title: Mesenchymal stromal cell therapy is associated with increased adenovirus-associated but not cytomegalovirus-associated mortality in children with severe acute graft-versus-host disease.
abstract: Beneficial effects of mesenchymal stromal cells (MSCs) in patients with severe steroid-refractory acute graft-versus-host disease (aGvHD) have been reported. However, controversy exists about the effect of MSCs on virus-specific T cells. We evaluated 56 patients with grade II-IV aGvHD who responded to steroids (n = 21) or were steroid refractory receiving either MSCs (n = 22) or other second-line therapy (n = 13). Although the overall incidence of cytomegalovirus (CMV), Epstein-Barr virus, and human adenovirus (HAdV) infections was not significantly increased, HAdV infection was associated with decreased survival in children treated with MSCs. Thus, we investigated in vitro the effects of MSCs on virus-specific T cells. Both CMV-specific and, to a lesser extent, HAdV-specific T-cell activation and proliferation were negatively affected by MSCs either after induction of a response in peripheral blood mononuclear cells (PBMCs) or after restimulation of virus-specific T-cell lines. In patient-derived PBMCs, CMV-specific proliferative responses were greatly decreased on first-line treatment of aGvHD with systemic steroids and slowly recovered after MSC administration and tapering of steroids. HAdV-specific T-cell proliferation could not be detected. In contrast, the proportion of CMV- and HAdV-specific effector T cells, measured as interferon-γ-secreting cells, remained stable or increased after treatment with MSCs. In conclusion, although in vitro experimental conditions indicated a negative impact of MSCs on CMV- and HAdV-specific T-cell responses, no solid evidence was obtained to support such an effect of MSCs on T-cell responses in vivo. Still, the susceptibility of steroid-refractory severe aGvHD patients to viral reactivation warrants critical viral monitoring during randomized controlled trials on second-line treatment including MSCs.
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada f.g.j.calkoen@lumc.nl.
authors.forename: Friso G J
authors.initials: FG
authors.lastname: Calkoen
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Carly
authors.initials: C
authors.lastname: Vervat
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Astrid G S
authors.initials: AG
authors.lastname: van Halteren
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Veltrop-Duits
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Ball
authors.affiliation: Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Maarten J D
authors.initials: MJ
authors.lastname: van Tol
mesh_terms: D000208:Acute Disease; D000258:Adenovirus Infections, Human / Q000175:diagnosis / Q000276:immunology / Q000401:mortality* / Q000821:virology; D000367:Age Factors; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D018920:Coculture Techniques; D003586:Cytomegalovirus Infections / Q000175:diagnosis / Q000276:immunology / Q000401:mortality* / Q000821:virology; D004351:Drug Resistance; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000401:mortality / Q000601:surgery*; D006801:Humans; D015994:Incidence; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality*; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D012307:Risk Factors; D012720:Severity of Illness Index; D013256:Steroids / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C573415:IFNG protein, human; D013256:Steroids; D007371:Interferon-gamma
keywords: Adenovirus; Bone marrow stromal cells; Cellular therapy; Cytomegalovirus; Hematopoietic stem cell transplantation; T cells