HLA Class I Antibodies Provoke Graft Arteriosclerosis in Human Arteries Transplanted into SCID/Beige Mice

Galvani, Sylvain; Augé, Nathalie; Calise, Denis; Thiers, Jean-Claude; Canivet, Cindy; Kamar, Nassim; Rostaing, Lionel; Abbal, M.; Sallusto, Fédérico; Salvayre, Robert; Böhler, Torsten; Zou, Yizhou; Šťastný, Peter; Nègre‐Salvayre, Anne; Thomsen, Mögens

doi:10.1111/j.1600-6143.2009.02804.x

Cited by 34 publications

(56 citation statements)

References 22 publications

(29 reference statements)

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“…This experimental animal system has been characterized extensively, 30 -32 and its use with anti-HLA mAbs has been reported in a recent methodological article 17 and is briefly described in the online-only Data Supplement. The use of human mesentery from cadaveric organ donors was approved by the French Agence de Biomédecine and the Ethics Committee of the University Hospital of Toulouse.…”

Section: Human Mesenteric Arterial Segments Grafted Into Scid/beige Micementioning

confidence: 99%

“…17 Histological studies were performed on the grafted human mesenteric artery segments recovered at the end of the treatment. In mice injected with phosphate-buffered saline vehicle ("untreated") or irrelevant mAb, we observed neither major histological alteration nor thrombosis ( Figure 3A).…”

Section: Histological Study Of Human Mesenteric Arterial Segments Gramentioning

confidence: 99%

“…24 -27 Because the precise mechanism of action of MMPs remains elusive, we hypothesized that MMPs and the sphingomyelin/ceramide pathways are activated by alloantibodies and thus contribute to the mitogenic signaling leading to intimal hyperplasia and vascular wall remodeling of human arteries grafted in SCID/beige mice. 17 This led us to investigate whether MMP and nSMase2 inhibitors may prevent alloantibody-induced SMC proliferation and transplant vasculopathy. This study was conducted in vitro in human cultured SMCs, ex vivo on human arterial segments, and in vivo on human arteries grafted into SCID/beige mice.…”

mentioning

confidence: 99%

“…16 On the basis of the response of vascular cells to anti-HLA monoclonal antibody (mAb) W6/32 reported by Reed et al, [11][12][13][14] we recently developed an original model of human mesenteric arteries grafted into severe combined immunodeficiency (SCID)/beige mice, in which passive transfer of W6/32 mAb toward HLA class I provokes transplant vasculopathy in the absence of cellular immunity. 17 The sphingomyelin/ceramide signaling pathway is involved in various stress-induced responses 18 and plays a role in the mitogenic response of vascular SMCs to TNF-␣, oxidized low-density lipoprotein, and H 2 O 2 . 19 -21 In this pathway, the activation of neutral sphingomyelinase-2 (nSMase2), which converts sphingomyelin into ceramide, requires the activation of the matrix metalloproteinases (MMPs) membrane type 1 MMP (MT1-MMP) and MMP2.…”

mentioning

confidence: 99%

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A Key Role for Matrix Metalloproteinases and Neutral Sphingomyelinase-2 in Transplant Vasculopathy Triggered by Anti-HLA Antibody

et al. 2011

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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. Methods and 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. Key Words: anti HLA class I mAb Ⅲ metalloproteinases Ⅲ proliferation Ⅲ smooth muscle cells Ⅲ transplant vasculopathy P rogress in surgical techniques, organ preservation, and immunosuppressive drugs has improved the outcome of organ allografts. 1 However, the late outcome of organ transplants is impaired by transplant vasculopathy (also known as transplant arteriosclerosis or chronic vascular rejection), which occurs in up to 50% of heart transplant recipients within 5 years after transplantation. 2,3 Transplant vasculopathy is mediated by immune and nonimmune mechanisms (such as ischemia/reperfusion, inflammation, viral infection, and hypertension) that trigger diffuse and concentric intimal hyperplasia and lead finally to arterial stenosis, chronic ischemia, and functional loss of the grafted organ. 2,4,5 Conclusions-These Clinical Perspective on p 2734Both cell-mediated and humoral immunologic mechanisms are thought to participate in the pathogenesis of transplant vasculopathy. [5][6][7][8] Experimental and clinical studies suggest that B cells and donor-specific alloantibodies play a role in Received January 25, 2011; accepted October 11, 2011. From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, Franc...

