title: KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.
abstract: BACKGROUND
  A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation.
  
  
  RESULTS
  KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720.
  
  
  CONCLUSIONS
  These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.
authors.affiliation: Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hakamata
authors.forename: Shinji
authors.initials: S
authors.lastname: Kudou
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kishi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fukuchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwanami
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kuriyama
authors.forename: Tokutaro
authors.initials: T
authors.lastname: Yasue
authors.forename: Shin
authors.initials: S
authors.lastname: Enosawa
authors.forename: Koshi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Izumi
authors.initials: I
authors.lastname: Takeyoshi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishita
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000517:prevention & control; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002908:Chronic Disease; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000188:drug therapy* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D015394:Molecular Structure; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D016038:Skin Transplantation / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; C501899:KRP-203; D011409:Propylene Glycols; D013438:Sulfhydryl Compounds; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine