Change From Cyclosporine to Combination Therapy of Mycophenolic Acid With the New Sphingosine-1-phosphate Receptor Agonist, KRP-203, Prevents Host Nephrotoxicity and Transplant Vasculopathy in Rats

Fujishiro, Jun; Suzuki, Chihiro; Kudou, Shinji; Yasue, Tokutaro; Hakamata, Yoji; Takahashi, Masafumi; Murakami, Takashi; Hashizume, Kohei; Kobayashi, Eiji

doi:10.1016/j.healun.2006.03.014

Cited by 12 publications

(4 citation statements)

References 42 publications

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“…However, interstitial fibrosis in the renal graft, another common finding of CAN, was markedly suppressed by the combinatorial treatment of KRP-203 with CsA. Besides this study, we reported that KRP-203 prevented transplant arteriosclerosis in mHC-desperate heart allografts (17) and MHC-mismatched aortic allografts when used in combination with mycophenolic acid (36). Furthermore, a recent report has detailed the antiangiogenic properties of FTY720 (37).…”

Section: Discussionsupporting

confidence: 55%

Use of Sphingosine-1-Phosphate 1 Receptor Agonist, KRP-203, in Combination with a Subtherapeutic Dose of Cyclosporine A for Rat Renal Transplantation

Fujishiro

Kudou²,

Iwai

et al. 2006

Transplantation

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Section: Discussionsupporting

confidence: 55%

Use of Sphingosine-1-Phosphate 1 Receptor Agonist, KRP-203, in Combination with a Subtherapeutic Dose of Cyclosporine A for Rat Renal Transplantation

Fujishiro

Kudou²,

Iwai

et al. 2006

Transplantation

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“…KRP‐203 prolonged allograft survival but attenuated side effects seen by FTY720. In an orthotopic aortic transplantation model, changing from cyclosporine treatment to a mycophenolate mofetil/KRP‐203 combination therapy reduced vasculopathy in the animals (Fujishiro et al ., 2006b). In another study by the same group, KRP‐203 in combination with sub‐therapeutic doses of cyclosporine not only prolonged allograft survival but also rather improved graft kidney function in a rat model (Fujishiro et al ., 2006a).…”

Section: S1p Receptor Agonists and Antagonistsmentioning

confidence: 99%

Pharmacological relevance and potential of sphingosine 1‐phosphate in the vascular system

Schuchardt

Tölle

Prüfer

et al. 2011

British J Pharmacology

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Sphingosine-1-phosphate (S1P) was identified as a crucial molecule for regulating immune responses, inflammatory processes as well as influencing the cardiovascular system. S1P mediates differentiation, proliferation and migration during vascular development and homoeostasis. S1P is a naturally occurring lipid metabolite and is present in human blood in nanomolar concentrations. S1P is not only involved in physiological but also in pathophysiological processes. Therefore, this complex signalling system is potentially interesting for pharmacological intervention. Modulation of the system might influence inflammatory, angiogenic or vasoregulatory processes. S1P activates G-protein coupled receptors, namely S1P1-5, whereas only S1P1-3 is present in vascular cells. S1P can also act as an intracellular signalling molecule. This review highlights the pharmacological potential of S1P signalling in the vascular system by giving an overview of S1P-mediated processes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). After a short summary of S1P metabolism and signalling pathways, the role of S1P in EC and VSMC proliferation and migration, the cause of relaxation and constriction of arterial blood vessels, the protective functions on endothelial apoptosis, as well as the regulatory function in leukocyte adhesion and inflammatory responses are summarized. This is followed by a detailed description of currently known pharmacological agonists and antagonists as new tools for mediating S1P signalling in the vasculature. The variety of effects influenced by S1P provides plenty of therapeutic targets currently under investigation for potential pharmacological intervention. LINKED ARTICLESThis article is one of a set of reviews submitted to BJP in connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visit http://dx.doi.org/ 10.1111/j. 1476-5381.2010.01167.x, http://dx.doi.org/10.1111/j.1476-5381.2011.01235.x and http://dx.doi.org/10.1111/ j.1476-5381.2011.01366.x Abbreviations ABC, ATP-binding cassette; ApoE, apolipoprotein E; Bcl-2, B-cell lymphoma gene 2; Bim, bisindolylmaleimide; CAD, coronary artery disease; Compound 5,thio]-2′-[4-(heptylthio)methyl]-2-hydroxyphenyl hydroxymethyl biphenyl-3-sulfonate; CYM5442, 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino ethanol; EC, endothelial cell; ECM, extracellular matrix; EGF, endothelial growth factor; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FTY720, 2-amino-2-(4-octylphenethyl) propane-1,3-diol; FTY720-P, 2-amino-2-(4-octylphenethyl) propane-1,3-diol phosphate; GPCR, G-protein coupled receptor; HDL, high-density lipoprotein; HUVEC, human umbilical vein endothelial cell; ICAM, inducible cell adhesion molecule; IL-8, interleukin 8; iNOS, inducible nitric oxide synthase; IP3, inositol-1,4,5-triphosphate; IRI, ischemia-reperfusion injury; JNK...

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“…The first trials of this drug were published in 2005 and demonstrated that in a similar manner to FTY720, KRP-203 enhanced graft survival in animal transplant models [101][102][103][104]. No studies have yet been conducted in a liver transplant model.…”

Section: Inhibiting T Cell Activation In the Lymph Nodesmentioning

confidence: 99%

Liver Tolerance and the Manipulation of Immune Outcomes

Holz¹,

McCaughan²,

Benseler³

et al. 2008

IADT

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In recent years it has become apparent that the liver holds a distinct immunological position. Previously described as a "graveyard" for T cells activated in the periphery, emerging evidence indicates that this organ may have a more active role in mediating tolerance. Attenuated immune responses in the liver can be beneficial in the transplantation setting, as liver transplants are more readily accepted than other organ allografts even in the absence of immunosuppressive drugs. However, the ability of the liver to induce immunological unresponsiveness could be exploited by some pathogens, such as the hepatitis C virus (HCV), to establish chronic infections with potentially fatal outcomes. Understanding the mechanisms controlling the balance between intrahepatic tolerance and immunity is critical in order to design new strategies to enhance acceptance of solid organ allografts and to promote efficient immune responses against HCV. In this article, we will review current knowledge of the mechanisms regulating intrahepatic immunity and discuss how these mechanisms might potentially be targeted to achieve advantageous clinical outcomes in transplantation and persistent hepatotropic infections.

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Change From Cyclosporine to Combination Therapy of Mycophenolic Acid With the New Sphingosine-1-phosphate Receptor Agonist, KRP-203, Prevents Host Nephrotoxicity and Transplant Vasculopathy in Rats

Cited by 12 publications

References 42 publications

Use of Sphingosine-1-Phosphate 1 Receptor Agonist, KRP-203, in Combination with a Subtherapeutic Dose of Cyclosporine A for Rat Renal Transplantation

Use of Sphingosine-1-Phosphate 1 Receptor Agonist, KRP-203, in Combination with a Subtherapeutic Dose of Cyclosporine A for Rat Renal Transplantation

Pharmacological relevance and potential of sphingosine 1‐phosphate in the vascular system

Liver Tolerance and the Manipulation of Immune Outcomes

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