Efficacy of mycophenolic acid combined with KRP-203, a novel immunomodulator, in a rat heart transplantation model

Chihiro Suzuki, Masafumi Takahashi, Hajime Morimoto, Atsushi Izawa, Hirohiko Ise, Jun Fujishiro, Takashi Murakami, Junichi Ishiyama, Akihiro Nakada, Jun Nakayama, Kazuyuki Shimada, Uichi Ikeda, Eiji Kobayashi

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18 Citations (Scopus)

Abstract

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: RT1a) to Lewis (RT1l). 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-β1, 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.

Original languageEnglish
Pages (from-to)302-309
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume25
Issue number3
DOIs
Publication statusPublished - Mar 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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