Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis

Clin Exp Immunol. 2017 Jul;189(1):71-82. doi: 10.1111/cei.12956. Epub 2017 Mar 27.


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 Treg control. 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 .

Keywords: autoimmune hepatitis; co-inhibitory molecules; effector T cells; immunosuppressive drugs; proinflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Cell Proliferation
  • Child
  • Cyclosporine / therapeutic use
  • Female
  • Hepatitis, Autoimmune / drug therapy*
  • Hepatitis, Autoimmune / immunology
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Interferon-gamma / metabolism*
  • Kinetics
  • Middle Aged
  • Programmed Cell Death 1 Receptor / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • Tacrolimus / therapeutic use
  • Th1 Cells / immunology*
  • Young Adult


  • IFNG protein, human
  • Immunosuppressive Agents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma
  • Cyclosporine
  • Tacrolimus