title: Rat-to-Chinese tree shrew heart transplantation is a novel small animal model to study non-Gal-mediated discordant xenograft humoral rejection.
abstract: Since α-1,3-galactosyltransferase knockout (GalT-KO) pigs became available, there has been an increasing interest in non-Gal natural antibody (nAb)-mediated xenograft rejection. To better understand mechanisms of non-Gal nAb-mediated rejection, a simple small animal model without gene manipulation would be extremely valuable. Here, we tested whether the Chinese tree shrew (CTS), which is a small-sized mammal that is phylogenetically close to primates, could serve as a model for discordant xenograft rejection.
  
  
  METHODS
  Study 1: Expression of α-Gal antigens in hearts and kidneys of CTSs and rats was assessed by IB4 lectin binding. Presence of anti-Gal and anti-non-Gal IgM and IgG nAb in CTS sera was tested by FACS using Gal+ and GalTKO PBMC as well as BSA-ELISA. Study 2: Rat hearts were transplanted into CTS recipients (group 1, n = 7), and CTS hearts were transplanted in rats [n = 10; seven received no immunosuppression (group 2) and three received FK506 + leflunomide (group 3)].
  
  
  RESULTS
  Study 1: Both CTSs and rats had α-Gal expression in hearts and kidneys. ELISA showed CTSs do not have anti-Gal nAb, and flow cytometry indicated CTSs have anti-non-Gal IgM and IgG nAb in serum. Study 2: Rat hearts in CTSs were uniformly rejected within 35 mins, while CTS hearts in rats continued beating until day 5 without immunosuppression, and up to day 8 with immunosuppression.
  
  
  CONCLUSIONS
  Rat-to-CTS heart transplantation is a discordant xenotransplant model, CTS-to-Rat heart transplantation is a concordant xenotransplant model. CTSs are valuable small animals to study mechanisms and strategies to avoid non-Gal nAb-mediated xenograft rejection.
authors.affiliation: Organ Transplantation Institute, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: WeiLi
authors.initials: W
authors.lastname: Chen
authors.affiliation: Organ Transplantation Institute, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Organ Transplantation Institute, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: YinLong
authors.initials: Y
authors.lastname: Lian
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tasaki
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Villani
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Moran
authors.affiliation: Organ Transplantation Institute, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: JunJie
authors.initials: J
authors.lastname: Xia
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.|Organ Replacement and Xenotransplantation Surgery, Center for Advanced Biomedical Science and Swine Research, Kagoshima University, Kagoshima, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Organ Transplantation Institute, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: ZhongQuan
authors.initials: Z
authors.lastname: Qi
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D004195:Disease Models, Animal; D005700:Galactosyltransferases / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000379:methods; D064593:Heterografts / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D051381:Rats; D012788:Shrews; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: D000941:Antigens; D005700:Galactosyltransferases
keywords: Chinese tree shrews; animal model; cardiac transplantation; xenograft rejection; xenotransplantation