title: The Introduction of Human Heme Oxygenase-1 and Soluble Tumor Necrosis Factor-α Receptor Type I With Human IgG1 Fc in Porcine Islets Prolongs Islet Xenograft Survival in Humanized Mice.
abstract: Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase-1 (HO-1) or soluble tumor necrosis factor-α receptor type I with human IgG1 Fc (sTNF-αR-Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO-1, sTNF-αR-Fc, sTNF-αR-Fc/HO-1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood-derived CD34(+) stem cells into NOD-scid-IL-2Rγ(null) mice. Both HO-1 and sTNF-αR-Fc reduced islet apoptosis under in vitro hypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig-to-humanized mice transplantation. The sTNF-αR-Fc/HO-1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor-α and IL-6 in treatment groups; however, frequency of pig-specific interferon-γ-producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO-1 or sTNF-αR-Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO-1 or sTNF-αR-Fc transgenic pigs have potential for islet xenotransplantation.
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J-G
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Yeom
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Chung
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: B
authors.initials: B
authors.lastname: Kang
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Hurh
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: B
authors.initials: B
authors.lastname: Cho
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.|Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Park
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: J I
authors.initials: JI
authors.lastname: Hwang
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.|Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: J B
authors.initials: JB
authors.lastname: Park
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: C
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.|Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000517:prevention & control* / Q000601:surgery; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D007074:Immunoglobulin G; D047888:Receptors, Tumor Necrosis Factor, Type I; D051547:Heme Oxygenase-1
keywords: basic (laboratory) research / science; cell death: apoptosis; cytokines / cytokine receptors; innate immunity; islet transplantation; rejection; xenoantigen; xenotransplantation