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APT070 (Mirococept), a membrane-localizing C3 convertase inhibitor, attenuates early human islet allograft damage in vitro and in vivo in a humanized mouse model

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)575-587
JournalBritish Journal of Pharmacology
Volume173
Issue number3
Early online date13 Nov 2015
DOIs
Publication statusPublished - 1 Feb 2016

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Abstract

A major obstacle to islet cell transplantation is the early loss of transplanted islets resulted from the instant blood-mediated inflammation reaction (IBMIR). The activation of complement pathways plays a central role in IBMIR. The aim of this study was to test the inhibitory effect of "painting" human islets with APT070, a membrane-localizing C3 convertase inhibitor, on inflammation evoked by exposure to human serum in vitro and by transplantation in vivo in a humanized diabetic mouse model. In vitro human islets pre-incubated with APT070 were exposed to allogeneic whole blood. In vivo, similarly treated islets were transplanted underneath the kidney capsule of streptozotocin-induced diabetic NOD-scid IL2rγ(-/-) mice that has been reconstituted with human CD34(+) stem cells. Complement activation and islet hormone content were assayed using enzyme-linked immunosorbent assays. Supernatants and sera were assayed for cytokines using cytometric beads array. Morphology of the islets incubated with human serum in vitro and in graft-bearing kidney were evaluated using immunofluorescence staining. Our results showed that in vitro pre-incubation with APT070 decreased C-peptide release and iC3b production, with diminished deposition of C4d and C5b-9 in islets embedded in blood clots. In vivo, the APT070-treated islets maintained intact structure and showed less infiltration of inflammatory cells than untreated islets. The pretreatments also significantly reduced pro-inflammatory cytokines in supernatants and sera. These data indicate that pre-treatment of islets with APT070 might reduce intra-islet inflammation with accompanying preservation of insulin secretion by beta cells, and that APT070 could be as a potential therapeutical tool in islet transplantation.

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