Alteration of Naïve and Memory B‐Cell Subset in Chronic Graft‐Versus‐Host Disease Patients After Treatment With Mesenchymal Stromal Cells

Although mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the immune changes by which MSCs ameliorate cGVHD in vivo. Recent studies have suggested that B lymphocytes might play an important role in the pathogenesis of cGVHD. In this study, we investigated changes in the numbers, phenotypes, and subpopulations of B lymphocytes in cGVHD patients who showed a complete response (CR), partial response (PR), or no response (NR) after MSC treatment. We found that the frequencies and numbers of CD27 memory and pre-germinal center B lymphocytes were significantly increased in the CR and PR cGVHD patients after MSC treatment but decreased in theNR patients. A further analysis of CR/PR cGVHDpatients showed thatMSC treatment led to a decrease in the plasma levels of B cell-activating factor (BAFF) and increased expression of the BAFF receptor (BAFF-R) on peripheral B lymphocytes but no changes in plasma BAFF levels or BAFF-R expression on B lymphocytes in NR patients. Overall, our findings imply that MSCs might exert therapeutic effects in cGVHD patients, accompanied by alteration of näıve and memory B-cell subsets, modulating plasma BAFF levels and BAFF-R expression on B lymphocytes. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:1023–1031

[1]  Bodo Grimbacher,et al.  B-cell biology and development. , 2013, The Journal of allergy and clinical immunology.

[2]  J. Ritz,et al.  B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. , 2012, Blood.

[3]  Armand Keating,et al.  Mesenchymal stromal cells: new directions. , 2012, Cell stem cell.

[4]  Bruce R. Blazar,et al.  Advances in graft-versus-host disease biology and therapy , 2012, Nature Reviews Immunology.

[5]  S. Kim,et al.  B cell homeostasis and the development of chronic graft-versus-host disease: implications for B cell-depleting therapy , 2012, Leukemia & lymphoma.

[6]  Xiaoying Fu,et al.  B lymphocytes that migrate to tuberculous pleural fluid via the SDF‐1/CXCR4 axis actively respond to antigens specific for Mycobacterium tuberculosis , 2011, European journal of immunology.

[7]  Julia Jellusova,et al.  Signaling by the tumor necrosis factor receptor superfamily in B‐cell biology and disease , 2011, Immunological reviews.

[8]  Changyou Wu,et al.  The immune responses of central and effector memory BCG-specific CD4+ T cells in BCG-vaccinated PPD+ donors were modulated by Treg cells. , 2011, Immunobiology.

[9]  R. Storb,et al.  Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. , 2011, Blood.

[10]  Xiaoying Fu,et al.  Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors , 2011, Cellular and Molecular Immunology.

[11]  J. Ritz,et al.  Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. , 2011, Blood.

[12]  J. Tolar,et al.  Mesenchymal stromal cells for graft-versus-host disease. , 2011, Human gene therapy.

[13]  Antonio Uccelli,et al.  Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? , 2010, Current opinion in immunology.

[14]  Y. Min,et al.  Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study , 2010, Haematologica.

[15]  K. Wood,et al.  Mesenchymal stromal cells: facilitators of successful transplantation? , 2010, Cell stem cell.

[16]  A. Xiang,et al.  Mesenchymal stem cell as salvage treatment for refractory chronic GVHD , 2010, Bone Marrow Transplantation.

[17]  R. Bataille,et al.  Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. , 2010, Kidney international.

[18]  F. Mackay,et al.  B‐cell stage and context‐dependent requirements for survival signals from BAFF and the B‐cell receptor , 2010, Immunological reviews.

[19]  M. Suthanthiran,et al.  Identification of a B cell signature associated with renal transplant tolerance in humans. , 2010, The Journal of clinical investigation.

[20]  R. Zhao,et al.  Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[21]  R. Herrmann,et al.  Prochymal Improves Response Rates In Patients With Steroid-Refractory Acute Graft Versus Host Disease (SR-GVHD) Involving The Liver And Gut: Results Of A Randomized, Placebo-Controlled, Multicenter Phase III Trial In GVHD , 2010 .

[22]  J. Ritz,et al.  Current challenges in chronic graft-versus-host disease. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[23]  R. Storb,et al.  The role of B cells in the pathogenesis of graft-versus-host disease. , 2009, Blood.

[24]  H. Jim,et al.  Quality of life after allogeneic hematopoietic cell transplantation. , 2009, Blood.

[25]  J. Ritz,et al.  Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. , 2009, Blood.

[26]  R. Soiffer,et al.  Immune modulation and chronic graft-versus-host disease , 2008, Bone Marrow Transplantation.

[27]  I. Sanz,et al.  Phenotypic and functional heterogeneity of human memory B cells. , 2008, Seminars in immunology.

[28]  M. Kouba,et al.  Elevated numbers of immature/transitional CD21- B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic graft-versus-host disease. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[29]  G. Vogelsang,et al.  Chronic graft versus host disease , 2004, British journal of haematology.

[30]  B. Lahn,et al.  Critical role of phosphoinositide 3-kinase cascade in adipogenesis of human mesenchymal stem cells , 2008, Molecular and Cellular Biochemistry.

[31]  J. Ritz,et al.  High Levels of B-Cell Activating Factor in Patients with Active Chronic Graft-Versus-Host Disease , 2007, Clinical Cancer Research.

[32]  B. Lahn,et al.  Proteomic identification of differently expressed proteins responsible for osteoblast differentiation from human mesenchymal stem cells , 2007, Molecular and Cellular Biochemistry.

[33]  J. Ritz,et al.  Rituximab for steroid-refractory chronic graft-versus-host disease. , 2006, Blood.

[34]  R. Fanin,et al.  The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery. , 2006, Experimental hematology.

[35]  M. Turner,et al.  National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[36]  W. Heath,et al.  B Cells Directly Tolerize CD8+ T Cells , 1998, The Journal of experimental medicine.

[37]  J. Węsierska‐Gądek,et al.  Autoantibodies in chronic GVHD: high prevalence of antinucleolar antibodies. , 1990, Bone marrow transplantation.