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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Ma, Liang Lombardi, Giovanna Xiao, Fang Zhao, Min Smith, Richard A. Dorling, Anthony Huang, Guocai Pingitore, Attilio Jones, Peter M. Persaud, Shanta Lechler, Robert |
| Description | Author Affiliation: Xiao F ( Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Ma L ( Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Zhao M ( Department of Diabetes & Endocrinology, King's College London, 2nd Floor, The Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, UK.); Smith RA ( Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Huang G ( Department of Diabetes & Endocrinology, King's College London, 2nd Floor, The Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, UK.); Jones PM ( Division of Diabetes & Nutritional Sciences, School of Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Persaud S ( Division of Diabetes & Nutritional Sciences, School of Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Pingitore A ( Division of Diabetes & Nutritional Sciences, School of Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Dorling A ( Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Lechler R ( Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.); Lombardi G ( Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.) |
| Abstract | 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. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 3 |
| Volume Number | 173 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2016-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Complement C3-C5 Convertases Antagonists & Inhibitors Islets Of Langerhans Transplantation Islets Of Langerhans Drug Effects Animals Cells, Cultured Cytokines Blood Metabolism Interleukin Receptor Common Gamma Subunit Genetics Mice, Inbred NOD Mice, Knockout Mice, SCID Transplantation, Heterologous Research Support, Non-U.S. Gov't Pharmacology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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