Swine leukocyte antigen (SLA) induces significant antibody production after pig-to-rhesus monkey kidney xenotransplantation
Hao Feng1,2, Man Zhang1,2, Jiaxiang Du4, Tao Li3, Song Chen1,2, Lan Zhu1,2, Zheng Hu6, Yongguang Yang6, Dengke Pan Pan5, Yi Wang3, Gang Chen1,2.
1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; 2Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, People's Republic of China; 3Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan, Hainan, People's Republic of China; 4Genetic Engineering Department, Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, People's Republic of China; 5Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, People's Republic of China; 6Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, Jilin University, Changchun, People's Republic of China
Background: The generation of glycoprotein galactosyltransferase α 1, 3 (GGTA1) knockout pigs has greatly contributed to the reduction of hyperacute xenograft rejection. However, it is not clear whether porcine major histocompatibility complex antigen SLA can induce significant xenoantibody production in primate recipients after kidney xenotransplantation.
Methods: We have performed six renal xenotransplants in rhesus monkeys using kidneys from GTKO/hCD55 pigs. The recipient monkeys received induction therapy with anti-thymocyte globulin (thymoglobulin) and anti-CD20mAb (rituximab) and maintenance therapy with tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Two of the six recipient monkeys (17R02 and 17R05) generated high levels of circulating antibodies against non-Gal antigens and developed acute humoral xenograft rejection on days 19 and 20. To investigate the presence of anti-SLA antibodies in xenograft rejection, we used serum samples collected before transplantation (day -7) and at the time of rejection (days 19 and 20) to measure IgM/IgG antibody binding against GTKO/hCD55 or GTKO/SLA-I/II KO pig PBMCs by flow cytometry.
Results: The binding of IgM and IgG antibodies to GTKO/hCD55 pig PBMCs was significantly (5 to 10 times) higher in the serum of both monkeys at the time of rejection than in serum collected before transplantation (day -7), indicating that a large proportion of the antibody against non-Gal antigens was newly generated after transplantation. In the serums of both monkeys at the time of rejection, the levels of IgM and IgG binding decreased significantly after the additional deletion of SLA-I/II (IgM decreased by 45% and 83%, IgG decreased by 54.4% and 57.7%, respectively), suggesting that anti-SLA antibodies accounted for about half or more of the non-Gal-specific antibodies generated after transplantation.
Conclusions: In conclusion, we demonstrate for the first time that porcine SLA antigen can induce higher levels of anti-SLA antibodies after xenotransplantation and may play important roles in GTKO pig-to-rhesus monkey xenotransplantation. It is suggested that knockout of the SLA antigen is necessary for pig-to-rhesus xenotransplantation.
Major Scientific and Technological Project of Hainan province (ZDKJ2019009), China.
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