title: Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis.
abstract: Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+CD25-cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4+CD25-cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+CD25-cells more susceptible to Tregcontrol. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs.
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Grant
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.|Department of Paediatrics, Imperial College, London.
authors.forename: B S
authors.initials: BS
authors.lastname: Holder
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.|Gastroenterology Department, Centro Hospitalar São João, Faculty of Medicine of the University of Porto, Porto, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Liberal
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Heneghan
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.|MowatLabs Paediatric Liver, GI and Nutrition Centre, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: D
authors.initials: D
authors.lastname: Vergani
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.|Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: M S
authors.identifier: 0000-0002-4510-1249
authors.initials: MS
authors.lastname: Longhi
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism*; D007700:Kinetics; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016559:Tacrolimus / Q000627:therapeutic use; D018417:Th1 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: C573415:IFNG protein, human; D007166:Immunosuppressive Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D016572:Cyclosporine; D016559:Tacrolimus
keywords: autoimmune hepatitis; co-inhibitory molecules; effector T cells; immunosuppressive drugs; proinflammatory cytokines