Efficacy of mycophenolic acid combined with KRP-203, a novel immunomodulator, in a rat heart transplantation model.
BACKGROUND
To explore a more effective and less toxic immunosuppressive strategy in organ transplantation, we recently developed the novel sphingosine-1-phosphate receptor agonist KRP-203. This study examined the efficacy of KRP-203 combined with mycophenolic acid (MPA), an active metabolite of mycophenolate mofetil, in rat heart allografts.


METHODS
Heterotopic heart transplantation was performed in a rat combination of DA (MHC haplotype: RT1(a)) to Lewis (RT1). The recipients were divided into 12 groups (n = 5-7): Syngeneic (Lewis to Lewis), Vehicle, KRP-203 (0.3 and 1 mg/kg), MPA (10 and 20 mg/kg), 10 mg/kg MPA with KRP-203 (0.03, 0.3, 1, and 3 mg/kg), and 20 mg/kg MPA with KRP-203 (0.3 and 1 mg/kg). MPA, KRP-203, and vehicle were given orally.


RESULTS
The mean days of survival were 5.8 (vehicle), 7 and 7.9 (0.3 and 1 mg/kg KRP-203, respectively), 12.7 and >54.4 (10 and 20 mg/kg MPA), >39.6 and >30.5 (10 mg/kg MPA with 1 and 3 mg/kg KRP-203), >100 and >87.8 (20 mg/kg MPA with 0.3 and 1 mg/kg KRP-203). Histologic and immunohistochemical analysis revealed that diffuse mononuclear cell infiltration (macrophages and T cells), hemorrhage, myocardial necrosis and fibrosis, and expression of endothelin-1, transforming growth factor-beta1, monocyte chemoattractant protein-1, interleukin-8, and E-selectin were markedly diminished in the allografts treated with MPA combined with KRP-203. Pharmacokinetic experiments indicated no interaction between MPA and KRP-203, and both combination regimens were well tolerated.


CONCLUSIONS
Combination therapy of MPA with KRP-203 has a therapeutic potential as a novel immunosuppressant strategy in clinical transplantation.
Suzuki
Chihiro
C
Division of Cardiovascular Science, Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Takahashi
Masafumi
M
Morimoto
Hajime
H
Izawa
Atsushi
A
Ise
Hirohiko
H
Fujishiro
Jun
J
Murakami
Takashi
T
Ishiyama
Junichi
J
Nakada
Akihiro
A
Nakayama
Jun
J
Shimada
Kazuyuki
K
Ikeda
Uichi
U
Kobayashi
Eiji
E
D000818:Animals; D001773:Blood Cells / Q000166:cytology; D002465:Cell Movement; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008264:Macrophages / Q000502:physiology; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000502:physiology
D007166:Immunosuppressive Agents; C501899:KRP-203; D013438:Sulfhydryl Compounds; D009173:Mycophenolic Acid