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

Article

关键词: ENDOTHELIAL-CELLS;    HEME OXYGENASE-1;    HUMAN-COMPLEMENT;    VIRAL-HEPATITIS;    EXPRESSION;    ACTIVATION;    APOPTOSIS;    SURVIVAL;    MICE;    XENOTRANSPLANTATION;   

DOI  :  10.1161/CIRCULATIONAHA.105.534271

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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