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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.
AuthorsH Cardinal, M Dieudé, N Brassard, S Qi, N Patey, M Soulez, D Beillevaire, F Echeverry, C Daniel, Y Durocher, F Madore, M J Hébert
JournalAmerican journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 13 Issue 4 Pg. 861-874 (Apr 2013) ISSN: 1600-6143 [Electronic] United States
PMID23432943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.
Chemical References
  • Antigens
  • Heparan Sulfate Proteoglycans
  • Immunoglobulin G
  • Recombinant Proteins
  • perlecan
Topics
  • Adult
  • Animals
  • Antigens (immunology)
  • Aorta (pathology)
  • Apoptosis
  • Case-Control Studies
  • Endothelial Cells (pathology)
  • Female
  • Graft Rejection (blood, immunology)
  • Heparan Sulfate Proteoglycans (immunology)
  • Humans
  • Immunization, Passive
  • Immunoglobulin G (blood, immunology)
  • Inflammation (pathology)
  • Kidney (blood supply, pathology)
  • Kidney Transplantation (adverse effects, methods)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Recombinant Proteins (immunology)
  • Retrospective Studies
  • Vascular Diseases (blood, immunology)

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