Direct and indirect effects of alloantibodies link neointimal and medial remodeling in graft arteriosclerosis.
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.


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.
Thaunat
Olivier
O
Université Pierre et Marie Curie-Paris6, INSERM UMRS 681, Centre de recherche des Cordeliers, Paris, France. olivier.thaunatpastu@free.fr
Louedec
Liliane
L
Dai
Jianping
J
Bellier
Florence
F
Groyer
Emilie
E
Delignat
Sandrine
S
Gaston
Anh-Thu
AT
Caligiuri
Giuseppina
G
Joly
Etienne
E
Plissonnier
Didier
D
Michel
Jean-Baptiste
JB
Nicoletti
Antonino
A
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000503:physiopathology; D001161:Arteriosclerosis / Q000276:immunology / Q000503:physiopathology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D002908:Chronic Disease; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000276:immunology / Q000503:physiopathology*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006133:Growth Substances / Q000235:genetics; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D007700:Kinetics; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014019:Tissue Donors; D014158:Transcription, Genetic; D018183:Transplantation Chimera; D017539:Tunica Intima / Q000276:immunology / Q000503:physiopathology*; D017540:Tunica Media / Q000276:immunology / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects
D017077:Culture Media, Conditioned; D006133:Growth Substances; D007518:Isoantibodies