Mechanisms of human smooth muscle cell proliferation and transplant vasculopathy induced by HLA class I antibodies: in vitro and in vivo studies.
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.
Inserm UMR 1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France.
Magali
M
Trayssac
Anne
A
Nègre-Salvayre
Mogens
M
Thomsen
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D032389:Myocytes, Smooth Muscle / Q000276:immunology* / Q000378:metabolism*; D014652:Vascular Diseases / Q000276:immunology*
D000906:Antibodies; D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007519:Isoantigens