Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/80450
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dc.contributor.author | Hughes, A. | - |
dc.contributor.author | Mohanasundaram, D. | - |
dc.contributor.author | Kireta, S. | - |
dc.contributor.author | Jessup, C. | - |
dc.contributor.author | Drogemuller, C. | - |
dc.contributor.author | Coates, P. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Transplantation, 2013; 95(5):671-678 | - |
dc.identifier.issn | 0041-1337 | - |
dc.identifier.issn | 1534-6080 | - |
dc.identifier.uri | http://hdl.handle.net/2440/80450 | - |
dc.description.abstract | <h4>Background</h4>The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life.<h4>Methods</h4>We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed.<h4>Results</h4>Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (P<0.05, log-rank [Mantel-Cox] test).<h4>Conclusions</h4>Antiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation. | - |
dc.description.statementofresponsibility | Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F.; Drogemuller, Chris J.; Coates, P. Toby H. | - |
dc.language.iso | en | - |
dc.publisher | Lippincott Williams & Wilkins | - |
dc.rights | © 2013 by Lippincott Williams & Wilkins | - |
dc.source.uri | http://dx.doi.org/10.1097/tp.0b013e31827fa453 | - |
dc.subject | Apoptosis | - |
dc.subject | [beta]-Cells | - |
dc.subject | Insulin-like growth factor-II | - |
dc.subject | Gene therapy | - |
dc.subject | Islet transplantation. | - |
dc.title | Insulin-like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1097/TP.0b013e31827fa453 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Jessup, C. [0000-0003-1184-6653] | - |
dc.identifier.orcid | Drogemuller, C. [0000-0001-9770-4845] | - |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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hdl_80450.pdf | Accepted version | 777.37 kB | Adobe PDF | View/Open |
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