XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury.
Recent advances in clinical islet transplantation have allowed patients with type 1 diabetes to become insulin independent, but the procedure is limited since islets from two donors per recipient are typically required. This limitation arises because within a few days of the islets being embolized into the portal circulation, at least half of the transplanted beta-cells have undergone apoptotic cell death triggered by hypoxic and chemokine/cytokine-mediated stress. We hypothesized that the survival of beta-cells in the early post-transplant period would be enhanced if naturally occurring inhibitor of apoptosis proteins (IAPs) were transiently overexpressed in the grafts. In the present study, we used a growth-regulatable beta-cell line (betaTC-Tet) as a model for beta-cells within islets, and examined whether adenovirally delivered XIAP (X-linked IAP-a highly potent IAP) could enhance beta-cell survival. In vitro, XIAP-expressing betaTC-Tet cells were markedly resistant to apoptosis in an ischemia-reperfusion injury model system and following exposure to cytokines. When Ad-XIAP transduced betaTC-Tet cells were transplanted subcutaneously into immunodeficient mice, the grafts were able to reverse diabetes in 3 days, vs. 21 days for Ad-betaGal transduced cells. This approach may allow more efficient use of the limited existing supply of human islets.
Emamaullee
Juliet
J
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
Liston
Peter
P
Korneluk
Robert G
RG
Shapiro
A M James
AM
Elliott
John F
JF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006085:Graft Survival; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D014185:Transplantation, Isogeneic; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein
D018398:Homeodomain Proteins; D007328:Insulin; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C064658:RAG-1 protein; D005947:Glucose