title: Immunogenicity of allogeneic mesenchymal stem cells.
abstract: Mesenchymal stem cells (MSCs) inhibit proliferation of allogeneic T cells and express low levels of major histocompatibility complex class I (MHCI), MHCII and vascular adhesion molecule-1 (VCAM-1). We investigated whether their immunosuppressive properties and low immunophenotype protect allogeneic rat MSCs against cytotoxic lysis in vitro and result in a reduced immune response in vivo. Rat MSCs were partially protected against alloantigen-specific cytotoxic T cells in vitro. However, after treatment with IFN-γ and IL-1β, MSCs upregulated MHCI, MHCII and VCAM-1, and cytotoxic lysis was significantly increased. In vivo, allogeneic T cells but not allogeneic MSCs induced upregulation of the activation markers CD25 and CD71 as well as downregulation of CD62L on CD4(+)  T cells from recipient rats. However, intravenous injection of allo-MSCs in rats led to the formation of alloantibodies with the capacity to facilitate complement-mediated lysis, although IgM levels were markedly decreased compared with animals that received T cells. The allo-MSC induced immune response was sufficient to lead to significantly reduced survival of subsequently injected allo-MSCs. Interestingly, no increased immunogenicity of IFN-γ stimulated allo-MSCs was observed in vivo. Both the loss of protection against cytotoxic lysis under inflammatory conditions and the induction of complement-activating antibodies will likely impact the utility of allogeneic MSCs for therapeutic applications.
authors.affiliation: College of Medicine, Nursing and Health Sciences, School of Medicine, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schu
authors.forename: Mikhail
authors.initials: M
authors.lastname: Nosov
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Flynn
authors.forename: Georgina
authors.initials: G
authors.lastname: Shaw
authors.forename: Oliver
authors.initials: O
authors.lastname: Treacy
authors.forename: Frank
authors.initials: F
authors.lastname: Barry
authors.forename: Mary
authors.initials: M
authors.lastname: Murphy
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
authors.forename: Thomas
authors.initials: T
authors.lastname: Ritter
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D049109:Cell Proliferation; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D011990:Receptors, Transferrin / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous / Q000379:methods*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; D010446:Peptide Fragments; D011990:Receptors, Transferrin; D019010:Vascular Cell Adhesion Molecule-1; C104514:interferon-gamma (95-133); D019041:L-Selectin; D007371:Interferon-gamma