FR235222, a novel immunosuppressant which possesses potent inhibitory effects on the activity of mammalian histone deacetylases (HDACs), has been isolated from the fermentation broth of a fungus, Acremonium sp. No. 27082. FR235222 exhibited marked immunosuppressive effects on mouse ex vivo splenic T-lymphocyte proliferation, mouse delayed type hypersensitivity (DTH) response, rat adjuvant-induced arthritis (AA) and rat heterotopic cardiac transplantation. These results showed potential clinical use of this compound as a new type immunosuppressant in the fields of autoimmune diseases and organ transplantations.In the prior paper1), we showed a novel HDAC inhibitor FR235222 as a fungal metabolite that has potent and selective immunosuppressive activities. During the past ten years or more, several families of natural products have been discovered or rediscovered as HDAC inhibitors, such as short chain fatty acids (ex; n-butyrate2)), trichostatins (ex; trichostatin A3)), bicyclic depsipeptides (ex; FK2284)), depudecin5) and cyclic tetrapeptides (ex; trapoxin A6)). FR235222 was found to be a new constituent of the cyclic tetrapeptide family which include trapoxin A, trapoxin B7), HC-toxin8), Cyl-29), WF-316110), Chlamidocin11), apicidin12), TAN-174613), phoenistatin14) and so on. Immunosuppressive activity of HDAC inhibitors has been shown in recent several reports26). Most reports have been limited to the descriptions of in vitro activity. To the best of our knowledge, only one paper described by TAKAHASHI et al. showed the in vivo effectiveness of TSA in mouse DTH response27), although it seems less effective than that of CsA and not without toxicity. Therefore in this paper, we tested FR235222 in a mouse ex vivo splenic Tlymphocyte proliferation model, a mouse delayed type hypersensitivity (DTH) reaction model, a rat adjuvantinduced arthritis (AA) model and a rat heterotopic cardiac transplantation model, to ascertain not only the posibility of