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
- 1 January 2009
- journal article
- clinical trial
- Published by American Society of Hematology in Blood
- Vol. 113 (1), 214-223
- https://doi.org/10.1182/blood-2008-07-168286
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. This trial was registered at www.clinicaltrials.gov as #NCT00742300.Keywords
This publication has 39 references indexed in Scilit:
- Duration of Humoral Immunity to Common Viral and Vaccine AntigensNew England Journal of Medicine, 2007
- Direct access to CD4+ T cells specific for defined antigens according to CD154 expressionNature Medicine, 2005
- B lymphocyte reconstitution after hematopoietic stem cell transplantation: functional immaturity and slow recovery of memory CD27+ B cellsExperimental Hematology, 2005
- Short-lived Plasmablasts and Long-lived Plasma Cells Contribute to Chronic Humoral Autoimmunity in NZB/W MiceThe Journal of Experimental Medicine, 2004
- Homeostatic Expansion of T Cells during Immune Insufficiency Generates AutoimmunityCell, 2004
- Identification and characterization of SmD183–119‐reactive T cells that provide T cell help for pathogenic anti–double‐stranded DNA antibodiesArthritis & Rheumatism, 2003
- Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral BloodThe Journal of Experimental Medicine, 2002
- Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?Blood, 2002
- From T to B and back again: positive feedback in systemic autoimmune diseaseNature Reviews Immunology, 2001
- Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitutionThe Lancet, 2000