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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2359.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Direct and Indirect Effects of Alloantibodies Link Neointimal and Medial Remodeling in Graft Arteriosclerosis

Olivier Thaunat; Liliane Louedec; Jianping Dai; Florence Bellier; Emilie Groyer; Sandrine Delignat; Anh-Thu Gaston; Giuseppina Caligiuri; Etienne Joly; Didier Plissonnier; Jean-Baptiste Michel; Antonino Nicoletti

From the Université Pierre et Marie Curie-Paris6 (O.T., F.B., E.G., S.D., A.-T.G., G.C., A.N.), INSERM UMRS 681, Centre de recherche des Cordeliers, Paris; INSERM U698 and Université Denis Diderot (L.L., D.J., J.-B.M.), Hopital Xavier Bichat, Paris; INSERM U563 (E.J.), IFR Claude de Preval, Toulouse; and Department of Vascular Surgery (D.P.), Hopital Universitaire de Rouen, France.

Correspondence to Dr Olivier Thaunat, INSERM UMRS 681, Institut Biomedical des Cordeliers, 15 rue de l’école de médecine, 75006 Paris, France. E-mail olivier.thaunatpastu{at}free.fr

Objective— Chronic vascular rejection, the main cause of allograft failure, is characterized by the destruction of smooth muscle cells (SMCs) in the media concomitantly with the proliferation of SMCs in the adjacent neointima. We hypothesized that alloantibodies might be responsible for these 2 opposite but coordinated events.

Methods and Results— We used the rat aortic interposition model of chronic vascular rejection. During the rejection process, a neointima composed of proliferating SMCs from the recipient developed, whereas the SMCs in the media, all of donor origin, underwent apoptosis. Alloantibody deposition was detected only in the media. Using in vitro cultures experiments, we observed that alloantibody binding to donor SMCs exerts (1) a rapid upregulation of the transcription of growth factors genes, followed by (2) the induction of apoptosis after 24 hours. The transient production of growth factors by donor SMCs in response to the binding of alloantibodies induced the proliferation of recipient SMCs in culture supernatant transfer experiments. Additional data suggest that among the repertoire of alloantibodies, those directed against major histocompatibility complex I might carry the remodeling effect.

Conclusions— Our data suggest that during chronic vascular rejection, alloantibody binding to donor medial SMCs is a crucial event that links neointimal and medial remodeling.

A rat model of graft arteriosclerosis was used to show that binding of alloantibodies on SMCs of medial donor sequentially triggers (1) the production of growth factors responsible for the proliferation of recipient SMCs in the neointima and (2) the apoptosis of donor SMCs in the media.

Key Words: anti-MHC antibodies • chronic rejection • graft arteriosclerosis • remodeling • smooth muscle cells

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