Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury

Am J Transplant. 2013 Apr;13(4):861-874. doi: 10.1111/ajt.12168. Epub 2013 Feb 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens / immunology
  • Aorta / pathology
  • Apoptosis
  • Case-Control Studies
  • Endothelial Cells / pathology
  • Female
  • Graft Rejection / blood
  • Graft Rejection / immunology*
  • Heparan Sulfate Proteoglycans / immunology*
  • Humans
  • Immunization, Passive
  • Immunoglobulin G / blood*
  • Immunoglobulin G / immunology
  • Inflammation / pathology
  • Kidney / blood supply
  • Kidney / pathology
  • Kidney Transplantation / adverse effects
  • Kidney Transplantation / methods
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Recombinant Proteins / immunology
  • Retrospective Studies
  • Vascular Diseases / blood
  • Vascular Diseases / immunology*

Substances

  • Antigens
  • Heparan Sulfate Proteoglycans
  • Immunoglobulin G
  • Recombinant Proteins
  • perlecan