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A20 as an immune tolerance factor that can determine islet transplant outcomes

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dc.contributor.authorZammit, N.W.
dc.contributor.authorWalters, S.N.
dc.contributor.authorSeeberger, K.L.
dc.contributor.authorO'Connell, P.J.
dc.contributor.authorKorbutt, G.S.
dc.contributor.authorGrey, S.T.
dc.date.issued2019
dc.description.abstractIslet 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.
dc.description.statementofresponsibilityNathan W. Zammit, Stacey N. Walters, Karen L. Seeberger, Philip J. O’Connell, Gregory S. Korbutt, and Shane T. Grey
dc.identifier.citationJCI Insight, 2019; 4(21):e131028-1-131028-16
dc.identifier.doi10.1172/jci.insight.131028
dc.identifier.issn2379-3708
dc.identifier.issn2379-3708
dc.identifier.orcidGrey, S.T. [0000-0003-2160-1625]
dc.identifier.urihttp://hdl.handle.net/2440/122740
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigation
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/596825
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1130222
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1140691
dc.rights© 2019, American Society for Clinical Investigation.
dc.source.urihttps://doi.org/10.1172/jci.insight.131028
dc.subjectHumans
dc.subjectIslets of Langerhans Transplantation
dc.subjectTransplantation, Homologous
dc.subjectImmune Tolerance
dc.subjectGraft Survival
dc.subjectTumor Necrosis Factor alpha-Induced Protein 3
dc.titleA20 as an immune tolerance factor that can determine islet transplant outcomes
dc.typeJournal article
pubs.publication-statusPublished

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