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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These authors share senior authorship: Kelen C. R. Malmegrim, Maria Carolina Oliveira.
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Arruda, L.C.M., Lima-Júnior, J.R., Clave, E. et al. Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis. Bone Marrow Transplant 53, 1319–1327 (2018). https://doi.org/10.1038/s41409-018-0162-0
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DOI: https://doi.org/10.1038/s41409-018-0162-0
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