Elimination of GGTA1,CMAH,β4GalNT2 and CIITA genes in pigs compromises human versus pig xenogeneic immune reactions  

作　　者：Jing Xu Jilong Ren Kai Xu Minghui Fang Meina Ka Fei Xu Xin Wang Jing Wang Zhiqiang Han Guihai Feng Ying Zhang Tang Hai Wei Li Zheng Hu 

机构地区：[1]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China [2]Key Laboratory of Organ Regeneration and Reconstruction,Chinese Academy of Sciences,Beijing,China [3]University of Chinese Academy of Sciences,Beijing,China [4]Beijing Institute for Stem Cell and Regenerative Medicine,Beijing,China [5]Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education,The First Hospital,Jilin University,Changchun,China [6]Beijing Farm Animal Research Center,Institute of Zoology,Chinese Academy of Sciences,Beijing,China

出　　处：《Animal Models and Experimental Medicine》2024年第4期584-590,共7页动物模型与实验医学（英文）

基　　金：National Key Research and Development Program,Grant/Award Number:2019YFA0903800,2021YFA0805701,2021YFA0805905 and 2022YFA1103603;CAS Project for Young Scientists in Basic Research,Grant/Award Number:YSBR-012;STI 2030-Major Project,Grant/Award Number:2023ZD0407503;National Natural Science Foundation of China,Grant/Award Number:32071456 and 82241224;Strategic Priority Research Program of the Chinese Academy of Sciences,Grant/Award Number:XDA16030000。

摘　　要：Background:Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic,while immunogenic genes need to be eliminated to improve the immune compatibility between humans and pigs.Current knockout strategies are mainly aimed at the genes causing hyperacute immune rejection(HAR)that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure,in which process the MHCⅡmolecule plays critical roles.Methods:Thus,we generate a 4-gene(GGTA1,CMAH,β4GalNT2,and CIITA)knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions simultaneously.Results:We successfully obtained 4KO piglets with deficiency in all alleles of genes,and at cellular and tissue levels.Additionally,the safety of our animals after gene editing was verified by using whole-genome sequencing and karyotyping.Piglets have survived for more than one year in the barrier,and also survived for more than 3 months in the conventional environment,suggesting that the piglets without MHCⅡcan be raised in the barrier and then gradually mated in the conventional environment.Conclusions:4KO piglets have lower immunogenicity,are safe in genomic level,and are easier to breed than the model with both MHCⅠandⅡdeletion.

关 键 词：CD4 T cell genetically edited pig immune rejection major histocompatibility complex II XENOTRANSPLANTATION 

分 类 号：R392[医药卫生—免疫学]