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.


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.
Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
Michael
M
Mendicino
MingFeng
M
Liu
Anand
A
Ghanekar
Wei
W
He
Cheryl
C
Koscik
Itay
I
Shalev
Mojib
M
Javadi
Julie
J
Turnbull
Wenhao
W
Chen
Laisum
L
Fung
Seisuke
S
Sakamoto
Phillip
P
Marsden
Thomas K
TK
Waddell
M James
MJ
Phillips
Reginald
R
Gorczynski
Gary A
GA
Levy
David
D
Grant
D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D015478:Antigens, Heterophile / Q000235:genetics; D003165:Complement System Proteins / Q000032:analysis; D005340:Fibrinogen / Q000235:genetics*; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation; D007132:Immunoglobulin Isotypes / Q000097:blood; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous
D000910:Antibodies, Heterophile; D015478:Antigens, Heterophile; C490637:Fgl2 protein, mouse; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D005340:Fibrinogen; D003165:Complement System Proteins