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 diabetogenic 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 (~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.

Public Health Relevance

(provided by applicant): This proposal is part of an overall development plan 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 rates of insulin-independence at I year after the completion transplant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI089317-03
Application #
8119525
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O1))
Program Officer
Bridges, Nancy D
Project Start
2009-09-25
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$1
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322