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Updated: Mar 22, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Antibody-Mediated Rejection in a Blood Group A-Transgenic Mouse Model of ABO-Incompatible Heart Transplantation
Bruce Motyka1, Nella Fisicaro, Szu-I Wang
11 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.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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