Bone marrow or stem cell transplantation

Oral

Rebooting Autoimmunity After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients by Newly-Generated Regulatory T- and B-Cells

Friday, June 16
3:45 PM - 4:00 PM

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is more effective to treat severe systemic sclerosis (SSc) than conventional immunosuppression (IS). However, its therapeutic mechanisms still need to be understood. Thirty-one transplanted and sixteen IS-treated SSc patients had PBMCs collected before and semiannually until 36 months after inclusion. Immune reconstitution analyses evidenced higher thymic function than baseline at 24 months as measured by β- and signal-joint (sj)-TCR excision circles (sjTREC) RT-qPCR, correlating with CD3+CD4+CD31+CD45RA+ recent thymic emigrants exportation. The TCR new generation sequencing (NGS) depicted higher TCR diversity from 1-2 years post-transplant. Additionally, at 6 months post-AHSCT, increased numbers of CD8+CD28-CD57+ exhausted T-cells correlated with reduced telomere T/S ratio and reduced TCR diversity. CD4+CD25hiFoxP3+(GITR+/CTLA-4+) regulatory T-cells (Tregs) increased at 12 months post-transplantation, correlating with sjTREC values, having higher CD45RA expression and IL-10 production after anti-CD3/CD28 stimulation than baseline. Bone marrow output of naive B-cells, as quantified by coding-joint (Cj) and sj-kappa-deleting recombination excision circles (sjKREC) RT-qPCR, increased from 12-36 months post-AHSCT, resulting in reduced B-cell division (N=LOG(Cj/sjKREC)/LOG2) and persistent increase of CD19+CD27-IgD+ naive and CD19+CD38lowIgD+ Bm2 B-cell counts. Finally, CD19+CD24hiCD38hi regulatory B-cell (Breg) counts increased from 6-12 months post-AHSCT, correlating with sjKREC values and presenting higher IL-10 production after CpG±CD40L stimulation than baseline. Skin biopsies presented higher IL-10 expression at 6-12 months post-transplantation. Six transplanted patients relapsed, presenting lower FoxP3, GITR and CTLA-4 expressions, reduced Breg counts and lower TCR diversity. Our results suggest that increased counts of newly-generated regulatory B- and T-cells post-AHSCT are associated with clinical improvement in SSc patients.

Lucas C. M.. Arruda

Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo

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João R. Lima-Júnior

INCTC, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo

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Emmanuel Clave

Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie

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Daniela A. Moraes

Division of Clinical Immunology, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo

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Corinne Douay

Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie

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Isabelle Fournier

Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie

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Hélène Moins-Teisserenc

Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie

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Dimas T. Covas

INCTC, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo

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Kelen C. R. Malmegrim

INCTC, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo

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Dominique Farge

Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie

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Leandra N. Z. Ramalho

Department of Pathology, Ribeirão Preto Medical School, University of São Paulo

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Maria Carolina Oliveira

Division of Clinical Immunology, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo

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Rebooting Autoimmunity After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients by Newly-Generated Regulatory T- and B-Cells



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