Abstract

In the months that follow autologous hematopoietic stem cell transplantation (AHSCT), lymphopenia drives homeostatic proliferation, leading to oligoclonal expansion of residual cells. Here we evaluated how replicative senescent and exhausted cells associated with clinical outcomes of 25 systemic sclerosis (SSc) patients who underwent AHSCT. Patients were clinically monitored for skin (modified Rodnan’s skin score, mRSS) and internal organ involvement and had blood samples collected before and semiannually, until 3 years post-AHSCT, for quantification of telomere length, CD8+CD28 and PD-1+ cells, and serum cytokines. Patients were retrospectively classified as responders (n = 19) and non-responders (n = 6), according to clinical outcomes. At 6 months post-AHSCT, mRSS decreased (P < 0.001) and the pulmonary function stabilized, when compared with pre-transplant measures. In parallel, inflammatory cytokine (IL-6 and IL-1β) levels and telomere lengths decreased, whereas PD-1 expression on T-cells and the number of CD8+CD28 cells expressing CD57 and FoxP3 increased. After AHSCT, responder patients presented higher PD-1 expression on T- (P < 0.05) and B- (P < 0.01) cells, and lower TGF-β, IL-6, G-CSF (P < 0.01), and IL-1β, IL-17A, MIP-1α, and IL-12 (P < 0.05) levels than non-responders. Homeostatic proliferation after AHSCT results in transient telomere attrition and increased numbers of senescent and exhausted cells. High PD-1 expression is associated with better clinical outcomes after AHSCT.

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Acknowledgements

This work was supported by the financial research agencies CNPq, INSERM, and FAPESP (Scholarship numbers: 2013/18678-3, 2014/20922-2; Center for Cell-Based Therapy, CEPID-FAPESP, grant number 2013/08135-2).

Author contributions

MCO and KCRM are the principal investigators and take primary responsibility for the paper. LCMA, KCRM, AT, and MCO designed the study. LCMA, JRL-J, CD, IF, and EC performed the experiments. LCMA, JRL-J, DAM, BPS, and HM-T collected the data and performed data analysis. DTC provided essential funding to the development of this work. LCMA, KCRM, AT, EC, and MCO wrote the final report. All authors contributed to the editing of the final report. All authors agree on all of the content of the submitted manuscript.

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Author notes

  1. These authors contributed equally: Kelen C. R. Malmegrim, Maria Carolina Oliveira.

Affiliations

  1. Basic and Applied Immunology Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    • Lucas C. M. Arruda
    • , Kelen C. R. Malmegrim
    •  & Maria Carolina Oliveira
  2. Center for Cell-based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    • Lucas C. M. Arruda
    • , João R. Lima-Júnior
    • , Dimas T. Covas
    • , Belinda P. Simões
    • , Kelen C. R. Malmegrim
    •  & Maria Carolina Oliveira
  3. Graduate Program on Bioscience Appliedto Pharmacy, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    • João R. Lima-Júnior
  4. INSERM UMR-1160, Institut Universitaire d’Hématologie, Hôpital Saint-Louis-APHP, Paris, France

    • Emmanuel Clave
    • , Corinne Douay
    • , Isabelle Fournier
    • , Hélène Moins-Teisserenc
    • , Dominique Farge
    •  & Antoine Toubert
  5. Université Paris Diderot, Sorbonne Paris Cité, Paris, France

    • Emmanuel Clave
    • , Hélène Moins-Teisserenc
    • , Dominique Farge
    •  & Antoine Toubert
  6. Division of Clinical Immunology, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    • Daniela A. Moraes
    • , Belinda P. Simões
    •  & Maria Carolina Oliveira
  7. Unité Clinique de Médecine Interne, Maladies Autoimmunes et Pathologie Vasculaire, UF 04 AP-HP, Hôpital Saint-Louis, Denis Diderot University (Paris 7), Paris, France

    • Dominique Farge
  8. Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    • Kelen C. R. Malmegrim

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Correspondence to Maria Carolina Oliveira.

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DOI

https://doi.org/10.1038/s41409-018-0162-0

Article notes

These authors contributed equally: Kelen C. R. Malmegrim, Maria Carolina Oliveira.

Article notes

These authors share senior authorship: Kelen C. R. Malmegrim, Maria Carolina Oliveira.