title: Defective expression of apoptosis-related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation.
abstract: Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis-related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)-based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL, FAS, FASL, A1, BCL2, BCLXL, CFLIPLand CIAP2 genes were up-regulated after AHSCT. With the exception of BIK, BIMELand A1, all genes reached levels similar to controls at day + 720 post-transplantation. Furthermore, in these patients, we observed increased CD8+Fas+T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPLand CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post-AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXLand CIAP1 was similar to that of controls. Protein analyses showed increased Bcl-2 expression before transplantation. At 1 year post-AHSCT, expression of Bak, Bim, Bcl-2, Bcl-xL and cFlip-L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis-related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re-establishment of immune tolerance during the first 2 years post-transplantation.
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil.|Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: G L V
authors.initials: GL
authors.lastname: de Oliveira
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil.|Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: A F
authors.initials: AF
authors.lastname: Ferreira
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil.
authors.forename: E P L
authors.initials: EP
authors.lastname: Gasparotto
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: S
authors.initials: S
authors.lastname: Kashima
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.|Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: D T
authors.initials: DT
authors.lastname: Covas
authors.affiliation: Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: C T
authors.initials: CT
authors.lastname: Guerreiro
authors.affiliation: Department of Neurology, Psicology and Psiquiatry, School of Medicine of Botucatu, University of State of São Paulo (UNESP), Botucatu.
authors.forename: D G
authors.initials: DG
authors.lastname: Brum
authors.affiliation: Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: A A
authors.initials: AA
authors.lastname: Barreira
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil.|Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: J C
authors.initials: JC
authors.lastname: Voltarelli
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.|Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: B P
authors.initials: BP
authors.lastname: Simões
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.|Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: M C
authors.initials: MC
authors.lastname: Oliveira
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil.
authors.forename: F A
authors.initials: FA
authors.lastname: de Castro
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil.|Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, São Paulo, Brazil, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
authors.forename: K C R
authors.initials: KC
authors.lastname: Malmegrim
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics*; D019172:Transplantation Conditioning / Q000379:methods; D014182:Transplantation, Autologous / Q000379:methods; D055815:Young Adult
chemical_list: D000071187:Autophagy-Related Protein 5; D003520:Cyclophosphamide
keywords: apoptosis-related molecules; autologous haematopoietic stem cell transplantation; autoreactive cells; immune tolerance; multiple sclerosis