title: In Vivo Interleukin-13-Primed Macrophages Contribute to Reduced Alloantigen-Specific T Cell Activation and Prolong Immunological Survival of Allogeneic Mesenchymal Stem Cell Implants.
abstract: Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue-for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins-is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since "off-the-shelf" cell preparations could be readily available for instant therapeutic intervention following acute injury. Although we confirmed the in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard coculture experiments, allogeneic MSC grafts were irrevocably rejected by the host's immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allogeneic MSC grafts in muscle tissue coincided with the induction of an alternatively activated macrophage phenotype in vivo and a reduced number of alloantigen-reactive IFNγ- and/or IL2-producing CD8(+) T cells compared to nonmodified allografts. Similarly, intracerebral IL13-expressing MSC allografts also exhibited prolonged survival and induction of an alternatively activated macrophage phenotype, although a peripheral T cell component was absent. In summary, this study demonstrates that both innate and adaptive immune responses are effectively modulated in vivo by locally secreted IL13, ultimately resulting in prolonged MSC allograft survival in both muscle and brain tissue. Stem Cells 2016;34:1971-1984.
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Chloé J
authors.initials: CJ
authors.lastname: Hoornaert
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Evi
authors.initials: E
authors.lastname: Luyckx
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristien
authors.initials: K
authors.lastname: Reekmans
authors.affiliation: Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Dhainaut
authors.affiliation: Bio-Imaging Laboratory, University of Antwerp, Antwerp, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Guglielmetti
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Debbie
authors.initials: D
authors.lastname: Le Blon
authors.affiliation: Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
authors.forename: Dearbhaile
authors.initials: D
authors.lastname: Dooley
authors.affiliation: StatUa Centre for Statistics, University of Antwerp, Antwerp, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Jasmijn
authors.initials: J
authors.lastname: Daans
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Louca
authors.initials: L
authors.lastname: Verbeeck
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Quarta
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: De Vocht
authors.affiliation: Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
authors.forename: Evi
authors.initials: E
authors.lastname: Lemmens
authors.affiliation: Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Goossens
authors.affiliation: Bio-Imaging Laboratory, University of Antwerp, Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van der Linden
authors.affiliation: Stem Cell Institute, Stem Cell Biology and Embryology Unit, KU Leuven, Leuven, Belgium.
authors.forename: Valerie D
authors.initials: VD
authors.lastname: Roobrouck
authors.affiliation: Stem Cell Institute, Stem Cell Biology and Embryology Unit, KU Leuven, Leuven, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Verfaillie
authors.affiliation: Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Hendrix
authors.affiliation: Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Moser
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Zwi N
authors.initials: ZN
authors.lastname: Berneman
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Ponsaerts
mesh_terms: D064591:Allografts / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000938:Antigen-Presenting Cells / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D005818:Genetic Engineering; D006085:Graft Survival / Q000276:immunology*; D056747:Immunomodulation / Q000187:drug effects; D018793:Interleukin-13 / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D018793:Interleukin-13; D007519:Isoantigens
keywords: Allogeneic transplantation; Alternative activation; Graft survival; Interleukin-13; Macrophages; Mesenchymal stem cells; T cell activation