Key result
Donor Fgl-2 deletion mitigates acute vascular rejection and enables long-term xenograft acceptance in rodents.
Why the study?
Does targeted deletion of Fgl-2 in the donor prevent acute vascular rejection in a mouse-to-rat cardiac xenotransplantation model?
Does targeted deletion of Fgl-2 in the donor prevent acute vascular rejection in a mouse-to-rat cardiac xenotransplantation model?
Targeted deletion of Fgl-2 in donor hearts ameliorates acute vascular rejection and downregulates xenoantigens, suggesting a potential strategy for clinical heart xenotransplantation.
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.
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Mendicino et al. (2005) studied Acute vascular rejection in cardiac xenografts. Targeted deletion of Fgl-2 (Fgl-2-/-) in the donor vs. Fgl-2+/+ (wild-type) grafts was evaluated on Acute vascular rejection and graft acceptance. Targeted deletion of Fgl-2 in donor hearts ameliorated acute vascular rejection by downregulating xenoantigens and, with immunosuppression, led to long-term graft acceptance in a mouse-to-rat model.