title: Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients.
abstract: Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T- and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4(+)CD25(hi)FoxP3(+) regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4(+)CD25(hi) T cells. We found transient increase in exhausted PD-1(+) T cells and of suppressive CD8(+)CD28(-)CD57(+) T cells. At baseline, CD4(+) and CD8(+) T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.
authors.affiliation: 1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: L C M
authors.initials: LC
authors.lastname: Arruda
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: J C C
authors.initials: JC
authors.lastname: Lorenzi
authors.affiliation: 1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: A P A
authors.initials: AP
authors.lastname: Sousa
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: D L
authors.initials: DL
authors.lastname: Zanette
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: P V B
authors.initials: PV
authors.lastname: Palma
authors.affiliation: 1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Division of Hematology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: R A
authors.initials: RA
authors.lastname: Panepucci
authors.affiliation: Department of Neuroscience and Behavioral Science, Hospital das Clínicas, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: D S
authors.initials: DS
authors.lastname: Brum
authors.affiliation: Department of Neuroscience and Behavioral Science, Hospital das Clínicas, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: A A
authors.initials: AA
authors.lastname: Barreira
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: D T
authors.initials: DT
authors.lastname: Covas
authors.affiliation: 1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: B P
authors.initials: BP
authors.lastname: Simões
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: W A
authors.initials: WA
authors.lastname: Silva
authors.affiliation: 1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: M C
authors.initials: MC
authors.lastname: Oliveira
authors.affiliation: 1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Department of Clinical, Toxicological and Bromatological Analyses, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: K C R
authors.initials: KC
authors.lastname: Malmegrim
mesh_terms: D000328:Adult; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D019172:Transplantation Conditioning / Q000379:methods*; D014182:Transplantation, Autologous; D055815:Young Adult
chemical_list: D035683:MicroRNAs