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Mechanisms of human smooth muscle cell proliferation and transplant vasculopathy induced by HLA class I antibodies: in vitro and in vivo studies.: Antibody-induced transplant vasculopathy

Abstract : Vascular smooth muscle cells (SMC) play an important role in the pathophysiology of transplant vasculopathy (TV), a major cause of late death in patients receiving an organ transplant. In this review we describe the proliferative effect in vitro and in vivo of HLA class I antibodies on human SMC. We have developed an experimental model using segments of human mesenteric arteries transplanted in the position of the infrarenal aorta in immunodeficient mice (SCID/beige). Weekly injections of transplanted mice with a monoclonal antibody towards HLA class I provoked typical lesions of TV after 6 weeks in the human graft while transplanted mice receiving an irrelevant antibody did not develop any significant lesion. In vitro, the anti-HLA antibodies were mitogenic to SMC and we showed that they activate a stress-induced signaling pathway implicating matrix metalloproteinases (MMP) and neutral sphingomyelinase 2 (nSMase-2). The proliferative effect of anti-HLA antibodies could be blocked by pharmacological inhibitors or by siRNA. Administration of pharmacological inhibitors diminished the development of TV in grafted mice injected with anti-HLA antibodies demonstrating an important role of the MMP/nSMase-2 pathway in antibody-induced TV. This observation opens new perspectives for the management of TV in clinical settings.
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https://www.hal.inserm.fr/inserm-00726886
Contributor : Marie Francoise Simon <>
Submitted on : Tuesday, September 11, 2012 - 3:27:17 PM
Last modification on : Friday, January 10, 2020 - 9:09:54 PM
Long-term archiving on: : Friday, December 16, 2016 - 9:11:45 AM

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Magali Trayssac, Anne Nègre-Salvayre, Mogens Thomsen. Mechanisms of human smooth muscle cell proliferation and transplant vasculopathy induced by HLA class I antibodies: in vitro and in vivo studies.: Antibody-induced transplant vasculopathy. Human Immunology, Elsevier, 2012, 73 (12), pp.1253-60. ⟨10.1016/j.humimm.2012.06.012⟩. ⟨inserm-00726886⟩

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