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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

A Novel Sphingosine 1-Phosphate Receptor Agonist, 2-Amino-2-propanediol Hydrochloride (KRP-203), Regulates Chronic Colitis in Interleukin-10 Gene-Deficient Mice

Departments of Surgery (J.S., C.M., Y.K., T.N., K.N., Y.S., T.I.) and Complementary and Alternative Medicine (T.I.), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Surgery, Rinku General Medical Center, Osaka, Japan (T.M.); and Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan (M.K., T.Y.)

Current treatments for patients with Crohn's disease (CD) are based on recent advances in elucidating the pathophysiology of the disease. A satisfactory therapeutic strategy has not been well established. A new sphingosine 1-phosphate (S1P) receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), has been developed for immunomodulation in autoimmune diseases and organ transplantation. We aimed to evaluate the efficacy and potency of KRP-203 on the treatment of chronic colitis in an interleukin (IL)-10 gene-deficient (IL-10^–/–) mouse model. KRP-203 agonistic activity on S1P receptor was assessed in vitro. KRP-203 was administered for 1 or 4 weeks to IL-10^–/– mice with clinical signs of colitis. The histological appearance of the colon and the numbers, phenotype, and cytokine production of lymphocytes were compared with a control group. KRP-203 treatment was effective in preventing body weight loss in the IL-10^–/– colitis model. One-week administration resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. After 4 weeks of treatment, highly significant reductions were observed in number of CD4⁺ T cell and B220⁺ B cell subpopulations in the lamina propria of the colon and peripheral blood. KRP-203 obviously inhibited the production of interferon-, IL-12, and tumor necrosis factor- by the colonic lymphocytes, but had no influence on IL-4 production. KRP-203 significantly inhibits ongoing IL-10^–/– colitis in part through decreasing the infiltration of lymphocytes at inflammatory sites and by blocking T-helper 1 cytokine production in the colonic mucosa. Therefore, the possibility arises that KRP-203 plays a potential role in control of chronic colitis.

Address correspondence to: Dr. Toshinori Ito, Department of Complementary and Alternative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: juki{at}cam.med.osaka-u.ac.jp

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