title: Inhibition of nuclear factor-κB activation in pancreatic β-cells has a protective effect on allogeneic pancreatic islet graft survival.
abstract: 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-κB activation is involved in cytokine-mediated β-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of β-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-β transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in β-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that β-cell-specific blockade of NF-κB 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-κB 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.
authors: Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel.
authors: Roy
authors: R
authors: Eldor
authors: Roy
authors: R
authors: Abel
authors: Dror
authors: D
authors: Sever
authors: Gad
authors: G
authors: Sadoun
authors: Amnon
authors: A
authors: Peled
authors: Ronit
authors: R
authors: Sionov
authors: Danielle
authors: D
authors: Melloul
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000378:metabolism; D004789:Enzyme Activation; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D054357:Chemokine CXCL10; D006183:H-2 Antigens; D053583:Interleukin-1beta; D016328:NF-kappa B; D009573:Nitrites; D047428:Protein Kinase Inhibitors; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex