Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody.
Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine-1-phosphate (S1P), is involved in intimal hyperplasia elicited by W6/32. Studies were done on cultured hmSMC and on an in vivo model of TV, consisting of human mesenteric arteries grafted into SCID/beige mice, injected weekly with W6/32. hmSMC migration and DNA synthesis elicited by W6/32 were inhibited by the sphingosine kinase-1 (SK1) inhibitor dimethylsphingosine, the anti-S1P antibody Sphingomab and the S1PR1/R3 inhibitor VPC23019. W6/32 stimulated SK1 activity, while siRNA silencing SK1, S1PR1 and S1PR3 inhibited hmSMC migration. In vivo, Sphingomab significantly reduced the intimal thickening induced by W6/32. These data emphasize the role of S1P in intimal hyperplasia elicited by the humoral immune response, and open perspectives for preventing TV with S1P inhibitors.
INSERM UMR-1048, Toulouse, France.|Biochemistry Department, University of Toulouse, Faculty of Medicine, Toulouse, France.
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Trayssac
INSERM UMR-1048, Toulouse, France.|Biochemistry Department, University of Toulouse, Faculty of Medicine, Toulouse, France.
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Galvani
INSERM UMR-1048, Toulouse, France.
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Augé
Lpath, Inc., and Department of Biology, San Diego State University, San Diego, CA.
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Sabbadini
INSERM UMR-1048, Toulouse, France.
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Calise
INSERM UMR-1048, Toulouse, France.|Biochemistry Department, University of Toulouse, Faculty of Medicine, Toulouse, France.
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Mucher
CHU Rangueil, Department of Nephrology, Toulouse, France.
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Sallusto
INSERM UMR-1048, Toulouse, France.|INSERM UMR-1027, Toulouse, France.
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Thomsen
INSERM UMR-1048, Toulouse, France.|Biochemistry Department, University of Toulouse, Faculty of Medicine, Toulouse, France.
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Salvayre
INSERM UMR-1048, Toulouse, France.
A
A
Nègre-Salvayre
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D016377:Organ Transplantation / Q000009:adverse effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D014652:Vascular Diseases / Q000209:etiology*
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
chronic; major histocompatibility complex (MHC); murine; rejection; signaling/signaling pathways