RRC ID 149
Author Shimizu H, Takahashi M, Kaneko T, Murakami T, Hakamata Y, Kudou S, Kishi T, Fukuchi K, Iwanami S, Kuriyama K, Yasue T, Enosawa S, Matsumoto K, Takeyoshi I, Morishita Y, Kobayashi E.
Title KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.
Journal Circulation
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.
METHODS AND 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.
Volume 111(2)
Pages 222-9
Published 2005-1-18
DOI 10.1161/01.CIR.0000152101.41037.AB
PII 01.CIR.0000152101.41037.AB
PMID 15642767
MeSH Animals Bradycardia / prevention & control Chemotaxis, Leukocyte / drug effects Chronic Disease Cyclosporine / administration & dosage Cyclosporine / therapeutic use Drug Evaluation, Preclinical Drug Therapy, Combination Fingolimod Hydrochloride Graft Rejection / drug therapy* Graft Rejection / prevention & control Graft Survival / drug effects* Guinea Pigs Heart Rate / drug effects Heart Transplantation / immunology* Immunosuppressive Agents / chemistry Immunosuppressive Agents / pharmacology Immunosuppressive Agents / therapeutic use* Male Molecular Structure Propylene Glycols / pharmacology Propylene Glycols / therapeutic use Rats Rats, Inbred F344 Rats, Inbred Lew Rats, Inbred Strains Rats, Wistar Skin Transplantation / immunology* Sphingosine / analogs & derivatives Sulfhydryl Compounds / administration & dosage Sulfhydryl Compounds / chemistry Sulfhydryl Compounds / pharmacology Sulfhydryl Compounds / therapeutic use* Transplantation, Heterotopic Transplantation, Homologous / immunology
IF 23.603
Times Cited 94