KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.
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.
Shimizu
Hisashi
H
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Takahashi
Masafumi
M
Kaneko
Takashi
T
Murakami
Takashi
T
Hakamata
Yoji
Y
Kudou
Shinji
S
Kishi
Tetsuya
T
Fukuchi
Kazunori
K
Iwanami
Satoru
S
Kuriyama
Kazuhiko
K
Yasue
Tokutaro
T
Enosawa
Shin
S
Matsumoto
Koshi
K
Takeyoshi
Izumi
I
Morishita
Yasuo
Y
Kobayashi
Eiji
E
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
D007166:Immunosuppressive Agents; C501899:KRP-203; D011409:Propylene Glycols; D013438:Sulfhydryl Compounds; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine