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.
Both IgM and IgG anti-blood type A antibodies were induced in wild-type mice by sensitization using human blood type A antigen. Heterotopic ABOi heart transplantation was performed from human blood type A-transgenic C57BL/6J mice to sensitized wild-type DBA/2 mice.
Either anti-C5 antibody or conventional triple immunosuppressants (corticosteroid, tacrolimus, mycophenolate mofetil) 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. T-cell activation and differentiation into Th1, Th2, and Th17 cells were suppressed along with CD49dhighCD4+ T and follicular helper T cells in the combination treatment group. CD24+ B cells, including both CD24+CD23+ marginal zone B cells and CD24+CD23− T2-marginal zone B cells, were increased in the accommodation group.
C5 inhibitor-based immunosuppression induced accommodation in murine ABOi heart transplantation, presenting a promising strategy for ABOi deceased-donor transplantation.
1 Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
2 Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.
3 Biotechnology Research Institute, Celltrion, Inc, Incheon, Republic of Korea.
4 Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
6 Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
7 Department of Pediatrics, Surgery and Immunology, Alberta Transplant Institute, Canadian National Transplant Research Program, University of Alberta, Edmonton, AB, Canada.
8 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
9 Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea.
Received 28 February 2019. Revision received 28 April 2019.
Accepted 17 May 2019.
S.P., J-G.L., and J.Y.J. contributed equally to this article.
S.P., J-G.L., J.C., and J.Y. participated in research design and the writing of the article. S.P., J-G.L., J.Y.J., J-H.R., D.K., and H.K. participated in the performance of the research. S.P., J-G.L., J.Y.J., S.J.C., J.C., L.W., and J.Y. participated in data analysis.
The authors declare no conflicts of interest.
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Correspondence: Jaeseok Yang, MD, PhD, Department of Surgery, Transplantation Center, Seoul National University Hospital, 101 Daehak-no, Jongno-gu, Seoul 03080, Republic of Korea. (firstname.lastname@example.org).