sr-31747 and Graft-vs-Host-Disease

SR 31747 is a sigma ligand which prevents the development of acute graft-versus-host reaction (GvHR) in hybrid B6D2F1 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.

Topics: Acute Disease; Animals; Base Sequence; Cyclohexanes; Cytokines; Female; Graft vs Host Disease; Granulocyte-Macrophage Colony-Stimulating Factor; Interferon-gamma; Leukocytes; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Sequence Data; Polymerase Chain Reaction; Receptors, sigma; RNA, Messenger; Spleen

In our preceding paper, we demonstrated that both human and rat lymphocytes possess saturable high-affinity binding sites for the new sigma ligand SR 31747. Here we investigate the potential activity of this ligand on immune responses. In vitro, our study shows that SR 31747 exerts a concentration- and time-dependent inhibition of proliferative response to mitogens on mouse and human lymphocytes without affecting cell viability. This suppressive effect elicited by SR 31747 occurs over a concentration range which correlates with the pharmacological profile of the molecule in binding assays, strongly suggesting that SR 31747 acts through a receptor-mediated process. We showed that the SR 31747 effect, which was observed on purified T lymphocytes, affects a late event in the activation process which occurs after the G1 during the S phase of the cell cycle. Interestingly, no anti-proliferative effect was observed in a variety of tumor cell lines, supporting a specific effect limited to normal immune cells. In vivo, in mice, treatment with SR 31747 prevented both graft-versus-host disease and delayed-type hypersensitivity granuloma formation, while antibody response to sheep red blood cells was not affected. These results strongly suggest that the sigma-related receptor recognized by SR 31747 is very likely coupled to a biological function of lymphocytes.

Topics: Animals; Antibody Formation; Cyclohexanes; Female; Graft vs Host Disease; Graft vs Host Reaction; Granuloma; Humans; Hybridization, Genetic; Hypersensitivity, Delayed; Immunity, Cellular; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred Strains; Palatine Tonsil; Spleen; Splenomegaly