title: The innate immune system contributes to tissue-engineered vascular graft performance.
abstract: The first clinical trial of tissue-engineered vascular grafts (TEVGs) identified stenosis as the primary cause of graft failure. In this study, we aimed to elucidate the role of the host immune response in the development of stenosis using a murine model of TEVG implantation. We found that the C.B-17 wild-type (WT) mouse (control) undergoes a dramatic stenotic response, which is nearly completely abolished in the immunodeficient SCID/beige (bg) variant. SCID mice, which lack an adaptive immune system due to the absence of T and B lymphocytes, experienced rates of stenosis comparable to WT controls (average luminal diameter, WT: 0.071 ± 0.035 mm, SCID: 0.137 ± 0.032 mm, SCID/bg: 0.804 ± 0.039 mm; P < 0.001). The bg mutation is characterized by NK cell and platelet dysfunction, and systemic treatment of WT mice with either NK cell-neutralizing (anti-NK 1.1 antibody) or antiplatelet (aspirin/Plavix [clopidogrel bisulfate]; Asp/Pla) therapy achieved nearly half the patency observed in the SCID/bg mouse (NK Ab: 0.356 ± 0.151 mm, Asp/Pla: 0.452 ± 0.130 mm). Scaffold implantation elicited a blunted immune response in SCID/bg mice, as demonstrated by macrophage number and mRNA expression of proinflammatory cytokines in TEVG explants. Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs.
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Hibino
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Dane
authors.initials: D
authors.lastname: Mejias
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pietris
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Dean
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Best
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shinoka
authors.affiliation: *Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA; and Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA christopher.breuer@nationwidechildrens.org.
authors.forename: Christopher
authors.initials: C
authors.lastname: Breuer
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D001807:Blood Vessel Prosthesis / Q000009:adverse effects / Q000592:standards*; D019917:Blood Vessel Prosthesis Implantation / Q000009:adverse effects / Q000592:standards*; D003251:Constriction, Pathologic / Q000209:etiology / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D007107:Immune System / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D016207:Cytokines; D018836:Inflammation Mediators; C036763:monocyte-macrophage differentiation antigen
keywords: NK cell; macrophage; platelet; stenosis