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Type: Journal article
Title: A20 as an immune tolerance factor that can determine islet transplant outcomes
Author: Zammit, N.W.
Walters, S.N.
Seeberger, K.L.
O'Connell, P.J.
Korbutt, G.S.
Grey, S.T.
Citation: JCI Insight, 2019; 4(21):e131028-1-131028-16
Publisher: American Society for Clinical Investigation
Issue Date: 2019
ISSN: 2379-3708
Statement of
Nathan W. Zammit, Stacey N. Walters, Karen L. Seeberger, Philip J. O’Connell, Gregory S. Korbutt, and Shane T. Grey
Abstract: Islet transplantation can restore lost glycemic control in type 1 diabetes subjects, but is restricted in its clinical application by limiting supplies 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-κB signalling 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 regulatory T cells, 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-κB signalling, graft hyper-inflammation 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 signalling thresholds to favour immune tolerance and promotes islet allogeneic survival. Clinically this would allow for reduced immunosuppression and support the use of alternate islet sources.
Keywords: Humans; Islets of Langerhans Transplantation; Transplantation, Homologous; Immune Tolerance; Graft Survival; Tumor Necrosis Factor alpha-Induced Protein 3
Rights: © 2019, American Society for Clinical Investigation.
RMID: 1000001408
DOI: 10.1172/jci.insight.131028
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Appears in Collections:Medicine publications

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