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

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.

[1]  S. Zhuo,et al.  Transplantation with survivin‐engineered mesenchymal stem cells results in better prognosis in a rat model of myocardial infarction , 2009, European journal of heart failure.

[2]  Lingyun Sun,et al.  Mesenchymal Stem Cell Transplantation Reverses Multiorgan Dysfunction in Systemic Lupus Erythematosus Mice and Humans , 2009, Stem cells.

[3]  S. Itakura,et al.  Mesenchymal stem cells suppress B-cell terminal differentiation. , 2009, Experimental hematology.

[4]  P Rod Dunbar,et al.  Human adipose‐derived stem cells: isolation, characterization and applications in surgery , 2009, ANZ journal of surgery.

[5]  A. Gasbarrini,et al.  Mesenchymal stromal cells multipotency and plasticity: induction toward the hepatic lineage. , 2009, European review for medical and pharmacological sciences.

[6]  Lingyun Sun,et al.  Mesenchymal Stem Cell Transplantation Reverses Multi-Organ Dysfunction in Systemic Lupus Erythematosus Mice and Humans , 2009 .

[7]  O. Rosen,et al.  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. , 2009, Blood.

[8]  Lingyun Sun,et al.  Transplantation of Human Bone Marrow Mesenchymal Stem Cell Ameliorates the Autoimmune Pathogenesis in MRL/lpr Mice , 2008, Cellular and Molecular Immunology.

[9]  S. Kyurkchiev,et al.  Characterization of mesenchymal stem cells isolated from the human umbilical cord , 2008, Cell biology international.

[10]  F. Ezquer,et al.  Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[11]  G. Dini,et al.  Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study , 2008, The Lancet.

[12]  G. Hamdy,et al.  CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematosus (SLE) patients: the possible influence of treatment with corticosteroids. , 2008, Clinical immunology.

[13]  G. Behre,et al.  Marked improvement of severe progressive systemic sclerosis after transplantation of mesenchymal stem cells from an allogeneic haploidentical-related donor mediated by ligation of CD137L , 2008, Leukemia.

[14]  E. Chi,et al.  Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. , 2008, Immunity.

[15]  T. Lehner.  Special regulatory T cell review: The resurgence of the concept of contrasuppression in immunoregulation , 2008, Immunology.

[16]  Yongchang Chen,et al.  Human mesenchymal stem cells isolated from the umbilical cord , 2008, Cell biology international.

[17]  A. Nauta,et al.  Immunomodulatory properties of mesenchymal stromal cells. , 2007, Blood.

[18]  Y. Soong,et al.  Functional Network Analysis of the Transcriptomes of Mesenchymal Stem Cells Derived from Amniotic Fluid, Amniotic Membrane, Cord Blood, and Bone Marrow , 2007, Stem cells.

[19]  Franco Locatelli,et al.  Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. , 2007, Blood.

[20]  Wei-Yuan Zhang,et al.  Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells , 2007, Cell and Tissue Research.

[21]  F. Powrie,et al.  Emerging Challenges in Regulatory T Cell Function and Biology , 2007, Science.

[22]  B. Cohen,et al.  Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used. , 2007, Blood.

[23]  P. Lipsky,et al.  Deficient CD4+CD25high T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus1 , 2007, The Journal of Immunology.

[24]  Deficient CD4 CD25 T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus , 2007 .

[25]  S. Ziegler,et al.  Defective regulatory and effector T cell functions in patients with FOXP3 mutations. , 2006, The Journal of clinical investigation.

[26]  L. Pasquier,et al.  Orphanet Journal of Rare Diseases , 2006 .

[27]  S. Perez,et al.  Interactions Between Human Mesenchymal Stem Cells and Natural Killer Cells , 2006, Stem cells.

[28]  M. Urowitz,et al.  Mortality in systemic lupus erythematosus. , 1987, Arthritis and rheumatism.

[29]  Qin-jun Zhao,et al.  Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. , 2006, Haematologica.

[30]  Yi Zhang,et al.  Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. , 2005, Blood.

[31]  B. Liu,et al.  Characterization and Neural Differentiation of Fetal Lung Mesenchymal Stem Cells , 2005, Cell transplantation.

[32]  A. Rudensky,et al.  TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells , 2005, The Journal of experimental medicine.

[33]  J. Balow.  Clinical presentation and monitoring of lupus nephritis , 2005, Lupus.

[34]  E. Guinan,et al.  Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation , 2003, Transplantation.

[35]  R. Hoffman,et al.  T cells in the pathogenesis of systemic lupus erythematosus. , 2004, Frontiers in bioscience : a journal and virtual library.

[36]  A. Falus,et al.  Measurement of intracellular interferon-gamma and interleukin-4 in whole blood T lymphocytes from patients with systemic lupus erythematosus. , 2000, Immunology letters.

[37]  S. Mujais,et al.  Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study , 2000, The Lancet.

[38]  W. Janssen,et al.  Adult Bone Marrow Stromal Cells Differentiate into Neural Cells in Vitro , 2000, Experimental Neurology.

[39]  R. Shmerling,et al.  The American College of Rheumatology criteria for the classification of systemic lupus erythematosus: Strengths, weaknesses, and opportunities for improvement , 1999, Lupus.

[40]  K. Moore,et al.  IFN-gamma limits macrophage expansion in MRL-Fas(lpr) autoimmune interstitial nephritis: a negative regulatory pathway. , 1998, Journal of immunology.

[41]  D. Prockop.  Marrow Stromal Cells as Stem Cells for Nonhematopoietic Tissues , 1997, Science.

[42]  D. Gladman,et al.  Mortality in systemic lupus erythematosus. , 2006, The Journal of rheumatology. Supplement.

[43]  B. Hahn,et al.  Restricted subpopulations of DNA antibodies in kidneys of mice with systemic lupus. Comparison of antibodies in serum and renal eluates. , 1980, Arthritis and rheumatism.