Sunjoo Park1, Jae-Ghi Lee1, Joon Young Jang1, Jung-Hwa Ryu2, Dong Jo Kim3, Shin Jae Chang3, Hyori Kim4, Junho Chung5,6, Lori West7, Jaeseok Yang1,2,6,8. 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.
Abstract
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 CD49dCD4 T and follicular helper T cells in the combination treatment group. CD24 B cells, including both CD24CD23 marginal zone B cells and CD24CD23 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.
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 CD49dCD4 T and follicular helper T cells in the combination treatment group. CD24 B cells, including both CD24CD23 marginal zone B cells and CD24CD23 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.
Authors: Andrew B Adams; Brendan P Lovasik; David A Faber; Christopher Burlak; Cynthia Breeden; Jose L Estrada; Luz M Reyes; Rodrigo M Vianna; Matthew F Tector; Alfred J Tector Journal: Ann Surg Date: 2021-09-01 Impact factor: 13.787