title: Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury.
abstract: Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 antibodies of potential importance in regulating allograft vascular injury. We performed a case-control study in which we compared anti-LG3 IgG titers in kidney transplant recipients with AVR (n=15) versus those with acute tubulo-interstitial rejection (ATIR) (n=15) or stable graft function (n=30). Patients who experienced AVR had elevated anti-LG3 titers pre and posttransplantation compared to subjects with ATIR or stable graft function (p<0.05 for both mediators). Elevated pretransplant anti-LG3 titers (OR: 4.62, 95% CI: 1.08-19.72) and pretransplant donor-specific antibodies (DSA) (OR 4.79, 95% CI: 1.03-22.19) were both independently associated with AVR. To address the functional role of anti-LG3 antibodies in AVR, we turned to passive transfer of anti-LG3 antibodies in an animal model of vascular rejection based on orthotopic aortic transplantation between fully MHC-mismatched mice. Neointima formation, C4d deposition and allograft inflammation were significantly increased in recipients of an ischemic aortic allograft passively transferred with anti-LG3 antibodies. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling.
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: H
authors: H
authors: Cardinal
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: M
authors: M
authors: Dieudé
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: N
authors: N
authors: Brassard
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: S
authors: S
authors: Qi
authors: Research Centre, Hôpital Ste-Justine, Montreal, Quebec, Canada.
authors: N
authors: N
authors: Patey
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: M
authors: M
authors: Soulez
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: D
authors: D
authors: Beillevaire
authors: INRS-Institut Armand-Frappier, Laval, QC, Canada.
authors: F
authors: F
authors: Echeverry
authors: INRS-Institut Armand-Frappier, Laval, QC, Canada.
authors: C
authors: C
authors: Daniel
authors: Biotechnology Research Institute, Montreal, QC, Canada.
authors: Y
authors: Y
authors: Durocher
authors: Research Centre, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.
authors: F
authors: F
authors: Madore
authors: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada.
authors: M J
authors: MJ
authors: Hébert
mesh_terms: D000328:Adult; D000818:Animals; D000941:Antigens / Q000276:immunology; D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D016022:Case-Control Studies; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology*; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011994:Recombinant Proteins / Q000276:immunology; D012189:Retrospective Studies; D014652:Vascular Diseases / Q000097:blood / Q000276:immunology*
chemical_list: D000941:Antigens; D019812:Heparan Sulfate Proteoglycans; D007074:Immunoglobulin G; D011994:Recombinant Proteins; C071927:perlecan