Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia

Abstract

Autologous hematopoietic stem cell (HSC) and mesenchymal stem cell (MSC) transplantation is currently being evaluated as a novel treatment for autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we report a case of autologous HSC transplantation combined with MSCs in a 25-year-old severe SLE patient with multiple life-threatening complications and refractory to conventional cyclophosphamide (CYC) therapy. After being pretreated with CYC, ﬂudarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient’s clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. Moreover, CD4+CD25+FoxP3+Treg cells increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This result suggests that the combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission. Although a longer follow-up is required for assessing the long-term efficacy, our present results suggest that the combined transplantation of HSCs and MSCs may be a novel and effective therapy for refractory SLE.

Keywords

Hematopoietic stem cell transplant mesenchymal stem cells systemic lupus erythematosus Treg cells

Get full access to this article

View all access options for this article.

References

Rahman

Isenberg

. Systemic lupus erythematosus. N Engl J Med 2008; 358: 929–939.

Lipsky

. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2001; 2: 764–766.

Shlomchik

Craft

Mamula

. From T to B and back again: Positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1: 147–153.

Burt

Traynor

Statkute

. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 2006; 295: 527–535.

Smith-Berdan

Gille

Weissman

. Reversal of autoimmune disease in lupus-prone New Zealand black/New Zealand white mice by nonmyeloablative transplantation of puriﬁed allogeneic hematopoietic stem cells. Blood 2007; 110: 1370–1378.

Loh

Oyama

Statkute

. Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used. Blood 2007; 109: 2643–2648.

Friedenstein

Chailakhyan

Latsinik

. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues.Cloning in vitro and retransplantation in vivo. Transplantation 1974; 17: 331–340.

Owen

Friedenstein

. Stromal stem cells: Marrow-derived osteogenic precursors. Ciba Found Symp 1998; 136: 42–60.

Nauta

Fibbe

. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499–3506.

10.

Sotiropoulou

Perez

Gritzapis

. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24: 74–85.

11.

Chen

Armstrong

. Mesenchymal stem cells in immunoregulation. Immunol Cell Biol 2006; 84: 413–421.

12.

Burt

Traynor

Pope

. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. Blood 1998; 92: 3505–3514.

13.

Sanna

Bertolaccini

Mathieu

. Central nervous system lupus: A clinical approach to therapy. Lupus 2003; 12: 935–942.

14.

Traynor

Barr

Rosa

. Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis after five years and fifteen patients. Arth Rheum 2002; 46: 2917–2923.

15.

Burt

Marmont

Schroeder

. Intense immune suppression for systemic lupus – the role of hematopoietic stem cells. J Clin Immunol 2000; 20: 31–37.

16.

Alchi

Jayne

Labopin

. Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: Data from the European Group for Blood and Marrow Transplantation registry. Lupus 2013; 22: 245–253.

17.

Euler

Marmont

Bacigalupo

. Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation. Blood 1996; 88: 3621–3625.

18.

Tse

Pendleton

Beyer

. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75: 389–397.

19.

Maccario

Podesta

Moretta

. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005; 90: 516–525.

20.

La Cava

. T-regulatory cells in systemic lupus erythematosus. Lupus 2008; 17: 421–425.

21.

Wang

Zhang

. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: A multicenter clinical study. Arth Res Ther 2014; 25; 16(2): R79–R79.

22.

Wang

Feng

. A CD8 T cell/indoleamine 2,3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus. Arth Rheum 2014; 66: 2234–2245.

23.

Liu

Zhou

. Supplementing mesenchymal stem cells improves the therapeutic effect of hematopoietic stem cell transplantation in the treatment of murine systemic lupus erythematosus. Transplant Proc 2014; 46: 1621–1627.