title: Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressive Effects of Mycophenolate Mofetil and Hepatitis B Virus Infection.
abstract: The purpose of this study is to investigate whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) affect the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBV) infection. Hepatic NK cells were isolated from C57BL/6 and C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice treated with MMF in the presence or absence of IL-15. After incubation of isolated hepatic NK cells in the presence or absence of MPA, reverse transcription polymerase chain reaction and immunolabeling were used to assess the expression of NK receptors Ly49A, NKG2A and NKG2D. In addition, cytokine enzyme-linked immunosorbent assay and [H]-TdR-release assay were carried out to assess NK cell activation and cytotoxic capacity. After treatment with MMF in the presence or absence of IL-15, HBsAg titers were measured in C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice. Treatment with either MPA or MMF resulted in reduced NK cell cytotoxicity, downregulated NKG2D and Ly49A expression and upregulated NKG2A. Interestingly, NKG2D downregulation was ameliorated by IL-15. In HBV-transgenic mice, MMF treatment impaired NK cell activity but did not affect virus replication, whereas IL-15 treatment reduced HBsAg titers. MPA and MMF mediate NKG2D downregulation both in vitro and in vivo, reducing the cytotoxic capacity of NK cells. These findings indicate that NKG2D regulation may be important in the immunosuppressive effect NK cells and involved in HBV infection.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital, College of Medicine, ZheJiang University, Hangzhou, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Dong
authors.forename: Lei
authors.initials: L
authors.lastname: Geng
authors.forename: Miao-Da
authors.initials: MD
authors.lastname: Shen
authors.forename: Shu-Sen
authors.initials: SS
authors.lastname: Zheng
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006509:Hepatitis B / Q000276:immunology / Q000473:pathology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid