title: Human Wharton's jelly-derived mesenchymal stromal cells engineered to secrete Epstein-Barr virus interleukin-10 show enhanced immunosuppressive properties.
abstract: OBJECTIVE
  Mesenchymal stromal cells (MSCs) modulate the immune response and represent a potential treatment for inflammatory and autoimmune diseases. We hypothesized that this feature could be potentiated by co-administering anti-inflammatory cytokines. In this article, we asked whether engineering of Wharton Jelly-derived human MSCs (WJ-hMSCs) to express an anti-inflammatory cytokine increases cell immunomodulatory properties without altering their native features.
  
  
  METHODS
  We used Epstein-Barr virus-derived interleukin-10 (vIL-10), which shares some immunosuppressive properties with human IL-10 but lacks immunostimulatory activity. Engineering was accomplished by transducing WJ-hMSCs with a self-inactivating feline immunodeficiency virus-derived vector co-expressing vIL-10 and herpes simplex virus type-1 thymidine kinase (TK). TK was added to allow future tracking of WJ-hMSC in vivo by positron electron tomography (PET).
  
  
  RESULTS
  The results show that (i) expression of TK and/or vIL-10 does not change WJ-hMSC phenotypic and functional properties; (ii) vIL-10 is secreted, biologically active and enhances the immunosuppressing functions of WJ-hMSCs; (iii) v-IL10 and TK can be produced simultaneously by the same cells and do not interfere with each other.
  
  
  CONCLUSIONS
  WJ-hMSCs engineered to secrete vIL-10 could be a powerful tool for adoptive cell therapy of immune-mediated diseases, and therefore, additional studies are warranted to confirm their efficacy in suitable animal disease models.
authors.affiliation: Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; ARPA Foundation, Pisa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Quaranta
authors.affiliation: North-Western Tuscany Blood Bank, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Focosi
authors.affiliation: Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Di Iesu
authors.affiliation: Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cursi
authors.affiliation: Transfusion Medicine and Transplant Biology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zucca
authors.affiliation: Transfusion Medicine and Transplant Biology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Curcio
authors.affiliation: Transfusion Medicine and Transplant Biology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Lapi
authors.affiliation: Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Boldrini
authors.affiliation: Center for Spinal Cord Injuries, Department of Neurosciences, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Stampacchia
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Paolicchi
authors.affiliation: Transfusion Medicine and Transplant Biology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Scatena
authors.affiliation: Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Freer
authors.affiliation: Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address: mauro.pistello@med.unipi.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pistello
mesh_terms: D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000235:genetics; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016219:Immunotherapy, Adoptive / Q000379:methods; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D059631:Wharton Jelly / Q000166:cytology* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D016753:Interleukin-10; D013937:Thymidine Kinase
keywords: ELISpot; bicistronic vector; immunosuppression; interferon-γ; lentiviral vectors; thymidine kinase; umbilical cord mesenchymal stromal cells; viral interleukin 10