Suppression of liver transplant rejection by anti-donor MHC antibodies via depletion of donor immunogenic dendritic cells

Hisashi Ueta, Xue Dong Xu, Bin Yu, Yusuke Kitazawa, Enqiao Yu, Yoshiaki Hara, Miwa Morita-Nakagawa, Shu Zhou, Yasushi Sawanobori, Satoshi Ueha, Kazuhito Rokutan, Toshiya Tanaka, Nobuko Tokuda, Kouji Matsushima, Kenjiro Matsuno

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: We previously found two distinct passenger dendritic cell (DC) subsets in the rat liver that played a central role in the liver transplant rejection. In addition, a tolerance-inducing protocol, donor-specific transfusion (DST), triggered systemic polytopical production of depleting alloantibodies to donor class I MHC (MHCI) antigen (DST-antibodies). METHODS: We examined the role of DST-antibodies in the trafficking of graft DC subsets and the alloresponses in a rat model. We also examined an anti-donor class II MHC (MHCII) antibody that recognizes donor DCs more selectively. RESULTS: Preoperative transfer of DST-antibodies or DST pretreatment eliminated all passenger leukocytes, including both DC subsets and depleted the sessile DCs in the graft to ~20% of control. The CD172a+CD11b/c+ immunogenic subset was almost abolished. The intrahost direct or semi-direct allorecognition pathway was successfully blocked, leading to a significant suppression of the CD8+ T-cell response in the recipient lymphoid organs and the graft with delayed graft rejection. Anti-donor MHCII antibody had similar effects without temporary graft damage. Although DST pretreatment had a priming effect on the proliferative response of recipient regulatory T cells, DST-primed sera and the anti-donor MHCII antibody did not. CONCLUSION: DST-antibodies and anti-donor MHCII antibodies could suppress the CD8+ T-cell-mediated liver transplant rejection by depleting donor immunogenic DCs, blocking the direct or semi-direct pathways of allorecognition. Donor MHCII-specific antibodies may be applicable as a selective suppressant of anti-donor immunity for clinical liver transplantation without the cellular damage of donor MHCII- graft cells and recipient cells.

Original languageEnglish
Pages (from-to)261-272
Number of pages12
JournalInternational immunology
Volume33
Issue number5
DOIs
Publication statusPublished - 22 Apr 2021

Keywords

  • CD8 T cells
  • donor-specific transfusion
  • leukocyte trafficking
  • multicolor immunohistochemistry
  • sensitization pathway

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