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.
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.
Alexander
Tobias
T
German Rheumatism Research Center, and Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin, Charitéplatz 1, Berlin, Germany. tobias.alexander@charite.de
Thiel
Andreas
A
Rosen
Oliver
O
Massenkeil
Gero
G
Sattler
Arne
A
Kohler
Siegfried
S
Mei
Henrik
H
Radtke
Hartmut
H
Gromnica-Ihle
Erika
E
Burmester
Gerd-Rüdiger
GR
Arnold
Renate
R
Radbruch
Andreas
A
Hiepe
Falk
F
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
D000906:Antibodies; D001324:Autoantigens; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell