213 ABO-tolerance in a murine model of ABO-incompatible heart transplantation (ABOi HTx)
Monday November 16, 2015 from 07:00 to 08:00
Room 109

Lori J. West, Canada

Professor of Pediatrics, Surgery & Immunology

University of Alberta


ABO-tolerance in a murine model of ABO-incompatible heart transplantation (ABOi HTx)

Bruce Motyka1,2, Katrina Labonte1, Fahim H Rahman1, Jean Pearcey1,2, Kesheng Tao1,2, Michael Mengel2,3,4, Banu Sis2,3, Nella Fisicaro5, Peter J Cowan5, Lori J West1,2,4,6.

1Dept of Pediatrics, University of Alberta, Edmonton, AB, Canada; 2Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada; 3Dept of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada; 4Canadian National Transplant Research Program investigator, University of Alberta, Edmonton, AB, Canada; 5Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; 6Depts of Surgery and Medical Microbiology & Immunology, University of Alberta, Edmonton, AB, Canada

Background: ABOi HTx can be performed safely in infants when ABO antibody levels are low or absent. Following ABOi HTx in infants, immune tolerance develops to the donor A/B antigen(s) by mechanisms not well understood. For further study of ABO-related immunobiology in the transplant setting, we generated transgenic mice (A-Tg, C57BL/6 [B6] background) expressing blood group A-antigen on vascular endothelium, and modeled ‘A into O’ ABOi HTx using A-Tg mice as donors and B6 wild-type (WT) mice as recipients. We previously showed that A-Tg heart grafts undergo antibody-mediated rejection (AMR) in adult WT recipients with preformed anti-A antibody. We hypothesized that, in contrast, exposure of young WT mice, lacking anti-A antibodies, to A-Tg heart grafts will result in A-antigen specific tolerance.
Methods: WT mice were transplanted at 4 weeks of age with A-Tg hearts (n=16). Serum anti-A antibodies were measured by agglutination assay. Transplanted mice and non-transplanted littermates (n=16) were injected with human A-erythrocytes (A-RBC) at 3-4 months of age. Grafts were assessed by histology for of AMR.
Results: Anti-A antibodies were detected in only 2/16 transplanted mice at low titre, whereas 8/16 non-transplanted littermates produced anti-A antibody. Following A-RBC injection, anti-A antibodies were detected in 7/16 transplanted mice, however titres remained low (median titre 1:4). All grafts survived and none showed morphological features of AMR, although five grafts showed C4d deposition. In contrast, injection of A-RBC resulted in sensitization of all non-transplanted littermates, inducing high anti-A antibody production (median titre 1:512).
Conclusion: Lack of anti-A antibody production in most transplant recipients compared to non-transplanted littermates, together with failure to effectively sensitize transplanted mice, suggests that exposure of juvenile mice to graft A-antigens resulted in A-antigen specific tolerance. The absence of graft damage in recipients that produced low titre anti-A antibody suggests combined partial tolerance/graft accommodation. This model will prove useful for addressing mechanisms of tolerance/accommodation in ABOi Tx.

Supported by a Heart and Stroke Foundation of Canada Grant-in-Aid. Supported by the Women and Children’s Health Research Institute, University of Alberta. Supported by the Stollery Children’s Hospital Foundation, Edmonton, Alberta.

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