Identification of clinical strategies that limit early islet loss and enhance long-term islet survival and function continue to be critical to the field of islet transplantation. The Clinical Component of this proposal will focus on treating islets pre-transplant, and recipients (during and post-transplant), with selected agents with a unique spectrum of anti-inflammatory, anti-apoptotic and beta cell enhancing properties (Lisofylline and Exenatide), to improve beta cell function and viability, maximizing pre-transplant functional islet mass, islet engraftment and long-term function, in patients with Type 1 diabetes. In order to clearly ascertain the effect of newly introduced agents, such as lisofylline (LSF) and Exenatide (EXN), on transplant outcome (CIT-02), it is essential to address issues related to immunological alterations (auto/allo reactivity) and metabolic function in order to compare the results to those of control subjects in CIT07. The central hypothesis of this application is that identification of reliable indicators of post-transplant metabolic function, as well as immune status, will enhance our ability to predict islet allograft dysfunction in patients with type 1 diabetes mellitus, thereby allowing for alteration of therapy to enhance islet engraftment, function and long-term survival.
Aim 1 : To assess islet engraftment, metabolic function and long-term survival in CIT07 control subjects by undertaking additional metabolic tests that we have previously observed to be early indicators of graft dysfunction and comparing the results obtained to data from CIT02 subjects.
Aim 2 : To undertake additional immune monitoring strategies in CIT07 patients that allow us to verify the efficacy of immune-suppression and/or identify perturbations of the immune system which precede early loss of function, rejection, or recurrent autoimmunity and comparing the results obtained to data from CIT02 subjects.
Aim 3 : To utilize the information obtained from these studies to clearly identify new metabolic and immunologic testing strategies that provide information that is superior to that attainable with more established assays;i.e., the data enables alteration of therapies to achieve enhanced graft survival

Public Health Relevance

(provided by the applicant): The identification of clinical interventions that will allow the survival of transplanted Islets is crucial to allow for better outcomes of Islet Transplantations. In addition to improving Islet survival at the time of transplantation there's a need for new immunosuppressive modalities that will protect Islets from being destroyed by the immune system and therefore leading to long term Islet function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01DK070460-08S1
Application #
8449771
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O1))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2004-09-30
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$991,842
Indirect Cost
$133,764
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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
Fotino, Nicoletta; Fotino, Carmen; Pileggi, Antonello (2015) Re-engineering islet cell transplantation. Pharmacol Res 98:76-85
Klein, Dagmar; Álvarez-Cubela, Silvia; Lanzoni, Giacomo et al. (2015) BMP-7 Induces Adult Human Pancreatic Exocrine-to-Endocrine Conversion. Diabetes 64:4123-34
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
Tomei, Alice Anna; Villa, Chiara; Ricordi, Camillo (2015) Development of an encapsulated stem cell-based therapy for diabetes. Expert Opin Biol Ther 15:1321-36
Cechin, Sirlene; Alvarez-Cubela, Silvia; Giraldo, Jaime A et al. (2014) Influence of in vitro and in vivo oxygen modulation on ? cell differentiation from human embryonic stem cells. Stem Cells Transl Med 3:277-89
Ricordi, Camillo (2014) The path for tolerance permissive immunomodulation in islet transplantation. Transplantation 98:1260-1
Fraker, Chris A; Cechin, Sirlene; Álvarez-Cubela, Silvia et al. (2013) A physiological pattern of oxygenation using perfluorocarbon-based culture devices maximizes pancreatic islet viability and enhances ?-cell function. Cell Transplant 22:1723-33

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