A novel immunosuppressant, IR‐1116, which has a different biological mechanism from that of cyclosporine A

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Abstract
The effects of an epifumagillol derivative, IR‐1116, on human lymphocytes in vitro, mouse antibody production in vivo and rat renal and cardiac transplantation were investigated. IR‐1116 suppressed the human primary mixed lymphocyte reaction (MLR) in a dose‐dependent manner with a value of the dose required for 50% suppression of 0.32 μM. IR‐1116 suppressed the antibody production by human B lymphocytes activated with pokeweed mitogen or Epstein‐Barr virus, but did not affect the interleukin‐2 production by human lymphocytes stimulated with phytohemagglutinin. Furthermore, IR‐1116 did not have any effect on the proliferation of B or T lymphocytes. IR‐1116 is thought to have a different mechanism from cyclosporine A (CsA). BALB/c mice were immunized by s.c. injection of bovine γ‐globulin (BGG) and then received IR‐1116 or CsA by i.p. injection at a dose of 20 mg/kg every other day for 2 weeks. IR‐1116 suppressed the production of serum antibodies against BGG as strongly as CsA. In this experiment, IR‐1116 apparently showed no adverse effects, while CsA‐treated mice suffered from diarrhea and appeared to be irritated. Histological studies showed that IR‐1116 suppressed the formation of germinal centers in the spleen of immunized mice. Flow cytometric analysis showed that IR‐1116 caused a reduction of B lymphocyte population in splenocytes. On the other hand, CsA caused a marked reduction of helper T lymphocyte population in splenocytes and thymocytes. Furthermore, the i.p. administration of IR‐1116 prolonged the survival time in a rat renal allograft model and the vital period of grafted hearts in rats. Based on the above, IR‐1116 seems to be a new type of immunosuppressant acting via novel mechanisms different from those of immunosuppressants such as CsA, a potent T lymphocyte suppressant.