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

Summary 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. In this study we investigate the in vitro effects of prednisolone, 6‐MP, cyclosporine, tacrolimus, MPA and rapamycin – immunosuppressive drugs normally used in the treatment of autoimmune hepatitis (AIH) – on the functional phenotype of peripheral blood‐derived CD4 effectors. We report that in treatment‐naïve patients with AIH, all immunosuppressive drugs restrain Th1 immunity and modulate PD1 expression. Our data also suggest that tacrolimus and cyclosporine may ameliorate effector cell responsiveness to regulatory T cells.