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Enhancing engraftment of islets of Langerhans and other cellular therapies for diabetes

  • Author / Creator
    McCall, Michael David
  • Islet transplantation is promising treatment for certain patients with type 1 diabetes who experience recurrent episodes of hypoglycemia with unawareness. One opportunity to improve on islet transplant outcomes and potentially broaden the recipient population, is to reduce the early post transplant islet loss. Another opportunity is to develop an alternative source of insulin-producing tissue; thus overcoming the need to rely on organ donation. Mouse islets are used throughout this thesis and their optimal isolation is a crucial step in many of the experiments contained herein. Histopaque provided the optimal isolation kinetics in addition to being the most cost-effective compound, as compared to dextran, iodixanol and ficoll. Apoptosis is the dominant mechanism by which islets are lost in the early post-transplant period. The caspase inhibitor IDN6556 reduced islet graft apoptosis and enhanced islet survival in both mouse and porcine models of islet transplantation. Cytokines, including TNFalpha and IL-1, contribute to islet toxicity in the early post-transplant period. As such, etanercept (TNFalpha inhibitor) has seen increased use in islet peri-transplant cocktails with minimal pre-clinical support. In our studies, the combination of etanercept, and anakinra (IL-1 receptor antagonist) led to improved islet engraftment as compared to either agent alone. One mechanism for this benefit was a significant reduction in apoptotic cells within the islet graft. We also attempted to enhance engraftment by utilizing resveratrol, a compound with known anti-oxidant and anti-inflammatory properties. Despite its benefit in other fields, it did not produce a benefit to islet engraftment over a wide dosing range. Stem cells are a promising alternative to cadaveric islet procurement. Herein we have demonstrated the ability to ship human embryonic stem cell-derived pancreatic cells (Cyt49) cells which developed pancreatic endocrine function after transplantation in immunodeficient mice. Although long-term teratoma formation was uncovered, this therapy has potential to overcome the reliance on organ donation and may broaden the diabetic recipient population. Overall, strategies to overcome early islet loss and the reliance on cadaveric donation of islets are presented here. The use of caspase inhibitors to prevent islet apoptosis is particularly encouraging and should be explored in clinical islet transplantation.

  • Subjects / Keywords
  • Graduation date
    2011-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3FB0B
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Surgery
  • Supervisor / co-supervisor and their department(s)
    • Shapiro, James AM (Surgery)
  • Examining committee members and their departments
    • Anderson, Colin (Surgery)
    • Light, Peter (Pharmacology)
    • Markmann, James (external)
    • West, Lori (Pediatrics)