| First Author | Eldor R | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 2 | Pages | e56924 |
| PubMed ID | 23437272 | Mgi Jnum | J:199335 |
| Mgi Id | MGI:5502285 | Doi | 10.1371/journal.pone.0056924 |
| Citation | Eldor R, et al. (2013) Inhibition of nuclear factor-kappaB activation in pancreatic beta-cells has a protective effect on allogeneic pancreatic islet graft survival. PLoS One 8(2):e56924 |
| abstractText | Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-kappaB activation is involved in cytokine-mediated beta-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of beta-cell-specific inhibition of NF-kappaB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-beta transgenic mouse, where NF-kappaB signalling can specifically and conditionally be inhibited in beta-cells by expressing an inducible and non-degradable form of IkappaBalpha regulated by the tet-on system. Our results show that beta-cell-specific blockade of NF-kappaB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-kappaB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process. |
