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 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.
Department of Immunopharmacology, Sanofi Recherche, Montpellier, France.
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Casellas
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Bourrié
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Canat
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Carayon
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Buisson
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Paul
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Brelière
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Le Fur
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D003510:Cyclohexanes / Q000276:immunology* / Q000494:pharmacology*; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications; D006087:Graft vs Host Reaction / Q000187:drug effects; D006099:Granuloma / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D006824:Hybridization, Genetic; D006968:Hypersensitivity, Delayed / Q000150:complications; D007111:Immunity, Cellular / Q000187:drug effects*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013163:Splenomegaly / Q000473:pathology
D003510:Cyclohexanes; C088447:SR 31747