Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function.
Transplantation of an excessive number of islets of Langerhans (two to four pancreata per recipient) into patients with type I diabetes is required to restore euglycemia. Hypoxia, nutrient deprivation, local inflammation, and the beta cell inflammatory response (up-regulation of NF-kappaB-dependent genes such as inos) result in beta cell destruction in the early post-transplantation period. Genetic engineering of islets with anti-inflammatory and antiapoptotic genes may prevent beta cell loss and primary nonfunction. We have shown in vitro that A20 inhibits NF-kappaB activation in islets and protects from cytokine- and death receptor-mediated apoptosis. In vivo, protection of newly transplanted islets would reduce the number of islets required for successful transplantation. Transplantation of 500 B6/AF(1) mouse islets into syngeneic, diabetic recipients resulted in a cure rate of 100% within 5 days. Transplantation of 250 islets resulted in a cure rate of only 20%. Transplantation of 250 islets overexpressing A20 resulted in a cure rate of 75% with a mean time to cure of 5.2 days, comparable to that achieved with 500 islets. A20-expressing islets preserve functional beta cell mass and are protected from cell death. These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation.
Grey
Shane T
ST
Immunobiology Research Center, Department of Surgery and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. sgrey@caregroup.harvard.edu
Longo
Christopher
C
Shukri
Tala
T
Patel
Virendra I
VI
Csizmadia
Eva
E
Daniel
Soizic
S
Arvelo
Maria B
MB
Tchipashvili
Vaja
V
Ferran
Christiane
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D003546:Cysteine Endopeptidases; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods* / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D011184:Postoperative Period; D020011:Protective Agents / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D014176:Protein Biosynthesis; D015202:Protein Engineering / Q000379:methods*; D011506:Proteins / Q000235:genetics* / Q000627:therapeutic use* / Q000633:toxicity; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use / Q000633:toxicity; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D004268:DNA-Binding Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D020011:Protective Agents; D011506:Proteins; D011994:Recombinant Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse