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

作者：Xiao Fang^*; Ma Liang; Zhao Min; Smith Richard A; Huang Guocai; Jones Peter M; Persaud Shanta; Pingitore Attilio; Dorling Anthony; Lechler Robert; Lombardi Giovanna^*

来源：British Journal of Pharmacology, 2016, 173(3): 575-587.

DOI：10.1111/bph.13388

Background and PurposeA 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 ApproachIn 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 IL2r(-/-) 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 ResultsPre-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 ImplicationsPre-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.

• 出版日期2016-2