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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
Author(s) -
Xiao Fang,
Ma Liang,
Zhao Min,
Smith Richard A,
Huang Guocai,
Jones Peter M,
Persaud Shanta,
Pingitore Attilio,
Dorling Anthony,
Lechler Robert,
Lombardi Giovanna
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13388
Subject(s) - islet , transplantation , in vivo , inflammation , complement system , renal capsule , in vitro , medicine , endocrinology , biology , chemistry , immunology , insulin , antibody , biochemistry , microbiology and biotechnology
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 i n 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.