Current data from centers performing islet transplantation worldwide indicates that in the presence of sirolimus-based, steroid-free, low-dose tacrolimus therapy, usually more than one donor pancreas graft is required to attain insulin independence. Furthermore, complications including accelerated nephrotoxicity (from tacrolimus), mouth ulceration, dyslipidemia and hypertension have been encountered in these patients. This study aims to address these issues with through the use of a novel immunosuppressive regimen comprised of basiliximab induction, with maintenance therapy including LEA29Y (BMS224818) and low dose sirolimus thus avoiding the use of two potent but diabetbgenic immunosuppressive agents steroids and calcineurin inhibitors. The clinical trial described in this proposal represents the first step of an overall development plan designed to define a protocol that achieves three goals: 1) to reduce or eliminate non-immune toxicities associated with the Edmonton Protocol, 2) to promote significantly higher rates of achieving insulin independence with islet transplants from single donors, and 3) to maintain or improve the overall excellent rates of insulin-independence (approximately 80%) at I year after the completion transplant. Our central hypothesis is that the use of the immunoselective CD28 blocker, LEA29Y as the primary agent will allow comparable efficacy in preventing rejection or recurrent autoimmunity while permitting the elimination of tacrolimus and if necessary sirolimus from our immunosuppressive regimen. In addition to the assessment of clinical outcome, mechanistic studies will be performed to: (1) provide insight into the immunological mechanisms associated with islet allograft survival and (2) determine the physiological capacity and functional viability of islet grafts. The studies will facilitate the development of improved care for these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI065191-01
Application #
6887122
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O3))
Program Officer
Bridges, Nancy D
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2004-09-30
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$2,900,000
Indirect Cost
Name
University of Alberta
Department
Type
DUNS #
208095844
City
Edmonton
State
AB
Country
Canada
Zip Code
T6 2-E1
Foster, Eric D; Bridges, Nancy D; Feurer, Irene D et al. (2018) Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care 41:1001-1008
Hering, Bernhard J; Bridges, Nancy D; Eggerman, Thomas L et al. (2017) Comment on Harlan. Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor. Diabetes Care 2016;39:1072-1074. Diabetes Care 40:e111-e112
Ricordi, Camillo; Goldstein, Julia S; Balamurugan, A N et al. (2016) National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. Diabetes 65:3418-3428
Hering, Bernhard J; Clarke, William R; Bridges, Nancy D et al. (2016) Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care 39:1230-40
Senior, Peter A; Bellin, Melena D; Alejandro, Rodolfo et al. (2015) Consistency of quantitative scores of hypoglycemia severity and glycemic lability and comparison with continuous glucose monitoring system measures in long-standing type 1 diabetes. Diabetes Technol Ther 17:235-42
Shapiro, A M James (2011) Strategies toward single-donor islets of Langerhans transplantation. Curr Opin Organ Transplant 16:627-31
Zuk, D M; Koh, A; Imes, S et al. (2011) Three cases of alopecia following clinical islet transplantation. Am J Transplant 11:163-8