title: Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation.
abstract: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated destruction of pancreatic β cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis-related gene expression in T1D patients was evaluated before and after treatment with high-dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI-AHSCT). We also correlated gene expression results with clinical response to HDI-AHSCT. We observed a decreased expression of bad, bax and fasL pro-apoptotic genes and an increased expression of a1, bcl-x(L)  and cIAP-2 anti-apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI-AHSCT, we found an up-regulation of fas and fasL and a down-regulation of anti-apoptotic bcl-x(L)  genes expression in post-HDI-AHSCT periods compared to pre-transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl-x(L)  and cIAP-1 genes expression were found similar to controls 2 years after HDI-AHSCT. Furthermore, over-expression of pro-apoptotic noxa at 540 days post-HDI-AHSCT correlated positively with insulin-free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis-related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI-AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI-AHSCT therapy.
authors.affiliation: School of Pharmaceutical Sciences, University of São Paulo, Department of Clinical Analysis, Ribeirão Preto, São Paulo, Brazil.
authors.forename: G L V
authors.initials: GL
authors.lastname: de Oliveira
authors.forename: K C R
authors.initials: KC
authors.lastname: Malmegrim
authors.forename: A F
authors.initials: AF
authors.lastname: Ferreira
authors.forename: R
authors.initials: R
authors.lastname: Tognon
authors.forename: S
authors.initials: S
authors.lastname: Kashima
authors.forename: C E B
authors.initials: CE
authors.lastname: Couri
authors.forename: D T
authors.initials: DT
authors.lastname: Covas
authors.forename: J C
authors.initials: JC
authors.lastname: Voltarelli
authors.forename: F A
authors.initials: FA
authors.lastname: de Castro
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D001323:Autoantibodies / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000601:surgery*; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D005968:Glutamate Decarboxylase / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014182:Transplantation, Autologous; D015854:Up-Regulation; D055815:Young Adult; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2