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

• Published in: International immunology 2021-05, Vol.33 (5), p.261-272
• Main Authors: Ueta, Hisashi, Xu, Xue-Dong, Yu, Bin, Kitazawa, Yusuke, Yu, Enqiao, Hara, Yoshiaki, Morita-Nakagawa, Miwa, Zhou, Shu, Sawanobori, Yasushi, Ueha, Satoshi, Rokutan, Kazuhito, Tanaka, Toshiya, Tokuda, Nobuko, Matsushima, Kouji, Matsuno, Kenjiro
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified - immunology; Antibody Formation - immunology; Antigens, Differentiation - immunology; CD11b Antigen - immunology; CD8-Positive T-Lymphocytes; Dendritic Cells - immunology; Editor's Choice; Graft Rejection - immunology; Graft Survival - immunology; Histocompatibility Antigens Class I - immunology; Immune Tolerance - immunology; Isoantibodies - immunology; Liver Transplantation - methods; Rats; Rats, Inbred Lew; T-Lymphocytes, Regulatory - immunology; Tissue Donors; Transplantation, Homologous - methods
• ISSN: 1460-2377; 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxaa076

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. Antibody-mediated donor-DC depletion prolongs liver-graft survival