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A20 as an immune tolerance factor can determine islet transplant outcomes

Abstract

Islet transplantation can restore lost glycemic control in type 1 diabetes subjects but is restricted in its clinical application by a limiting supply of islets and the need for heavy immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-kappaB signaling thresholds. Here, we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45% of recipients, and > 80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon Tregs and was antigen specific, and grafts showed reduced expression of inflammatory factors. Transplantation of islets with A20 containing a loss-of-function variant (I325N) resulted in increased RIPK1 ubiquitination and NF-kappaB signaling, graft hyperinflammation, and acute allograft rejection. Overexpression of A20 in human islets potently reduced expression of inflammatory mediators, with no impact on glucose-stimulated insulin secretion. Therapeutic administration of A20 raises inflammatory signaling thresholds to favor immune tolerance and promotes islet allogeneic survival. Clinically, this would allow for reduced immunosuppression and support the use of alternate islet sources.

Type Journal
ISBN 2379-3708 (Electronic) 2379-3708 (Linking)
Authors Zammit, N. W.; Walters, S. N.; Seeberger, K. L.; O'Connell, P. J.; Korbutt, G. S.; Grey, S. T.
Responsible Garvan Author A/Prof Shane Grey
Publisher Name Journal of Clinical Investigation Insight
Published Date 2019-11-01
Published Volume 4
Published Issue 21
Published Pages e131028
Status Published in-print
DOI 10.1172/jci.insight.131028
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/31581152