title: Beneficial effects of the transgenic expression of human sTNF-αR-Fc and HO-1 on pig-to-mouse islet xenograft survival.
abstract: Both human soluble tumor necrosis factor-α receptor-Fc (sTNF-αR-Fc) and heme oxygenase-1 (HO-1) transgenic pigs have been generated previously for xenotransplantation. Here, we investigated whether overexpression of sTNF-αR-Fc or HO-1 in pig islets prolongs islet xenograft survival. Adult porcine islets were isolated from human sTNF-αR-Fc or HO-1 transgenic and wild type pigs, and were transplanted into diabetic nude mice. Effects of the expression of both genes on islet apoptosis, chemokine expression, cellular infiltration, antibody production, and islet xenograft survival were analyzed. Human sTNF-αR-Fc transgenic pigs successfully expressed sTNF-αR-Fc in the islets; human HO-1 transgenic pigs expressed significant levels of HO-1 in the islets. Pig-to-mouse islet xenograft survival was significantly prolonged in both the sTNF-αR-Fc and HO-1 groups compared with that in the wild type group. Both the sTNF-αR-Fc and HO-1 groups exhibited suppressed intragraft expression of monocyte chemoattractant protein-1 (MCP-1) and decreased perigraft infiltration of immune cells. However, there was no difference in the anti-pig antibody levels between the groups. Apoptosis of islet cells during the early engraftment was suppressed only in the HO-1 group. Porcine islets from both sTNF-αR-Fc and HO-1 transgenic pigs prolonged xenograft survival by suppressing islet cell apoptosis or secondary inflammatory responses following islet death, indicating that these transgenic pigs might have applications in successful islet xenotransplantation.
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea.
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Yan
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea.
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Yeom
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea.
authors.forename: Jong Cheol
authors.initials: JC
authors.lastname: Jeong
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea.
authors.forename: Jae-Ghi
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea.
authors.forename: Eun Won
authors.initials: EW
authors.lastname: Lee
authors.affiliation: Institute of Green Bio Science and Technology, Seoul National University, Republic of Korea.
authors.forename: Bumrae
authors.initials: B
authors.lastname: Cho
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea.
authors.forename: Han Sin
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Seoul National University, Republic of Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Graduate School of Medicine, Korea University, Republic of Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea.
authors.forename: Sung Joo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Seoul National University, Republic of Korea.
authors.forename: Byeong-Chun
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea; Institute of Green Bio Science and Technology, Seoul National University, Republic of Korea; Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea; Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: jcyjs@dreamwiz.com.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000097:blood; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D006085:Graft Survival / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011961:Receptors, Fc / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D019076:Transgenes / Q000235:genetics; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000910:Antibodies, Heterophile; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D011961:Receptors, Fc; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Heme oxygenase-1; Islet transplantation; Soluble TNF-α receptor; Transgenic pig; Xenotransplantation