Grant CR, Holder BS, Liberal R et al.
Department of Liver Studies; Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King’s College London, Faculty of Life Sciences & Medicine, London, UK.
Clinical and experimental immunology. Mar 2017.
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 the autoimmune liver damage. Herein we investigate the in vitro effects of prednisolone, 6-mercaptopurine, cyclosporine, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of pro-inflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naïve patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of IFNγ, IL17 and TNF-α by CD4 effectors peaks at 48 hours and decreases at 96 hours to reach baseline levels. In contrast, in AIH the expression of all these pro-inflammatory cytokines continue rising between 48 and 96 hours. Levels of PD1, TIM3 and CTLA4 increase over 96-hour culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFNγ and PD1 expression in AIH, where also control over CD4(+) CD25(-) cell proliferation is noted upon exposure to MPA. Treatment with tacrolimus and cyclosporine render CD4(+) CD25(-) cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naïve patients with AIH, all ISDs restrain Th1 cells and modulate PD1 expression. Furthermore, they suggest that tacrolimus and cyclosporine may ameliorate effector cell responsiveness to Tregs. This article is protected by copyright. All rights reserved.