Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis

Abstract

Purpose: 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.

Materials and 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.

Keywords:

• Autoimmune hepatitis
• helper T cells
• monocytes
• programmed death protein 1
• human
• programmed cell death 1 ligand 1 protein
• human

Acknowledgements

We highly appreciate the technical support by laboratory technicians Rikke Andersen (Department of Hepatology and Gastroenterology, Aarhus University Hospital) and Karin Skovgaard (Department of Biomedicine). Janssen-Cilag contributed the Orthoclone/OKT3.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

The study was supported by an unrestricted grant from the Lundbeck Foundation, 10.13039/501100003554 [R144-2013-13900]. H.G. has received a clinical research fellowship grant from the NOVO Nordisk Foundation and funding from “Savværksejer Jeppe Juhl og hustru Ovita Juhls Memorial Foundation”.