Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis.
OBJECTIVE
Autoimmune hepatitis (AIH) is a chronic liver disease caused by impaired immune regulation. Programmed death-1 (PD-1) is an inhibitory receptor mainly expressed by T cells and with its ligands, PD-L1 and PD-L2 present on antigen-presenting cells. We hypothesised the PD-1 axis to be impaired in AIH and investigated systemic levels of soluble(s) PD-1 and T cells ability to up-regulate PD-1 following in vitro activation in AIH patients.


METHODS
We included 67 AIH patients; 9 with active disease, 31 responders and 27 incomplete-responders to standard therapy. Forty-seven healthy controls (HC) were included for comparison. Soluble PD-1 was measured by enzyme-linked immunosorbent assay. The PD-1 expression on T cells was measured using flow cytometry before and after 48-h stimulation in vitro with CD3/CD28 in 13 AIH patients and 10 HC.


RESULTS
Soluble PD-1 was significantly elevated in AIH patients with active disease [0.24 ng/mL (range 0.16-0.28)] and in incomplete responders to standard therapy [0.17 (0.11-0.22)] compared with responders [0.11 (0.08-0.16), p = .008 and p = .01, respectively] and HC [0.12 (0.05-0.16), p = .02, both]. Following in vitro activation, PD-1 was significantly up-regulated (3.3-fold) on CD4+T cells from AIH patients compared with HC (1.5-fold) (p = .0006).


CONCLUSIONS
AIH patients with active disease and incomplete response to standard treatment have similarly increased sPD-1 levels. Further, AIH patients have increased ability to up-regulate PD-1 following in vitro activation. Together these data suggests an impaired PD-1 axis in AIH.
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.
Kristian
K
Aarslev
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.
Anders
A
Dige
b Department of Biomedicine , Aarhus University , Aarhus C , Denmark.
Stinne R
SR
Greisen
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.
Martin
M
Kreutzfeldt
c Department of Endocrinology (MEA) , Aarhus University Hospital , Aarhus C , Denmark.
Niels
N
Jessen
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.
Hendrik
H
Vilstrup
b Department of Biomedicine , Aarhus University , Aarhus C , Denmark.|d Department of Rheumatology , Aarhus University Hospital , Aarhus C , Denmark.
Bent
B
Deleuran
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.
Henning
H
Grønbæk
D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003718:Denmark; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019693:Hepatitis, Autoimmune / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000097:blood*; D015854:Up-Regulation; D055815:Young Adult
D060890:B7-H1 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
Autoimmune hepatitis; helper T cells; human; monocytes; programmed cell death 1 ligand 1 protein; programmed death protein 1