THE SIGMA-LIGAND SR-31747 PREVENTS THE DEVELOPMENT OF ACUTE GRAFT-VERSUS-HOST DISEASE IN MICE BY BLOCKING IFN-GAMMA AND GM-CSF MESSENGER-RNA EXPRESSION

SR 31747 is a sigma ligand which prevents the development of acute graft-versus-host reaction (GvHR) in hybrid B6D2F 1 mice injected with C57BL/6 parental spleen cells. In the present study, we showed that this drug dramatically impaired the GvHR-associated increase in the numbers of both B-lymphocytes and polymorphonuclear cells (PMNs) in the spleen. Because SR 31747 blocked the GvHR-induced expression of both interleukin-2 and transferrin receptors on T-lymphocytes, it is very likely that this molecule prevented the disease through an inhibition of T-lymphocyte activation. Cytokine messenger RNA analyses on spleen cells revealed that SR 31747 blocked IFN-gamma and GM-CSF but not IL-4 transcription. These effects, which are different from those observed with either cyclosporin-A or dexamethasone, strongly suggest that SR 31747 preferentially inhibits the Th1 lymphocyte subset.