Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts

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Abstract
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.