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

Alexander, Tobias; Thiel, Andreas; Rosen, Oliver; Massenkeil, Gero; Sattler, Arne; Köhler, Siegfried; Mei, Henrik E.; Radtke, H.; Gromnica‐Ihle, Erika; Burmester, Gerd‐Rüdiger; Arnold, Renate; Radbruch, Andreas; Hiepe, Falk

doi:10.1182/blood-2008-07-168286

Cited by 274 publications

(220 citation statements)

References 41 publications

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“…Similar observations on naive and central memory T cells, recent thymic emigrants, and TCR repertoire following AHSCT with SLE patients have also been reported by Alexander et al [18]. Thus, not only do they corroborate the conclusions of Muraro et al [16], but they also suggest that AHSCT has properties that are disease independent.…”

Section: Introductionsupporting

confidence: 88%

“…Indeed, in 2004, Sun et al [19] concluded that the structural and functional phenotypes of reconstituted T cells post-AHSCT were similar to those of pre-transplantation T cells. However, these data were obtained at a 1-year follow-up, whereas the effects in the Muraro et al [16] and Alexander et al [18] studies were observed for a span of 2 years following transplantation. Considering that CD34 + hematopoietic stem cell (HSC) grafts are not instantaneous, and that important expansion of the peripheral T-cell compartment takes place during the first 6 months following AHSCT [16], a 1-year follow-up period may have been insufficient for assessing an immune system reconfiguration that has yet to reach its equilibrium.…”

Section: Introductionmentioning

confidence: 87%

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Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Gosselin

Rivest

2011

Neurotherapeutics

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A recent phase I/II clinical trial drew serious attention to the therapeutic potential of autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis. However, questions were raised as to whether these beneficial effects should be attributed to the newly reconstituted immune system per se, or to the lymphoablative conditioning regimeninduced immunosuppression, given that T-cell depleting combinational drug therapies were used in the study. We discuss here the possibility that both AHSCT and T-cell depleting therapies may re-program alternatively the immune system, and why transplantation of CD34 + hematopoietic stem cells may offer AHSCT a possible advantage regarding longterm remission.

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Section: Introductionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 87%

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Gosselin

Rivest

2011

Neurotherapeutics

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“…The disease in all of these patients was unresponsive to CYC or other immunosuppressants before MSCT. The dose of CYC used in our protocol was much lower than that used in autologous HSCT (5,29). There were no adverse events associated with the preconditioning regimen, and it was well tolerated.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, progressive immunosuppressive therapy may lead to the development of serious infection, cumulative drug toxicity, and an increased risk of cardiovascular disease and malignancy (4). In the last decade, hematopoietic stem cell transplantation (HSCT) has been reported as a promising therapy to achieve treatment-free, long-term remission in lupus (5), but the rates of relapse and treatmentrelated toxicity are high, as are the rates of the development of a secondary autoimmune disorder (6). Therefore, newer therapeutic approaches with enhanced efficacy and less toxicity than current treatment standards are urgently needed.…”

mentioning

confidence: 99%

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Sun

Wang

Liang

et al. 2010

Arthritis & Rheumatism

425

310

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Objective. Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE).Methods. We conducted a single-arm trial that involved 16 SLE patients whose disease was refractory to standard treatment or who had life-threatening visceral involvement. All of the patients gave consent and underwent UC MSCT. Clinical changes were evaluated before and after transplantation using the SLE Disease Activity Index (SLEDAI), measurement of serum antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, serum complement C3 and C4, and albumin levels, and assessment of and renal function. Evaluation of potential mechanisms of MSCT effects focused on the percentage of peripheral blood Treg cells and serum levels of cytokines.Results. From April 2007 to July 2009, a total of 16 patients with active SLE were enrolled and underwent UC MSCT. The median followup time after MSCT was 8.25 months (range 3-28 months). Significant improvements in the SLEDAI score, levels of serum ANA, anti-dsDNA antibody, serum albumin, and complement C3, and renal function were observed. Clinical remission was accompanied by an increase in peripheral Treg cells and a re-established balance between Th1-and Th2-related cytokines. Significant reduction in disease activity was achieved in all patients, and there has been no recurrence to date and no treatment-related deaths.Conclusion. Our findings indicate that UC MSCT results in amelioration of disease activity, serologic changes, and stabilization of proinflammatory cytokines. These data provide a foundation for conducting a randomized controlled trial of this new therapy for severe and treatment-refractory SLE.Systemic lupus erythematosus (SLE) is an inflammatory disease with protean manifestations, ranging from relatively minor skin and joint symptoms to severe life-threatening major organ involvement, such as nephritis and neuropsychiatric complications (1). It is characterized by the presence of autoreactive T and B lymphocytes, with polyclonal activation of B cells and the consequent production of autoantibodies by plasma ClinicalTrials.gov identifier: NCT00698191.

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“…The re-emergence of a functional and diverse adaptive immune system can be thus delayed up to years after HSCT (9). Autologous HSCT-induced lymphopenia can be as profound and lasting as in the setting of allogeneic HSCT.…”

Section: Infectious Complications Of Hsctmentioning

confidence: 99%

Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases

2012

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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

Cited by 274 publications

References 41 publications

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases

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