Antibody-Mediated Rejection in a Blood Group A-Transgenic Mouse Model of ABO-Incompatible Heart Transplantation.
ABO-incompatible (ABOi) organ transplantation is performed owing to unremitting donor shortages. Defining mechanisms of antibody-mediated rejection, accommodation, and tolerance of ABOi grafts is limited by lack of a suitable animal model. We report generation and characterization of a murine model to enable study of immunobiology in the setting of ABOi transplantation.



Transgenesis of a construct containing human A1- and H-transferases under control of the ICAM-2 promoter was performed in C57BL/6 (B6) mice. A-transgenic (A-Tg) mice were assessed for A-antigen expression by histology and flow cytometry. B6 wild-type (WT) mice were sensitized with blood group A-human erythrocytes; others received passive anti-A monoclonal antibody and complement after heart transplant. Serum anti-A antibodies were assessed by hemagglutination. "A-into-O" transplantation (major histocompatibility complex syngeneic) was modeled by transplanting hearts from A-Tg mice into sensitized or nonsensitized WT mice. Antibody-mediated rejection was assessed by morphology/immunohistochemistry.



A-Tg mice expressed A-antigen on vascular endothelium and other cells including erythrocytes. Antibody-mediated rejection was evident in 15/17 A-Tg grafts in sensitized WT recipients (median titer, 1:512), with 2 showing hyperacute rejection and rapid cessation of graft pulsation. Hyperacute rejection was observed in 8/8 A-Tg grafts after passive transfer of anti-A antibody and complement into nonsensitized recipients. Antibody-mediated rejection was not observed in A-Tg grafts transplanted into nonsensitized mice.



A-Tg heart grafts transplanted into WT mice with abundant anti-A antibody manifests characteristic features of antibody-mediated rejection. These findings demonstrate an effective murine model to facilitate study of immunologic features of ABOi transplantation and to improve potential diagnostic and therapeutic strategies.
1 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. 2 Alberta Transplant Institute, University of Alberta, Edmonton, Alberta, Canada. 3 Canadian National Transplant Research Program, University of Alberta, Edmonton, Alberta, Canada. 4 Immunology Research Centre, St Vincent's Hospital, and Department of Medicine, University of Melbourne, Melbourne, Australia. 5 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada. 6 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada. 7 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
Bruce
B
Motyka
Nella
N
Fisicaro
Szu-I
SI
Wang
Annetta
A
Kratochvil
Katrina
K
Labonte
Kesheng
K
Tao
Jean
J
Pearcey
Thuraya
T
Marshall
Michael
M
Mengel
Banu
B
Sis
Xiaohu
X
Fan
Anthony J F
AJ
dʼApice
Peter J
PJ
Cowan
Lori J
LJ
West
D000017:ABO Blood-Group System / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics; D001787:Blood Group Incompatibility / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D016695:Glycosyltransferases / Q000235:genetics; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D007108:Immune Tolerance; D007150:Immunohistochemistry; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic
D000017:ABO Blood-Group System; D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C480027:ICAM-2 protein, mouse; D016695:Glycosyltransferases