*Purpose: Plasmapheresis in combination with immunoglobulin and rituximab is often used to induce accommodation in ABO-incompatible (ABOi) living-donor transplantation; however, this regimen cannot be applied to cases of ABOi deceased-donor transplantation. Here, we investigated whether an anti-complement component 5 (C5) antibody-based regimen can induce accommodation in ABOi heart transplantation.

*Methods: Sensitization using human blood type A antigen, induced both IgM and IgG anti-A antibodies in wild-type mice. Heterotrophic ABOi heart transplantation was performed from human blood type A-transgenic C57BL/6J mice to sensitized syngeneic wild-type C57BL/6J or allogeneic DBA/2 mice.

*Results: Both anti-C5 antibody and triple immunosuppressants (corticosteroid, tacrolimus, mycophenolate mofetil) suppressed antibody-mediated rejection, immune cell infiltration, and deposition of IgG and C4d in ABOi heart syngrafts. Allogeneic ABOi heart transplantation induced ABMR to greater degree than syngeneic ABOi heart transplantation in mouse models. Either the C5 inhibitor or triple immunosuppressants alone did not induce accommodation in majority of ABOi heart allografts, whereas their combination induced accommodation in more than 70% of cases despite the presence of anti-A antibodies. The combination therapy markedly suppressed the infiltration of T cells and macrophages into ABOi allografts, despite mild deposition of IgG and C4d. Th1, Th2, and Th17 cells were suppressed along with CD49d^highCD4⁺ T and follicular helper T cells in the accommodation group. CD24⁺ B cells including IL-10⁺CD24⁺ B cells, were increased in the accommodation group.

*Conclusions: C5 inhibitor-based immunosuppression induced accommodation in murine ABOi heart transplantation, presenting a promising strategy for ABOi deceased-donor transplantation.

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