Purpose: ABOi HTx can be performed safely in infants when ABO antibody (Ab) levels are low or absent. Following ABOi HTx, 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 Ab-mediated rejection (AMR) in adult WT recipients with preformed anti-A Ab. We hypothesized that, in contrast, exposure of young WT mice, lacking anti-A Ab, to A-Tg heart grafts will result in A-antigen specific tolerance. Methods: WT mice were transplanted at 4 wk of age with A-Tg hearts (n=12). Serum anti-A Ab were measured by agglutination assay. Transplanted mice and non-transplanted littermates (n=12) were injected with human A-erythrocytes (A-RBC) at 3-4 months of age. Grafts were assessed by histology for features of AMR. Results: Anti-A Ab were detected in only 2/12 transplanted mice at low titre (1:4), whereas 7/12 non-transplanted littermates produced anti-A Ab (median titre 1:8). Following A-RBC injection, anti-A Ab were detected in 6/12 transplanted mice, however titres remained low (median titre 1:4). All grafts survived and none showed morphological features of AMR, although three grafts showed focal deposition of C4d. In contrast, injection of A-RBC resulted in sensitization of all non-transplanted littermates, inducing high anti-A Ab production (median titre 1:512). Conclusion: Lack of anti-A Ab 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 detectable but low titre anti-A Ab suggests combined partial tolerance/graft accommodation. This model will prove useful for addressing mechanisms of tolerance/accommodation in ABOi Tx.

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