Immunological response in cynomolgus macaques to porcine α-1,3 galactosyltransferase knockout viable skin xenotransplants: a pre-clinical study

Paul W. Holzer*, Elizabeth Chang, Joan Wicks, Linda Scobie, Claire Crossan, Rod Monroy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Background
Allogeneic skin recovered from human deceased donors (HDD) has been a mainstay interim treatment for severe burns, but unfortunately risk of infectious disease and availability limitations exist. Genetically engineered ɑ‐1,3 galactosyltransferase knockout (GalT‐KO) porcine source animals for viable skin xenotransplants may provide a promising clinical alternative.

Methods
Four cynomolgus macaque recipients received full‐thickness surgical wounds to model the defects arising from excision of full‐thickness burn injury and were treated with biologically active skin xenotransplants derived from GalT‐KO, Designated Pathogen Free (DPF) miniature swine. Evaluations were conducted for safety, tolerability, and recipient immunological response.

Results
All skin xenotransplants demonstrated prolonged survival, vascularity, and persistent dermal adhesion until the study endpoint at post‐operative day 30. No adverse outcomes were observed during the study. Varying levels of epidermolysis coincided with histologic detection of CD4+ and CD8+ T cells, and other cellular infiltrates in the epidermis. Recipient sera IgM and IgG demonstrated significant antibody immune response to non‐α‐1,3‐galactose porcine xenoantigens. Separately, specific wound healing mediators were quantified. Neither porcine cell migration nor PERV were detected in circulation or any visceral organs.

Conclusions
These results provide a detailed analysis of vital skin xenotransplants utilizing a non‐human primate model to predict the anticipated immunological response of human patients. The lack of adverse rejection even in the presence of elevated Ig indicates this is a prospective therapeutic option. The findings reported here directly supported regulatory clearance for a first‐in‐man, Phase I xenotransplantation clinical trial.
Original languageEnglish
Article numbere12632
Number of pages12
JournalXenotransplantation
Volume27
Issue number6
Early online date9 Aug 2020
DOIs
Publication statusPublished - Dec 2020

Keywords

  • α‐1,3 galactosyltransferase, GalT‐KO, human deceased donor allografts, pig, porcine endogenous retrovirus, porcine xenograft, rejection skin xenotransplant

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