IMMUNOPHARMACOLOGICAL PROFILE OF SR-31747 - IN-VITRO AND IN-VIVO STUDIES ON HUMORAL AND CELLULAR-RESPONSES

In our preceding paper, we demonstrated that both human and rat lympho cytes possess saturable high-affinity binding sites for the new sigma ligand SR 31747. Here we investigate the potential activity of this li gand on immune responses. In vitro, our study shows that SR 31747 exer ts a concentration- and time-dependent inhibition of proliferative res ponse to mitogens on mouse and human lymphocytes without affecting cel l viability. This suppressive effect elicited by SR 31747 occurs over a concentration range which correlates with the pharmacological profil e 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 e ffect limited to normal immune cells. In vivo, in mice, treatment with SR 31747 prevented both graft-versus-host disease and delayed-type hy persensitivity granuloma formation, while antibody response to sheep r ed blood cells was not affected. These results strongly suggest that t he sigma-related receptor recognized by SR 31747 is very likely couple d to a biological function of lymphocytes.