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

[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) and PD-1-negative (PD-1) 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 SSc T cells had a different and more regulatory transcriptional profile than the PD-1 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.