Engaging the PD-1 pathway in systemic sclerosis attenuates inflammation-driven fibrosis

Maithri Aspari; Voon Ong; Klaus Søndergaard; Esben Næser; Malene Hvid; Kim Ravnskjaer; Angela Tam; Shiwen Xu; Xinyue Bian; Henry Lopez; Christopher P Denton; David Abraham; Bent Deleuran; Stinne R Greisen

doi:10.1016/j.ard.2026.01.008

Engaging the PD-1 pathway in systemic sclerosis attenuates inflammation-driven fibrosis

Ann Rheum Dis. 2026 Feb 9:S0003-4967(26)00012-9. doi: 10.1016/j.ard.2026.01.008. Online ahead of print.

Authors

Affiliations

¹ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
² Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, UK.
³ Department of Rheumatology, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁴ Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁵ Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
⁶ Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, UK; MuriGenics, Vallejo, San Francisco, CA, USA.
⁷ Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Rheumatology, Aarhus University, Aarhus, Denmark.
⁸ Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Rheumatology, Aarhus University, Aarhus, Denmark. Electronic address: srg@biomed.dk.

PMID: 41667322
DOI: 10.1016/j.ard.2026.01.008

Abstract

Objectives: The study elucidates the impact of the programmed cell death protein 1 (PD-1) pathway on immune activation and fibrosis in diffuse cutaneous systemic sclerosis (dcSSc).

Methods: We obtained blood and skin biopsies from patients with dcSSc and healthy controls (HCs). Soluble PD-1 was measured in serum. Human recombinant PD-1 protein (PD-1:Fc) and anti-PD-1 antibodies were used to stimulate peripheral blood mononuclear cells (PBMCs), HC, and systemic sclerosis (SSc) dermal fibroblast cultures, and cocultures. PD-1-positive (PD-1^pos) and PD-1-negative (PD-1^neg) populations of dcSSc PBMCs were characterised. We used a murine bleomycin model of pulmonary injury to study the effect of PD-1:Fc on pulmonary fibrosis in vivo.

Results: Soluble and cellular PD-1 were elevated in dcSSc compared to HC. Naïve fibroblasts differed between HC and dcSSc, but did not respond to PD-1:Fc treatment. Transforming growth factor β (TGF-β)-stimulated fibroblasts from dcSSc displayed a myofibroblast profile with a differential clustering compared to HC fibroblasts. PD-1:Fc downregulated the secretion of extracellular matrix (ECM) proteins, surface markers of fibroblast activation, and the production of inflammatory cytokines in TGF-β-stimulated in vitro cultures. PD-1^pos SSc T cells had a different and more regulatory transcriptional profile than the PD-1^neg T cell population. In vivo studies demonstrated that treatment with PD-1:Fc inhibited the development of lung fibrosis and the production of profibrotic cytokines.

Conclusions: Administrating PD-1:Fc attenuated inflammation and ECM protein production in dcSSc in vitro models and decreased systemic inflammation and pulmonary fibrosis in the bleomycin-induced fibrosis model in mice. Our data indicate that modulating the PD-1/PD-Ligand 1 axis represents a novel therapeutic avenue in dcSSc.