KRP-203, a Novel Synthetic Immunosuppressant, Prolongs Graft Survival and Attenuates Chronic Rejection in Rat Skin and Heart Allografts

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-␤ 1 ; 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. (Circulation. 2005;111:222-229.)

International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature: TABLE 1

“…The success of FTY720 in the clinic has spurred the search for similar molecules, particularly with S1P 3 -sparing activity. FTY720-like prodrugs include 2-ammonio-4-(2-chloro-4-(3-phenoxyphenylthio)phenyl)-2-(hydroxymethyl)butyl hydrogen phosphate (KRP-203) (Shimizu et al, 2005) and 1-[1-amino-3-(4-octylphenyl)cyclopentyl]methanol (VPC01091) (Zhu et al, 2007) and are, after phosphorylation, agonists for S1P 1 , S1P 4 , and S1P 5 but not S1P 2 or S1P 3 . Numerous compounds that target S1P 1 and S1P 5 as direct agonists have been described previously (Li et al, 2005); most of these remain visible only in the patent literature.…”

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

“…1). Furthermore, Shimizu et al (2005) have reported that KRP prolonged graft survival and attenuated chronic rejection in rat allograft models, which suggests that KRP regulates not only T cell response but also B cell response. In our previous report, however, FTY did not affect the number of B cells (Mizushima et al, 2004).…”

Predictability of Peripheral Lymphocyte Reduction of Novel S1P1 Agonists by In Vitro GPCR Signaling Profile

“…18,19 In addition, several other S1P 1 selective agonists have been reported to have similar therapeutic potential. 20,21 On the other hand, compelling evidence suggests S1P 1 agonists can also exert their function by tightening the stromal portal of the lymph node, therefore restricting lymphocyte efflux. 22 These different opinions of the mechanism underlining the function of existing S1P 1 agonists warrant the need for thorough understanding of the relationship of desired in vivo activity and potencies in different in vitro assays.…”