title: Immunological and regenerative aspects of hepatic mast cells in liver allograft rejection and tolerance.
abstract: The precise roles of mast cells in liver allograft rejection and tolerance are still unknown. This study aimed to explore the roles of mast cells in immune regulation and liver regeneration for tolerance induction by using rat models of orthotopic liver transplantation (OLT). Stem cell factor (SCF) and its receptor c-Kit, which are critical to the migration and development of not only stem cells but also mast cells, significantly increased in the tolerogenic livers as compared with rejected livers. The significant elevation of mast cell tryptase, high-affinity IgE receptor, and histamine suggested the activation of mast cells in liver allografts at the tolerogenic phase after OLT. Immunohistochemical analysis using confocal microscope clearly showed colocalization of mast cells, Foxp3+ Tregs, γδ T cells, and recipient-derived hepatic progenitor cells with higher expression of SCF, IL-9, IL-10, TGF-β1, and IL-17 related to immunoregulation and liver regeneration in the donor grafts of a tolerogenic OLT model. Cross-talk among mast cells and other cells was evaluated by in vitro studies demonstrating that syngeneic bone marrow-derived mast cells (BMMCs) co-cultured with naïve splenocytes or primary hepatocytes significantly increased the population of splenic γδ T cells by mitogen stimulation or by mast cell degranulation, and also significantly induced the hepatocyte proliferation, respectively. Our results suggested that mast cells in the donor grafts may play important roles in the induction/maintenance of immune tolerance and liver regeneration resulting in the replacement of hepatic cells from donor to recipient.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Niao-Sung, Taiwan. toshi.nakano@msa.hinet.net
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Lai
authors.forename: Shigeru
authors.initials: S
authors.lastname: Goto
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Hsu
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawamoto
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Ono
authors.forename: Kuang-Den
authors.initials: KD
authors.lastname: Chen
authors.forename: Chih-Che
authors.initials: CC
authors.lastname: Lin
authors.forename: King-Wah
authors.initials: KW
authors.lastname: Chiu
authors.forename: Chih-Chi
authors.initials: CC
authors.lastname: Wang
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Cheng
authors.forename: Chao-Long
authors.initials: CL
authors.lastname: Chen
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008115:Liver Regeneration / Q000502:physiology*; D016031:Liver Transplantation / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D051381:Rats; D013154:Spleen / Q000166:cytology; D019089:Stem Cell Factor / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D020381:Interleukin-17; D019089:Stem Cell Factor; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D019009:Proto-Oncogene Proteins c-kit