title: Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system.
abstract: Clinical trials have indicated that immunoablation followed by autologous hematopoietic stem cell transplantation (ASCT) has the potential to induce clinical remission in patients with refractory systemic lupus erythematosus (SLE), but the mechanisms have remained unclear. We now report the results of a single-center prospective study of long-term immune reconstitution after ASCT in 7 patients with SLE. The clinical remissions observed in these patients are accompanied by the depletion of autoreactive immunologic memory, reflected by the disappearance of pathogenic anti-double-stranded DNA (dsDNA) antibodies and protective antibodies in serum and a fundamental resetting of the adaptive immune system. The latter comprises recurrence of CD31(+)CD45RA(+)CD4(+) T cells (recent thymic emigrants) with a doubling in absolute numbers compared with age-matched healthy controls at the 3-year follow-up (P = .016), the regeneration of thymic-derived FoxP3(+) regulatory T cells, and normalization of peripheral T-cell receptor (TCR) repertoire usage. Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naive B-cell compartment within 1 year after ASCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE.
authors.affiliation: German Rheumatism Research Center, and Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin, Charitéplatz 1, Berlin, Germany. tobias.alexander@charite.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.forename: Andreas
authors.initials: A
authors.lastname: Thiel
authors.forename: Oliver
authors.initials: O
authors.lastname: Rosen
authors.forename: Gero
authors.initials: G
authors.lastname: Massenkeil
authors.forename: Arne
authors.initials: A
authors.lastname: Sattler
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kohler
authors.forename: Henrik
authors.initials: H
authors.lastname: Mei
authors.forename: Hartmut
authors.initials: H
authors.lastname: Radtke
authors.forename: Erika
authors.initials: E
authors.lastname: Gromnica-Ihle
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Renate
authors.initials: R
authors.lastname: Arnold
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood; D001284:Atrophy; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012038:Regeneration / Q000276:immunology; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology / Q000502:physiology; D014182:Transplantation, Autologous; D055815:Young Adult
chemical_list: D000906:Antibodies; D001324:Autoantigens; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell