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 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 microM. 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 gamma-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.
Matsumoto
S
S
Takeda Chemical Industries, LTD, Discovery Research Division, Osaka, Japan.
Marui
S
S
Shiho
O
O
Tsukamoto
K
K
Yoshimura
N
N
Oka
T
T
D000328:Adult; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012717:Sesquiterpenes / Q000494:pharmacology*
D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D012717:Sesquiterpenes; C079842:IR 1116; D016572:Cyclosporine