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Section: Human Mesenteric Arterial Segments Grafted Into Scid/beige Micementioning

confidence: 99%

Section: Histological Study Of Human Mesenteric Arterial Segments Gramentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Key Role for Matrix Metalloproteinases and Neutral Sphingomyelinase-2 in Transplant Vasculopathy Triggered by Anti-HLA Antibody

et al. 2011

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“…35 These findings were recently confirmed in a humanized mouse aortic transplant model using severe combined immunodeficiency mice as recipients, which were treated with anti-HLA I antibody. 36 However, other studies with different murine models of experimental transplant did not show a significant contribution of alloantibodies to the rejection process of transplanted allografts. 37,38 Recent reports suggest that donor-specific alloantibodies may induce the development of transplant arteriosclerosis by up-regulation of growth factors from endothelial and vascular smooth muscle cells; release of adhesion factors; consecutive induction of macrophages, lymphocytes, and dendritic cells; and activation of complement factors.…”

Section: Discussionmentioning

confidence: 92%

Reduction of Transplant Arteriosclerosis After Treatment With Mycophenolate Mofetil and Ganciclovir in a Mouse Aortic Allograft Model

Hoffmann¹,

Böhm²,

Abele-Ohl³

et al. 2012

Exp Clin Transplant

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Objectives: Transplant arteriosclerosis is a major obstacle for long-term allograft survival in heart transplant. The aim of this study was to investigate potential synergistic effects of combined treatment with mycophenolate mofetil and ganciclovir on the development of transplant arteriosclerosis, presence of regulatory T cells, and expression of donor specific alloantibodies. Materials and Methods: Donor aortas from C57BL/6 (H2b) mice that were fully mismatched to the major histocompatibility complex were transplanted into CBA (H2k) mouse recipients. Groups of mice received mycophenolate mofetil (100 or 300 mg/kg, oral), ganciclovir (10 or 72 mg/kg, intraperitoneal), or a mycophenolate mofetil and ganciclovir combination. Grafts were analyzed by histology and morphometry on day 30 after transplant. Numbers of regulatory T cells and donor-specific alloantibodies were examined by fluorescenceactivated cell sorting analysis of splenic tissue and peripheral blood. Results: Mycophenolate mofetil (100 mg/kg) and ganciclovir (10 mg/kg and 72 mg/kg) did not show effects on transplant arteriosclerosis formation or alloantibody production. However, groups treated with mycophenolate mofetil (300 mg/kg) or a lowor high-dose mycophenolate mofetil and ganciclovir combination had significantly reduced transplant arteriosclerosis and alloantibody levels. Expression of regulatory T cells within the spleen was similar between all experimental groups and untreated controls. Conclusions: The combination of mycophenolate mofetil and ganciclovir significantly reduced the development of transplant arteriosclerosis in a mouse abdominal aortic allograft model. This effect may be a result of decreased alloantibody production.

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Small Animal Models of Transplantation

Gunaratnam

Jevnikar

Mannon

2014

Textbook of Organ Transplantation

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HLA Class I Antibodies Provoke Graft Arteriosclerosis in Human Arteries Transplanted into SCID/Beige Mice

Cited by 34 publications

References 22 publications

A Key Role for Matrix Metalloproteinases and Neutral Sphingomyelinase-2 in Transplant Vasculopathy Triggered by Anti-HLA Antibody

A Key Role for Matrix Metalloproteinases and Neutral Sphingomyelinase-2 in Transplant Vasculopathy Triggered by Anti-HLA Antibody

Reduction of Transplant Arteriosclerosis After Treatment With Mycophenolate Mofetil and Ganciclovir in a Mouse Aortic Allograft Model

Small Animal Models of Transplantation

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