Kidney transplantation from triple‐knockout pigs expressing multiple human proteins in cynomolgus macaques

• Published in: American journal of transplantation Vol. 22; no. 1; pp. 46 - 57
• Main Authors: Ma, David, Hirose, Takayuki, Lassiter, Grace, Sasaki, Hajime, Rosales, Ivy, Coe, Taylor M., Rickert, Charles G., Matheson, Rudy, Colvin, Robert B., Qin, Wenning, Kan, Yinan, Layer, Jacob V., Paragas, Violette B., Stiede, Kathryn, Hall, Katherine C., Youd, Michele E., Queiroz, Luis M., Westlin, William F., Curtis, Michael, Yang, Luhan, Markmann, James F., Kawai, Tatsuo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.01.2022; John Wiley and Sons Inc
• Subjects: Animals; Animals, Genetically Modified; Antibodies; CD4 antigen; Complement regulatory proteins; Graft Rejection - genetics; Hogs; Humans; immunosuppression/immune modulation; Kidney Transplantation; Kidney transplants; Lymphocytes T; Macaca fascicularis; Monkeys & apes; Original; ORIGINAL ARTICLES; Swine; Transgenes; translational research/science; Transplantation, Heterologous; xenoantibody; xenoantigen; Xenoantigens; Xenografts; xenotransplantation; xenoantibody; xenotransplantation; translational research/science; immunosuppression/immune modulation; xenoantigen
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.16780

Porcine cells devoid of three major carbohydrate xenoantigens, αGal, Neu5GC, and SDa (TKO) exhibit markedly reduced binding of human natural antibodies. Therefore, it is anticipated that TKO pigs will be better donors for human xenotransplantation. However, previous studies on TKO pigs using old world monkeys (OWMs) have been disappointing because of higher anti‐TKO pig antibodies in OWMs than humans. Here, we show that long‐term survival of renal xenografts from TKO pigs that express additional human transgenes (hTGs) can be achieved in cynomolgus monkeys. Kidney xenografts from TKO‐hTG pigs were transplanted into eight cynomolgus recipients without pre‐screening for low anti‐pig antibody titers. Two recipients of TKO‐hTG xenografts with low expression of human complement regulatory proteins (CRPs) (TKO‐A) survived for 2 and 61 days, whereas six recipients of TKO‐hTG xenografts with high CRP expression (TKO‐B) survived for 15, 20, 71, 135, 265, and 316 days. Prolonged CD4+T cell depletion and low anti‐pig antibody titers, which were previously reported important for long‐term survival of αGal knock‐out (GTKO) xenografts, were not always required for long‐term survival of TKO‐hTG renal xenografts. This study indicates that OWMs such as cynomolgus monkeys can be used as a relevant model for clinical application of xenotransplantation using TKO pigs. The authors achieve long‐term survival in cynomolgus monkeys of porcine kidney xenografts devoid of three major carbohydrate xenoantigens with multiple human transgenes without pre‐screening for low anti‐pig antibody titers and prolonged T cell depletion.