title: Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.
abstract: Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4(+) T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.
authors.affiliation: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. murarop@ninds.nih.gov
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Amy
authors.initials: A
authors.lastname: Packer
authors.forename: Katherine
authors.initials: K
authors.lastname: Chung
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Guenaga
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cassiani-Ingoni
authors.forename: Catherine
authors.initials: C
authors.lastname: Campbell
authors.forename: Sarfraz
authors.initials: S
authors.lastname: Memon
authors.forename: James W
authors.initials: JW
authors.lastname: Nagle
authors.forename: Frances T
authors.initials: FT
authors.lastname: Hakim
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.forename: Henry F
authors.initials: HF
authors.lastname: McFarland
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D018952:Antigens, CD34 / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D011948:Receptors, Antigen, T-Cell
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