title: Costimulation-adhesion blockade is superior to cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation.
abstract: BACKGROUND
  Human embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraftment and survival of hESC derivatives as xenografts or allografts require effective immunosuppression to prevent immune cell infiltration and graft destruction.
  
  
  OBJECTIVE
  To test the hypothesis that a short-course, dual-agent regimen of two costimulation-adhesion blockade agents can induce better engraftment of hESC derivatives compared to current immunosuppressive agents.
  
  
  RESULTS
  We transduced hESCs with a double fusion reporter gene construct expressing firefly luciferase (Fluc) and enhanced green fluorescent protein, and differentiated these cells to endothelial cells (hESC-ECs). Reporter gene expression enabled longitudinal assessment of cell engraftment by bioluminescence imaging. Costimulation-adhesion therapy resulted in superior hESC-EC and mouse EC engraftment compared to cyclosporine therapy in a hind limb model. Costimulation-adhesion therapy also promoted robust hESC-EC and hESC-derived cardiomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardioprotective effect after myocardial injury, as assessed by magnetic resonance imaging. Mechanistically, costimulation-adhesion therapy is associated with systemic and intragraft upregulation of T-cell immunoglobulin and mucin domain 3 (TIM3) and a reduced proinflammatory cytokine profile.
  
  
  CONCLUSIONS
  Costimulation-adhesion therapy is a superior alternative to current clinical immunosuppressive strategies for preventing the post-transplant rejection of hESC derivatives. By extending the window for cellular engraftment, costimulation-adhesion therapy enhances functional preservation following ischemic injury. This regimen may function through a TIM3-dependent mechanism.
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Huber
authors.forename: Julia D
authors.initials: JD
authors.lastname: Ransohoff
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Ransohoff
authors.forename: Johannes
authors.initials: J
authors.lastname: Riegler
authors.forename: Antje
authors.initials: A
authors.lastname: Ebert
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kodo
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Gong
authors.forename: Veronica
authors.initials: V
authors.lastname: Sanchez-Freire
authors.forename: Devaveena
authors.initials: D
authors.lastname: Dey
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Kooreman
authors.forename: Sebastian
authors.initials: S
authors.lastname: Diecke
authors.forename: Wendy Y
authors.initials: WY
authors.lastname: Zhang
authors.forename: Justin
authors.initials: J
authors.lastname: Odegaard
authors.forename: Shijun
authors.initials: S
authors.lastname: Hu
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gold
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D042783:Endothelial Cells / Q000276:immunology / Q000637:transplantation; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000494:pharmacology*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000601:surgery; D011241:Prednisone / Q000494:pharmacology*; D011897:Random Allocation
chemical_list: D000911:Antibodies, Monoclonal; D002316:Cardiotonic Agents; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; C114320:anti-LFA-1 monoclonal antibody; D000069594:Abatacept; D016572:Cyclosporine; D011241:Prednisone
keywords: Costimulation blockade; Embryonic stem cells; Endothelial cells; Immune tolerance; Immunosuppressive drugs; Myocardial infarction
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