title: Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart.
abstract: This study was performed to investigate how to overcome immunorejection associated with allogeneic stem cell therapy in the infarcted heart. Allogeneic bone marrow mesenchymal stem cell (MSC) differentiation increases major histocompatibility complex II (MHC II) expression, inducing transition from immunoprivileged to immunogenic phenotype. MHC II expression is regulated by the class II transactivator (CIITA). We isolated and characterized mouse and human MSCs and knocked down CIITA expression. Wild-type (WT) or CIITA-knockout (CIITA(-)) mouse MSCs were implanted into infarcted mouse myocardia, and recipient allo-antibody formation, cell survival, and cardiac function were measured. WT mouse and human MSCs that were myogenically differentiated showed increased MHC II and CIITA expression. Differentiated CIITA(-) MSCs lacked MHC II induction and showed reduced cytotoxicity in allogeneic leukocyte coculture. Differentiation of human MSCs increased MHC II expression, which resulted in cytotoxicity in allogeneic leukocyte coculture and was prevented by CIITA small interfering RNA. In contrast to WT MSCs, CIITA(-) MSCs did not initiate recipient allo-antibody formation and instead survived in the injured myocardium and significantly improved ventricular function. Decreasing CIITA expression in allogeneic MSCs abolished MHC II induction during myogenic differentiation and prevented immunorejection of these cells from the infarcted myocardium, which enhanced beneficial functional effects of MSC implantation on myocardial repair.-Huang, X.-P., Ludke, A., Dhingra, S., Guo, J., Sun, Z., Zhang, L., Weisel, R. D., Li, R.-K. Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart.
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Ludke
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Dhingra
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Pathobiology and Immunology, and.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada renkeli@uhnres.utoronto.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators
keywords: cell therapy; immune privilege; myocardial infarction