Targeted deletion of Fgl-2/fibroleukin in the donor modulates immunologic response and acute vascular rejection in cardiac xenografts

Background-Xenografts ultimately fail as a result of acute vascular rejection (AVR), a process characterized by intravascular thrombosis, fibrin deposition, and endothelial cell activation. Methods and Results-We studied whether targeted deletion of Fgl-2, an inducible endothelial cell procoagulant, (Fgl-2^-/-) in the donor prevents AVR in a mouse-to-rat cardiac xenotransplantation model. By 3 days after transplant, Fgl-2^+/+ grafts developed typical features of AVR associated with increased levels of donor Fgl-2 mRNA. Grafts from Fgl-2^-/- mice had reduced fibrin deposition but developed cellular rejection. Treatment with a short course of cobra venom factor and maintenance cyclosporine resulted in long-term acceptance of both Fgl-2^+/+ and Fgl-2^-/- grafts. On withdrawal of cyclosporine, Fgl-2^+/+ grafts developed features of AVR; in contrast, Fgl-2^-/- grafts again developed acute cellular rejection. Rejecting Fgl-2^+/+ hearts stained positively for IgG, IgM, C3, and C5b-9, whereas rejecting Fgl-2^-/- hearts had minimal Ig and complement deposition despite xenoantibodies in the serum. Furthermore, serum containing xenoantibodies failed to stain Fgl-2^-/- long-term treated hearts but did stain wild-type heart tissues. Treatment of Fgl-2^-/- xenografts with mycophenolate mofetil and tacrolimus, a clinically relevant immune suppression protocol, led to long-term graft acceptance. Conclusions-Deletion of Fgl-2 ameliorates AVR by downregulation of xenoantigens and may facilitate successful clinical heart xenotransplantation.