title: Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network.
abstract: Despite a rapidly accumulating clinical experience with autologous stem cell transplantation (ASCT) as a treatment for severe refractory autoimmune disease, data on the mechanisms by which ASCT induces immune tolerance are still very scarce. In this study it is shown that ASCT restores immunologic self-tolerance in juvenile idiopathic arthritis (JIA) via 2 mechanisms. First, ASCT induces a restoration of the frequency of FoxP3 expressing CD4+CD25bright regulatory T cells (Tregs) from severely reduced numbers before ASCT to normal levels after ASCT. This recovery is due to a preferential homeostatic expansion of CD4+CD25+ Tregs during the lymphopenic phase of immunereconstitution, as measured by Ki67 and CD44 expression, and to a renewed thymopoiesis of naive mRNA FoxP3 expressing CD4+CD25+ Tregs after ASCT. Second, using artificial antigen-presenting cells to specifically isolate self-reactive T cells, we demonstrate that ASCT induces autoimmune cells to deviate from a proinflammatory phenotype (mRNA interferon-gamma [IFN-gamma] and T-bet high) to a tolerant phenotype (mRNA interleukin-10 [IL-10] and GATA-3 high). These data are the first to demonstrate the qualitative immunologic changes that are responsible for the induction of immune tolerance by ASCT for JIA: the restoration of the CD4+CD25+ immune regulatory network and reprogramming of autoreactive T cells.
authors.affiliation: University Medical Center Utrecht, Wilhelmina Children's Hospital, Home Mailbox KC.03.063.0, Department of Pediatric Immunology, PO Box 85090, 3508 AB Utrecht, The Netherlands. ikleer@umcutrecht.nl
authors.forename: Ismé
authors.initials: I
authors.lastname: de Kleer
authors.forename: Bas
authors.initials: B
authors.lastname: Vastert
authors.forename: Mark
authors.initials: M
authors.lastname: Klein
authors.forename: Gijs
authors.initials: G
authors.lastname: Teklenburg
authors.forename: Ger
authors.initials: G
authors.lastname: Arkesteijn
authors.forename: Gisella Puga
authors.initials: GP
authors.lastname: Yung
authors.forename: Salvo
authors.initials: S
authors.lastname: Albani
authors.forename: Wietse
authors.initials: W
authors.lastname: Kuis
authors.forename: Nico
authors.initials: N
authors.lastname: Wulffraat
authors.forename: Berent
authors.initials: B
authors.lastname: Prakken
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy*; D015704:CD4 Antigens / Q000097:blood*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000097:blood*; D017634:Self Tolerance; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology*; D014182:Transplantation, Autologous
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D007371:Interferon-gamma