title: A key role for matrix metalloproteinases and neutral sphingomyelinase-2 in transplant vasculopathy triggered by anti-HLA antibody.
abstract: BACKGROUND
  Outcomes for organ transplantation are constantly improving because of advances in organ preservation, surgical techniques, immune clinical monitoring, and immunosuppressive treatment preventing acute transplant rejection. However, chronic rejection including transplant vasculopathy still limits long-term patient survival. Transplant vasculopathy is characterized by progressive neointimal hyperplasia leading to arterial stenosis and ischemic failure of the allograft. This work sought to decipher the manner in which the humoral immune response, mimicked by W6/32 anti-HLA antibody, contributes to transplant vasculopathy.
  
  
  RESULTS
  Studies were performed in vitro on cultured human smooth muscle cells, ex vivo on human arterial segments, and in vivo in a model consisting of human arterial segments grafted into severe combined immunodeficiency/beige mice injected weekly with anti-HLA antibodies. We report that anti-HLA antibodies are mitogenic for smooth muscle cells through a signaling mechanism implicating matrix metalloproteinases (MMPs) (membrane type 1 MMP and MMP2) and neutral sphingomyelinase-2. This mitogenic signaling and subsequent DNA synthesis are blocked in smooth muscle cells silenced for MMP2 or for neutral sphingomyelinase-2 by small interfering RNAs, in smooth muscle cells transfected with a vector coding for a dominant-negative form of membrane type 1 MMP, and after treatment by pharmacological inhibitors of MMPs (Ro28-2653) or neutral sphingomyelinase-2 (GW4869). In vivo, Ro28-2653 and GW4869 reduced the intimal thickening induced by anti-HLA antibodies in human mesenteric arteries grafted into severe combined immunodeficiency/beige mice.
  
  
  CONCLUSIONS
  These data highlight a crucial role for MMP2 and neutral sphingomyelinase-2 in vasculopathy triggered by a humoral immune response and open new perspectives for preventing transplant vasculopathy with the use of MMP and neutral sphingomyelinase inhibitors, in addition to conventional immunosuppression.
authors.affiliation: INSERM UMR-1048, Toulouse, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Galvani
authors.forename: Magali
authors.initials: M
authors.lastname: Trayssac
authors.forename: Nathalie
authors.initials: N
authors.lastname: Augé
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Thiers
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Krell
authors.forename: Federico
authors.initials: F
authors.lastname: Sallusto
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Mogens
authors.initials: M
authors.lastname: Thomsen
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
authors.forename: Robert
authors.initials: R
authors.lastname: Salvayre
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000009:adverse effects / Q000494:pharmacology*; D001158:Arteries / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation*; D001597:Benzylidene Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D003251:Constriction, Pathologic / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000503:physiopathology; D066298:In Vitro Techniques; D053511:Matrix Metalloproteinase 14 / Q000187:drug effects / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000473:pathology / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D014652:Vascular Diseases / Q000209:etiology / Q000503:physiopathology*; D058017:Vascular Grafting
chemical_list: D000814:Aniline Compounds; D000888:Antibodies, Anti-Idiotypic; D001597:Benzylidene Compounds; C468773:GW 4869; D006680:HLA Antigens; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C453902:Ro 28-2653; C491484:SMPD3 protein, human; D013108:Sphingomyelin Phosphodiesterase; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14