Successful Long-Term TMA- and Rejection-Free Survival of a Kidney Xenograft With Triple Xenoantigen Knockout Plus Insertion of Multiple Human Transgenes
1Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, 2Pathology, Massachusetts General Hospital, Boston, MA, 3eGenesis Inc, Cambridge, MA
Meeting: 2021 American Transplant Congress
Abstract number: 348
Keywords: Kidney transplantation, Xenoreactive antibodies
Topic: Basic Science » Xenotransplantation
Session Information
Session Name: Xenotranplantation and Preclinical Studies
Session Type: Rapid Fire Oral Abstract
Date: Tuesday, June 8, 2021
Session Time: 6:00pm-7:00pm
Presentation Time: 6:30pm-6:35pm
Location: Virtual
*Purpose: Pigs with deletion of 3 carbohydrate xenoantigens (triple knock-out, TKO) are expected to be optimal donors for human xenotransplantation. However, anti-porcine natural antibodies of old world monkeys (OWM), such as baboons, cynomolgus or rhesus monkeys, have been shown to have higher bindings to TKO cells with rapid rejection of the renal xenografts in baboons. Therefore, it is crucial to establish a preclinical model that can reliably evaluate xenografts from TKO pigs. Here, we show, for the first time, the long-term TMA- and rejection- free renal xenograft survival from TKO pigs can be achieved using cynomolgus macaques.
*Methods: Eight cynomolgus monkeys received kidneys from two different TKO pigs lines with human complement, inflammation, and immune regulatory transgenes (TKO-A, TKO-B). The expression of transgenic human complement related genes (CD46, CD55 and CD59) was low on TKO-A, but high on TKO-B. The recipients were treated with ATG and anti-CD20 mAb as an induction, followed by weekly anti-CD154 mAb, daily MMF with or without 1-2 months course of rapamycin or tacrolimus. The levels of pre-transplant recipient IgG/IgM antibodies against donor porcine endothelial cells were measured by flow cytometry.
*Results: Anti-TKO IgG levels of all recipients were comparable to those of pooled human serum except for one recipient (TKO-A2), while anti-TKO IgM levels were consistently higher than those of pooled human serum (Fig. 1). TKO-A1 rejected xenograft rapidly on day 2, while TKO-A2 survived for 61 days, despite high anti-pig IgG and IgM titers. Among 6 recipients of TKO-B, although 2 monkeys (TKO-B1 and 2) rejected with TMA within 3 weeks (15 and 20 days) , 4 recipients (TKO-B3 to 6) achieved long-term survival (71, 135, 265 and 316 days) (Fig. 2). In the 3/4 long-term survivors, rejection or TMA was observed only after reduction of immunosuppression due to infectious complications, leading to rejection and TMA free xenograft survival reached up to 237 days. In this study, there was no significant correlation found between pre-transplant anti-TKO IgG and IgM levels and the transplant outcome.
*Conclusions: TKO with multiple human transgenes allowed kidney graft survival up to 316 days with TMA- and rejection-free xenograft survival up to 237 days.
To cite this abstract in AMA style:
Hirose T, Ma D, Lassiter G, Sasaki H, Rosales I, Coe T, Rickert C, Matheson R, Colvin R, Qin W, Kan Y, Layer J, Stiede K, Hall K, Youd M, Westlin W, Curtis M, Markmann JF, Kawai T. Successful Long-Term TMA- and Rejection-Free Survival of a Kidney Xenograft With Triple Xenoantigen Knockout Plus Insertion of Multiple Human Transgenes [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/successful-long-term-tma-and-rejection-free-survival-of-a-kidney-xenograft-with-triple-xenoantigen-knockout-plus-insertion-of-multiple-human-transgenes-2/. Accessed May 16, 2025.« Back to 2021 American Transplant Congress