro. Second, passive administration of purified GM, but not of normal peritoneal cells (PC), resulted, similarly, in significant reduction of granuloma size in vivo and specific lympho-proliferation in vitro. Moreover, cytokine analysis of supernatants from stimulated lymph node cells disclosed that the Th-1-derived cytokine IL-2 decreased to undetectable levels, at the same time as the Th-2-derived cytokines IL-4 and IL-10 increased, in animals receiving GM, in contrast to those receiving PC or no cells. These findings are consistent with the interpretation that accessory cells such as GM induce unresponsiveness in specific Th-1 cells that, in turn, results in the down-regulation of granulomatous schistosomal disease and its in vitro correlates.