title: Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation.
abstract: OBJECTIVE
  To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT).
  
  
  METHODS
  Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune-cell subsets were determined by flow cytometry, whereas thymic function was assessed using T-cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous system-autoreactive antigen-specific T-cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T-cell responses.
  
  
  RESULTS
  Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses.
  
  
  CONCLUSIONS
  Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT.
authors: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, and Laboratory of Immunology, University of Montreal Hospital Research Centre, Montreal, Quebec, Canada.
authors: Peter J
authors: PJ
authors: Darlington
authors: Tarik
authors: T
authors: Touil
authors: Jean-Sebastien
authors: JS
authors: Doucet
authors: Denis
authors: D
authors: Gaucher
authors: Joumana
authors: J
authors: Zeidan
authors: Dominique
authors: D
authors: Gauchat
authors: Rachel
authors: R
authors: Corsini
authors: Ho Jin
authors: HJ
authors: Kim
authors: Martin
authors: M
authors: Duddy
authors: Farzaneh
authors: F
authors: Jalili
authors: Nathalie
authors: N
authors: Arbour
authors: Hania
authors: H
authors: Kebir
authors: Jacqueline
authors: J
authors: Chen
authors: Douglas L
authors: DL
authors: Arnold
authors: Marjorie
authors: M
authors: Bowman
authors: Jack
authors: J
authors: Antel
authors: Alexandre
authors: A
authors: Prat
authors: Mark S
authors: MS
authors: Freedman
authors: Harold
authors: H
authors: Atkins
authors: Rafick
authors: R
authors: Sekaly
authors: Remi
authors: R
authors: Cheynier
authors: Amit
authors: A
authors: Bar-Or
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D000068717:Glatiramer Acetate; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D018655:Lymphocyte Count; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D009103:Multiple Sclerosis / Q000473:pathology* / Q000601:surgery*; D004676:Myelin Basic Protein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D018417:Th1 Cells / Q000187:drug effects / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007166:Immunosuppressive Agents; D008222:Lymphokines; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010455:Peptides; C057264:antigen-specific helper factors; D000068717:Glatiramer Acetate