Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We previously reported that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3 and that anti-LG3 IgG titers are increased in renal transplant patients with acute vascular rejection. Here, we evaluate the potential role of anti-LG3 antibodies as accelerators of vascular injury in a murine model of vascular rejection. Methods We performed passive transfer of 50 ug of anti-LG3 or 50 ug of control IgG every other day during three weeks in an animal model of vascular rejection based on orthotopic aortic transplantation between fully MHC-mismatched mice or in isografted mice as controls. The importance of pre-transplant ischemia for intravascular deposition of anti-LG3 was tested by submitting the aorta to warm ischemia for 15 minutes before harvesting. Transplanted aortas were harvested at 3 weeks post-transplantation. Aortic sections were H/E stained or immunohistochemistry was performed for the detection of NK cells (GM1 Asialo), T cells (CD3) or C4d deposition. Results Passive transfer of anti-LG3 IgGs in mice transplanted with a non-ischemic allograft led to a modest increase in neointima formation (p=0.17). Passive transfer of anti-LG3 in recipients of an ischemic isograft led to a trend towards increased neointima formation but this did not reach statistical significance (p=0.6). In ischemic allografts however, passive anti-LG3 transfer induced striking NK and T cell infiltration (p=0.003 and 0.03 respectively), C4d deposition and enhanced obliterative vascular remodelling(p=0.04). Conclusion These results suggest that anti-LG3 antibodies significantly increase vascular inflammation and obliterative remodelling in allografts exposed to an initial ischemic insult followed by ongoing immune-mediated vascular injury. These data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodelling.

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