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Induction of Accommodation by Anti–complement Component 5 Antibody-based Immunosuppression in ABO-incompatible Heart Transplantation

Park, Sunjoo PhD1; Lee, Jae-Ghi PhD1; Jang, Joon Young BS1; Ryu, Jung-Hwa PhD2; Kim, Dong jo PhD3; Chang, Shin Jae PhD3; Kim, Hyori PhD4; Chung, Junho PhD5,6; West, Lori PhD7; Yang, Jaeseok MD, PhD1,2,6,8

doi: 10.1097/TP.0000000000002808
Original Basic Science—General
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Background. 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. 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.

Results. 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.

Conclusions. 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.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Jaeseok Yang, MD, PhD, Department of Surgery, Transplantation Center, Seoul National University Hospital, 101 Daehak-no, Jongno-gu, Seoul 03080, Republic of Korea. (jcyjs@snu.ac.kr).

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