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

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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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: BONE MARROW TRANSPLANTATION; v. 53, n. 10, p. 1319-1327, OCT 2018.
• Citações Web of Science: 5

Resumo

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)

• Processo FAPESP: 13/18678-3 - Estudo dos mecanismos imunológicos envolvidos na resposta terapêutica de pacientes com esclerose sistêmica ao transplante autólogo de células-tronco hematopoéticas
• Beneficiário: Lucas Coelho Marlière Arruda
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/20922-2 - Avaliação da função tímica após transplante autólogo de células-tronco hematopoéticas em pacientes com esclerose sistêmica
• Beneficiário: Lucas Coelho Marlière Arruda
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs