{
  "abstract": "Introduction The programmed death 1 (PD-1) pathway decrease immune activity. However, reverse signalling through PD-L1 is proposed to promote myofibroblast differentiation and fibrosis progression. Antibodies towards PD-L1 seem to decrease lung fibrosis in mice models, whereas blocking this pathway with anti-PD-1 increases the burden of interstitial lung disease. Here we investigated the PD-1 pathway in SSc patients in relation to immune activation and fibrosis.Material and Methods Soluble PD-1 was measured in serum from SSc patients and correlated to disease activity. Peripheral blood mononuclear cells (PBMCs), skin and skin fibroblasts from SSc patients and healthy controls (HC) were investigated for activation markers and checkpoint receptors. Cultures were stimulated with TGFa and treated with recombinant PD-1Fc or its isotype. We performed a multiplex mesoscale for immune activation and qPCR for: ICAM, VCAM, PD-L1, IFNy and IL-6. Collagen-1 and fibronectin were measured in supernatants. Lung fibrosis was induced in mice by oropharyngeal delivery of bleomycin, with early murine PD-1Fc treatment at day 1,3,7, and late treatment at day 14 and 21. Systemic inflammation was evaluated by a multiplex cytokine panel and fibrosis was evaluated by histological scoring, soluble collagen in lung tissue and aSMA and CD4 expression in lung sections.Results The PD-1 pathway was upregulated in SSc, with significantly increased cell surface expression of PD-1 and PD-L1 (both p<0.01). Increased sPD-1 in serum correlated with mRSS and FVC (rho:0.37,p=0.03), and PD-1+ and aSMA+ cells localized together in SSc skin. SSc fibroblasts stimulated with TGF-b expressed myofibroblast markers and clustered differently from HC fibroblasts. PD-1Fc decreased the expression of myofibroblast markers, suggesting PD-1Fc to induce endotypic changes in the SSc fibroblasts. In PBMC-fibroblast co-cultures PD-1Fc downregulated pro-inflammatory cytokines, supporting an anti-inflammatory effect. PD-1Fc treatment decreased the production of fibronectin and collagen-1 both in fibroblast mono-cultures and in PBMC-fibroblast co-cultures. In vivo, we demonstrated that both early and late treatment with PD-1Fc decreased lung fibrosis evaluated by histology, and the peripheral inflammatory cytokine profile in bleomycin challenged mice. Only early treatment significantly reduced soluble collagen levels (p>0.01) and aSMA expression in the lungs, whereas no effects were seen on CD4 T cell infiltration.Conclusions Our data strongly suggest that the PD-1 pathway is a central regulator of inflammation and fibrosis in SSc, and targeting this pathway with PD-1Fc can revert myofibroblast-like changes, decrease production of extra cellular matrix proteins and alleviate lung fibrosis in the bleomycin model.",
  "authors": [
    {
      "affiliations": [
        "Department of Biomedicine, Aarhus University, Aarhus, Denmark"
      ],
      "name": "Maithri Aspari"
    },
    {
      "affiliations": [
        "Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, United Kingdom"
      ],
      "name": "Voon Ong"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Aarhus University Hopsital, Aarhus, Denmark"
      ],
      "name": "Klaus Søndergaard"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Aarhus University Hopsital, Aarhus, Denmark"
      ],
      "name": "Esben Næser"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Aarhus University, Aarhus, Denmark",
        "Department of Clinical medicine, Aarhus University, AArhus, Denmark"
      ],
      "name": "Malene Hvid"
    },
    {
      "affiliations": [
        "Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, United Kingdom"
      ],
      "name": "Angela Tam"
    },
    {
      "affiliations": [
        "Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, United Kingdom"
      ],
      "name": "Shiwen Xu"
    },
    {
      "affiliations": [
        "Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, United Kingdom"
      ],
      "name": "Xinyue Bian"
    },
    {
      "affiliations": [
        "Murigenics, San Fransisco, USA"
      ],
      "name": "Henry Lopez"
    },
    {
      "affiliations": [
        "Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, United Kingdom"
      ],
      "name": "Christopher Denton"
    },
    {
      "affiliations": [
        "Department of Inflammation and Rare Diseases, UCL Royal Free Campus, London, United Kingdom"
      ],
      "name": "David Abraham"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Aarhus University, Aarhus, Denmark",
        "Department of Rheumatology, Aarhus University Hopsital, Aarhus, Denmark"
      ],
      "name": "Bent Deleuran"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Aarhus University, Aarhus, Denmark",
        "Department of Rheumatology, Aarhus University Hopsital, Aarhus, Denmark"
      ],
      "name": "Stinne Greisen"
    }
  ],
  "title": "P.029 The PD-1 pathway as a new treatment target in systemic sclerosis",
  "uid": "792a92f5-a260-5b03-add8-491b2ac20f94"
}