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Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization

OBJECTIVE: Antibody-mediated rejection (AMR) could induce acute or chronic graft failure during organ transplantation. Several reports have shown that anti-C5 antibodies are effective against AMR after kidney transplantation. However, few reports have assessed the efficacy of anti-C5 antibodies agai...

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Autores principales: Shiina, Yuki, Suzuki, Hidemi, Hata, Atsushi, Kaiho, Taisuke, Matsumoto, Hiroki, Toyoda, Takahide, Sakairi, Yuichi, Wada, Hironobu, Motohashi, Shinichiro, Yoshino, Ichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663404/
https://www.ncbi.nlm.nih.gov/pubmed/35767165
http://dx.doi.org/10.1007/s11748-022-01844-0
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author Shiina, Yuki
Suzuki, Hidemi
Hata, Atsushi
Kaiho, Taisuke
Matsumoto, Hiroki
Toyoda, Takahide
Sakairi, Yuichi
Wada, Hironobu
Motohashi, Shinichiro
Yoshino, Ichiro
author_facet Shiina, Yuki
Suzuki, Hidemi
Hata, Atsushi
Kaiho, Taisuke
Matsumoto, Hiroki
Toyoda, Takahide
Sakairi, Yuichi
Wada, Hironobu
Motohashi, Shinichiro
Yoshino, Ichiro
author_sort Shiina, Yuki
collection PubMed
description OBJECTIVE: Antibody-mediated rejection (AMR) could induce acute or chronic graft failure during organ transplantation. Several reports have shown that anti-C5 antibodies are effective against AMR after kidney transplantation. However, few reports have assessed the efficacy of anti-C5 antibodies against AMR after lung transplantation. Therefore, this study aimed to evaluate the efficacy of this novel therapy against AMR after lung transplantation. METHODS: BALB/c and C57BL/6 mice were used as donors and recipients. One group was pre-sensitized (PS) by skin transplantation 14 days before lung transplantation. The other group was non-sensitized (NS). Orthotopic left-lung transplantation was performed in both groups. Animals were killed at 2 or 7 days after lung transplantation and evaluated for histopathology, C4d immunostaining, and serum donor-specific antibodies (DSAs) (n = 5 per group). Isograft (IS) models with C57BL/6 mice were used as controls. To evaluate the efficacy of C5 inhibition, other animals, which received similar treatments to those in the PS group, were treated with anti-C5 antibodies, cyclosporine/methylprednisolone, anti-C5 antibodies/cyclosporine/methylprednisolone, or isotype-matched irrelevant control monoclonal antibodies (n = 5 per group). RESULTS: Two days after lung transplantation, the NS group exhibited mild, localized graft-rejection features (rejection score: 0.45 ± 0.08, p = 0.107). The PS group exhibited AMR features with a significantly higher rejection score (2.29 ± 0.42, p = 0.001), C4d vascular-endothelium deposition, and substantial presence of serum DSA. On day 7 after lung transplantation, both groups showed extensive graft alveolar wall destruction, and high acute-rejection scores. Mice receiving anti-C5 antibodies or anti-C5/antibodies/cyclosporine/methylprednisolone demonstrated significantly lower acute-rejection scores (0.63 ± 0.23, p = 0.002; 0.59 ± 0.22, p = 0.001, respectively) than those receiving isotype control antibodies. CONCLUSIONS: Murine orthotopic allograft lung transplant models met the clinical diagnosis and pathogenesis classification criteria of AMR. In these models, anti-C5 antibodies suppressed AMR. Therefore, anti-C5 therapy may be effective against AMR after lung transplantation.
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spelling pubmed-96634042022-11-15 Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization Shiina, Yuki Suzuki, Hidemi Hata, Atsushi Kaiho, Taisuke Matsumoto, Hiroki Toyoda, Takahide Sakairi, Yuichi Wada, Hironobu Motohashi, Shinichiro Yoshino, Ichiro Gen Thorac Cardiovasc Surg Original Article OBJECTIVE: Antibody-mediated rejection (AMR) could induce acute or chronic graft failure during organ transplantation. Several reports have shown that anti-C5 antibodies are effective against AMR after kidney transplantation. However, few reports have assessed the efficacy of anti-C5 antibodies against AMR after lung transplantation. Therefore, this study aimed to evaluate the efficacy of this novel therapy against AMR after lung transplantation. METHODS: BALB/c and C57BL/6 mice were used as donors and recipients. One group was pre-sensitized (PS) by skin transplantation 14 days before lung transplantation. The other group was non-sensitized (NS). Orthotopic left-lung transplantation was performed in both groups. Animals were killed at 2 or 7 days after lung transplantation and evaluated for histopathology, C4d immunostaining, and serum donor-specific antibodies (DSAs) (n = 5 per group). Isograft (IS) models with C57BL/6 mice were used as controls. To evaluate the efficacy of C5 inhibition, other animals, which received similar treatments to those in the PS group, were treated with anti-C5 antibodies, cyclosporine/methylprednisolone, anti-C5 antibodies/cyclosporine/methylprednisolone, or isotype-matched irrelevant control monoclonal antibodies (n = 5 per group). RESULTS: Two days after lung transplantation, the NS group exhibited mild, localized graft-rejection features (rejection score: 0.45 ± 0.08, p = 0.107). The PS group exhibited AMR features with a significantly higher rejection score (2.29 ± 0.42, p = 0.001), C4d vascular-endothelium deposition, and substantial presence of serum DSA. On day 7 after lung transplantation, both groups showed extensive graft alveolar wall destruction, and high acute-rejection scores. Mice receiving anti-C5 antibodies or anti-C5/antibodies/cyclosporine/methylprednisolone demonstrated significantly lower acute-rejection scores (0.63 ± 0.23, p = 0.002; 0.59 ± 0.22, p = 0.001, respectively) than those receiving isotype control antibodies. CONCLUSIONS: Murine orthotopic allograft lung transplant models met the clinical diagnosis and pathogenesis classification criteria of AMR. In these models, anti-C5 antibodies suppressed AMR. Therefore, anti-C5 therapy may be effective against AMR after lung transplantation. Springer Nature Singapore 2022-06-29 2022 /pmc/articles/PMC9663404/ /pubmed/35767165 http://dx.doi.org/10.1007/s11748-022-01844-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Shiina, Yuki
Suzuki, Hidemi
Hata, Atsushi
Kaiho, Taisuke
Matsumoto, Hiroki
Toyoda, Takahide
Sakairi, Yuichi
Wada, Hironobu
Motohashi, Shinichiro
Yoshino, Ichiro
Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
title Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
title_full Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
title_fullStr Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
title_full_unstemmed Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
title_short Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
title_sort antibodies against complement component c5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663404/
https://www.ncbi.nlm.nih.gov/pubmed/35767165
http://dx.doi.org/10.1007/s11748-022-01844-0
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