Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis

Author(s):Show less -

Arruda, Lucas C. M. ^{[1, 2]} ; Lima-Junior, Joao R. ^{[2, 3]} ; Clave, Emmanuel ^{[4, 5]} ; Moraes, Daniela A. ^[6] ; Douay, Corinne ^[5] ; Fournier, Isabelle ^[5] ; Moins-Teisserenc, Helene ^{[4, 5]} ; Covas, Dimas T. ^[2] ; Simoes, Belinda P. ^{[2, 6]} ; Farge, Dominique ^{[4, 5, 7]} ; Toubert, Antoine ^{[4, 5]} ; Malmegrim, Kelen C. R. ^{[1, 8, 2]} ; Oliveira, Maria Carolina ^{[1, 2, 6]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Basic & Appl Immunol Program, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Ctr Cell Based Therapy, Reg Hemotherapy Ctr, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Grad Program Biosci Appliedto Pharm, Ribeirao Preto - Brazil

^[4] Univ Paris Diderot, Sorbonne Paris Cite, Paris - France

^[5] Inst Univ Hematol, Hop St Louis, AP HP, INSERM UMR 1160, Paris - France

^[6] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Div Clin Immunol, Ribeirao Preto - Brazil

^[7] Denis Diderot Univ Paris 7, Hop St Louis, AP HP, UF 04, Unite Clin Med Interne Malad Autoimmunes & Pathol, Paris - France

^[8] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Toxicol & Bromatol Anal, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: BONE MARROW TRANSPLANTATION; v. 53, n. 10, p. 1319-1327, OCT 2018.
• Web of Science Citations: 5

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-1 beta) 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-beta, IL-6, G-CSF (P < 0.01), and IL-1 beta, IL-17A, MIP-1 alpha, and IL-12 (P < 0.05) levels than nonresponders. 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. (AU)

• FAPESP's process: 14/20922-2 - Evaluation of thymic function after autologous hematopoietic stem cell transplantation in systemic sclerosis patients
• Grantee: Lucas Coelho Marlière Arruda
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/18678-3 - Study of immunological mechanisms involved in the therapeutic response of patients with systemic sclerosis to autologous hematopoietic stem cells transplantation
• Grantee: Lucas Coelho Marlière Arruda
• Support Opportunities: Scholarships in Brazil - Doctorate