Physiology and immunology of a pig-to-human decedent kidney xenotransplant.
Montgomery RA., Stern JM., Fathi F., Suek N., Kim JI., Khalil K., Vermette B., Tatapudi VS., Mattoo A., Skolnik EY., Jaffe IS., Aljabban I., Eitan T., Bisen S., Weldon EP., Goutaudier V., Morgand E., Mezine F., Giarraputo A., Boudhabhay I., Bruneval P., Sannier A., Breen K., Saad YS., Muntnich CB., Williams SH., Zhang W., Kagermazova L., Schmauch E., Goparaju C., Dieter R., Lawson N., Dandro A., Fazio-Kroll AL., Burdorf L., Ayares D., Lorber M., Segev D., Ali N., Goldfarb DS., Costa V., Hilbert T., Mehta SA., Herati RS., Pass HI., Wu M., Boeke JD., Keating B., Mangiola M., Sommer PM., Loupy A., Griesemer A., Sykes M.
Xenotransplantation of genetically modified pig kidneys offers a solution to the scarcity of organs for patients with end stage renal disease1. Here we performed a pig kidney thymic autograft transplantation from an α1,3-galactosyltransferase knockout (GGTA1-knockout, GTKO) pig into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification, and somatically supported the decendent for a pre-planned 61-day study. Haemodynamic and electrolyte stability and dialysis independence were achieved. Biopsies from post-operative day (POD) 10 revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype that is not seen in allotransplantation. On POD33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, complement C3 and C3b inhibition, and rabbit anti-thymocyte globulin (rATG) completely reversed xenograft rejection. After the xenotransplant, pre-existing donor-reactive T cell clones expanded progressively in the circulation and acquired an effector transcriptional profile, and were detected in the POD33 rejecting xenograft prior to rATG treatment. This study presents long-term physiological, immunological and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitopes present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiological functions in a human.