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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

BACKGROUND AND PURPOSE: A major obstacle to islet cell transplantation is the early loss of transplanted islets resulting 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 inhibito...

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Detalles Bibliográficos
Autores principales: Xiao, Fang, Ma, Liang, Zhao, Min, Smith, Richard A, Huang, Guocai, Jones, Peter M, Persaud, Shanta, Pingitore, Attilio, Dorling, Anthony, Lechler, Robert, Lombardi, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728428/
https://www.ncbi.nlm.nih.gov/pubmed/26565566
http://dx.doi.org/10.1111/bph.13388
Descripción
Sumario:BACKGROUND AND PURPOSE: A major obstacle to islet cell transplantation is the early loss of transplanted islets resulting 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. EXPERIMENTAL APPROACH: 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 had 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. KEY RESULTS: Pre‐incubation with APT070 decreased C‐peptide release and iC3b production in vitro, 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. CONCLUSIONS AND IMPLICATIONS: Pre‐treatment of islets with APT070 could reduce intra‐islet inflammation with accompanying preservation of insulin secretion by beta cells. APT070 could be as a potential therapeutic tool in islet transplantation.