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.