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(Circulation. 2005;112:248-256.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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

Michael Mendicino; MingFeng Liu; Anand Ghanekar, MD; Wei He; Cheryl Koscik; Itay Shalev; Mojib Javadi; Julie Turnbull; Wenhao Chen; Laisum Fung; Seisuke Sakamoto, MD; Phillip Marsden, MD; Thomas K. Waddell, MD, PhD; M. James Phillips, MD; Reginald Gorczynski, MD, PhD; Gary A. Levy, MD; David Grant, MD

From the Multi Organ Transplant Program, University Health Network (M.M., M.L., A.G., W.H., C.K., I.S., M.J., J.T., W.C., L.F., S.S., P.M., T.K.W., M.J.P., R.G., G.A.L., D.G.); Canadian Institutes of Health Research Group on Cellular and Molecular Mechanisms of Organ Injury (M.M., M.L., A.G., C.K., I.S., W.C., P.M., M.J.P., R.G., G.A.L.); Departments of Immunology (M.M., C.K., I.S., M.J., R.G., G.A.L.) and Surgery (A.G., T.K.W., R.G., D.G.), Faculty of Medicine, University of Toronto; Department of Pathology, Hospital For Sick Children (M.J.P.); and St Michael’s Hospital and Department of Medicine, University of Toronto (P.M.), Toronto, Ontario, Canada. Dr Mendicino is a Canadian Institutes of Health Research Trainee in Regenerative Medicine.

Correspondence to Gary A. Levy, MD, Toronto General Hospital, 585 University Ave, 11C-1236, Toronto, Ontario, Canada M5G 2N2. E-mail glfgl2{at}att.global.net

Received March 3, 2004; revision received January 5, 2005; accepted March 8, 2005.

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.

Key Words: apoptosis • endothelium • immunology • thrombosis • transplantation

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