Alterations in the Cellular Immune Compartment of Patients Treated with Third-Party Mesenchymal Stromal Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

Authors

  • Regina Jitschin,

    Corresponding author
    1. Department of Medicine, Karolinska Institutet, Hematology Center, Karolinska University Hospital, Stockholm, Sweden
    • Division of Clinical Immunology, Karolinska University Hospital Huddinge, 14186 Stockholm===

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    • Telephone: 46-85-858-361; Fax: +46 (0)8-585-836-05

  • Dimitrios Mougiakakos,

    1. Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
    2. Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Lena Von Bahr,

    1. Department of Medicine, Karolinska Institutet, Hematology Center, Karolinska University Hospital, Stockholm, Sweden
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Simon Völkl,

    1. Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Guido Moll,

    1. Department of Medicine, Karolinska Institutet, Hematology Center, Karolinska University Hospital, Stockholm, Sweden
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Olle Ringden,

    1. Center for Allogeneic Stem Cell Transplantation and Division of Therapeutic Immunology, Karolinska University Hospital, Stockholm, Sweden
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Rolf Kiessling,

    1. Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Stig Linder,

    1. Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.

  • Katarina Le Blanc

    1. Department of Medicine, Karolinska Institutet, Hematology Center, Karolinska University Hospital, Stockholm, Sweden
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    • Author contributions: R.J. and D.M.: designed the study, performed research, analyzed data, wrote the manuscript; L.V.B.: collected material, provided clinical information; S.V. and G.M.: helped analyzing data; O.R. designed the clinical study, helped writing the manuscript; R.K.: helped designing the experiments; S.L.: performed research; K.L.B.: designed the study, analyzed data, wrote the manuscript. R.J. and D.M. contributed equally to this study.


Abstract

Adoptive transfer of third-party mesenchymal stromal cells (MSCs) has emerged as a promising tool for the treatment of steroid-refractory graft-versus-host disease (GVHD). Despite numerous in vitro studies and preclinical models, little is known about their effects on the patients' immune system. We assessed immune alterations in the T-cell, B-cell, natural killer cell, dendritic cell, and monocytic compartments of steroid-refractory GVHD patients 30, 90, and 180 days after MSC (n = 6) or placebo (n = 5) infusion, respectively. Infused MSCs were bioactive as suggested by the significant reduction in epithelial cell death, which represents a biomarker for acute GVHD. There were several indications that MSCs shift the patients' immune system toward a more tolerogenic profile. Most importantly, infusion of MSCs was associated with increased levels of regulatory (forkhead box P3 (FOXP3)+ and interleukin (IL)-10+) T-cells, reduced pro-inflammatory IL-17+ T(Th17)-cells, and skewing toward type-2 T-helper cell responses. Furthermore, IL-2, which has been recently shown to exert a positive immune modulating effect in GVHD patients, was higher in the MSC patients at all evaluated time points during 6 months after MSC-infusion. Overall, our findings will contribute to the refinement of monitoring tools, for assessing MSC treatment-efficacy and increase our understanding regarding the MSCs' in vivo effects. STEM Cells 2013;31:1715–1725

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