Prolongation of islet allograft survival following ex vivo transduction with adenovirus encoding a soluble type 1 TNF receptor–Ig fusion decoy

Biological and Biomaterial Approaches for Improved Islet Transplantation

“…TNFR-Ig transfection, on the other hand, was shown to reduce cytokine-induced apoptotic human islet death in vitro and prolongation of normoglycemia after allotransplantation of BALB/c mice islets in streptozotocin-induced diabetic C57BL/6 mice. Machen et al (2004), however, did not analyze graft leukocyte infiltration (Machen et al, 2004). These studies strongly indicate the central role played by macrophage-secreted cytokines (IL-1␤ and TNF-␣) in mediating islet graft dysfunction and death, as well as the potential utility of intercepting cytokine pathways in improving the success of islet transplantation.…”

“…These observations indicate that islet treatment to antagonize TNF-␣ might improve the outcome of islet transplantation. Thus, Dobson et al (2000) investigated the utility Adv-mediated transfection of an inhibitor of TNF (TNFi), whereas Machen et al (2004) explored the use of soluble type 1 TNF receptor-Ig fusion protein. Dobson et al (2000) transfected human pancreatic islets with Adv-producing TNFi and transplanted 2000 IE under the kidney capsules of NOD-SCID mice.…”

The Introduction of Human Heme Oxygenase-1 and Soluble Tumor Necrosis Factor-α Receptor Type I With Human IgG1 Fc in Porcine Islets Prolongs Islet Xenograft Survival in Humanized Mice

“…sTNF-aR-Fc was reported to protect islets from apoptosis and to prolong islet allograft survival (29). We previously showed that sTNF-aR-Fc overexpression protects porcine endothelial cells from human sTNF-a-induced cytotoxicity and that fibroblasts isolated from human sTNF-aR-Fctransgenic pigs suppress the induction of chemokines and adhesion molecules (15).…”

Over-expression of AMP-activated protein kinase impairs pancreatic β-cell function in vivo

“…Strategies which inhibit these losses, and thus enhance -cell survival, are therefore likely to reduce the number of islet equivalents required initially, and to extend the usefulness of islet transplantation. To this end, adenovirusmediated introduction into islets of potentially cytoprotective genes, such as bcl-2 (Contreras et al 2001), insulin-like growth factor-1 (Giannoukakis et al 2000a), I -B kinase inhibitor (Rehman et al 2003), I -B repressor (Giannoukakis et al 2000b), erythropoietin (Fenjves et al 2004) or a tumour necrosis factor (TNF) receptor fusion decoy (Machen et al 2004), is considered an exciting approach.…”