Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury

• Published in: American journal of transplantation Vol. 13; no. 4; pp. 861 - 874
• Main Authors: Cardinal, H, Dieudé, M, Brassard, N, Qi, S, Patey, N, Soulez, M, Beillevaire, D, Echeverry, F, Daniel, C, Durocher, Y, Madore, F, Hébert, M. J
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.04.2013; Elsevier Limited; Elsevier
• Subjects: Acute rejection; Adult; animal experiment; Animals; antibodies; antibody; antibody titer; Antigens - immunology; Aorta - pathology; Apoptosis; Biological and medical sciences; blood vessel injury; calcineurin inhibitor; Case-Control Studies; CD4 antigen; Endothelial Cells - pathology; endothelium cell; Female; graft recipient; Graft Rejection - blood; Graft Rejection - immunology; graft survival; Hematology; Heparan Sulfate Proteoglycans - immunology; Human health and pathology; Humans; immune mediated injury; Immunization, Passive; immunoglobulin A nephropathy; immunoglobulin G; Immunoglobulin G - blood; Immunoglobulin G - immunology; Immunology; Inflammation - pathology; Kidney - blood supply; Kidney - pathology; kidney allograft rejection; kidney transplantation; Kidney Transplantation - adverse effects; Kidney Transplantation - methods; Life Sciences; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; neointima; perlecan; protein function; Recombinant Proteins - immunology; Retrospective Studies; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; Vascular Diseases - blood; Vascular Diseases - immunology; Graft(material); Acute rejection; Antibody; Acute; Homotransplantation; Trauma; Kidney; Rejection; Treatment; Urinary system; Cell death; Surgery; Blood vessel; Graft; antibodies; Circulatory system; Lesion; Accelerator; Apoptosis; Kidney transplantation; apoptosis; kidney transplantation
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/ajt.12168

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.
NRC publication: Yes