A NOVEL IMMUNOSUPPRESSANT, IR-1116, WHICH HAS A DIFFERENT BIOLOGICAL MECHANISM FROM THAT OF CYCLOSPORINE-A

The effects of an epifumagillol derivative, IR-1116, on human lymphocy tes in vitro, mouse antibody production in vivo and rat renal and card iac transplantation were investigated. IR-1116 suppressed the human pr imary mixed lymphocyte reaction (MLR) in a dose-dependent manner with a value of the dose required for 50 % suppression of 0.32 muM. IR-1116 suppressed the antibody production by human B lymphocytes activated w ith pokeweed mitogen or Epstein-Barr virus, but did not affect the int erleukin-2 production by human lymphocytes stimulated with phytohemagg lutinin. Furthermore, IR-1116 did not have any effect on the prolifera tion of B or T lymphocytes. IR-1116 is thought to have a different mec hanism from cyclosporine A (CsA). BALB/c mice were immunized by s.c. i njection of bovine gamma-globulin (BGG) and then received IR-1116 or C sA 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 adv erse effects, while CsA-treated mice suffered from diarrhea and appear ed to be irritated. Histological studies showed that IR-1116 suppresse d the formation of germinal centers in the spleen of immunized mice. F low cytometric analysis showed that IR-1116 caused a reduction of B ly mphocyte population in splenocytes. On the other hand, CsA caused a ma rked reduction of helper T lymphocyte population in splenocytes and th ymocytes. Furthermore, the i.p. administration of IR-1116 prolonged th e 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 suppres sant.