XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury

Am J Transplant. 2005 Jun;5(6):1297-305. doi: 10.1111/j.1600-6143.2005.00891.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis / physiology
  • Cell Hypoxia / physiology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / therapy
  • Genetic Vectors
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Graft Survival*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology
  • Insulin / metabolism
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Islets of Langerhans Transplantation / immunology*
  • Islets of Langerhans Transplantation / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Proteins / genetics
  • Proteins / metabolism*
  • Reperfusion Injury / immunology
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / therapy*
  • Transplantation, Isogeneic
  • Up-Regulation
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Homeodomain Proteins
  • Insulin
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • RAG-1 protein
  • Glucose