Gangliosides potentiate the immunosuppressive effects of cyclosporin A in rat skin allografts

In vitro gangliosides exert inhibitory effects on cellular immune responses, largely relying on an impairment of the IL-2/IL-2 receptor interaction. In a previous study we have demonstrated synergistic effects of gangliosides and cyclosporin A (CyA) in the inhibition of the generation of in vitro allospecific immune responses in humans. To evaluate the possibility of using these drugs in immunosuppressive therapy in organ transplantation, we investigated the effects of the combination of a gangliosides mixture (GAMIX) and suboptimal doses of CyA on rat skin allografts in vivo. Sprague-Dawley rats were implanted with skin grafts from Lewis rats and treated for 21 days by intraperitoneal administration of either GAMIX or CyA or a combination of the two drugs. Untreated, GAMIX-treated or CyA-treated rats rejected skin allografts. In contrast, when a combined GAMIX CyA treatment was administered, successful grafting could be obtained in 8 rats out of 10 tested. Cells derived from spleens on day 21 post graft were stimulated in vitro with PWM mitogen. We found that cells from transplanted rats, untreated or treated with low-dose CyA or GAMIX alone, showed comparable responses to PWM. Cells from rats treated with the combination of the two drugs were found to be virtually unresponsive to stimulation by PWM mitogen. Taken together, our results indicate that GAMIX potentiate in vivo and ex vivo immunosuppressive effects of low-dose CyA.