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 journalArticle

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
Early online date11 Aug 2020
DOIs
Publication statusE-pub ahead of print - 11 Aug 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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