Islet transplantation can restore endogenous insulin secretion in patients with type 1 diabetes (T1D) and consequently enable the attainment of near-normal glycemic control in the absence of severe episodes of hypoglycemia. At the University of Pennsylvania, we have been investigating the efficacy of combined B- and T- lymphocyte directed immunotherapy for promoting immunological tolerance to islet allografts in TID patients (CIT 05). We are also participating in the phase 3 FDA registration trial investigating a T-cell directed immunotherapy (CIT 07), and the islet-after-kidney (lAK) trial in T1D subjects following successful renal transplantation (CIT 06). Penn actively participated in the development of the Consortium Standard Operating Procedures using Serva collagenase in islet manufacturing. Penn became the first center to qualify to proceed with islet transplantations in 2008, and in that year performed three clinical transplants using single islet donors. The initiation of clinical islet transplantation provided the unique opportunity to utilize metabolic and immunologic mechanistic studies to gain insight into beta cell secretory capacity and immunological alterations in lymphocyte phenotype and function after islet transplantation, respectively. Having achieved these milestones of islet manufacturing and transplantation, we are committed to completing the Consortium clinical trials and the accompanying metabolic and immunologic studies.

Public Health Relevance

Type 1 diabetes (T1 D) results from the selective loss of insulin-producing beta cells in pancreatic islets. Despite a multitude of advanced insulin delivery systems, subjects with TID continue with abnormal fluctuations in glucose level, leading to the development of secondary complications of the disease. Islet transplantation has the potential to provide precise and long term control of glucose metabolism, thus preventing secondary complications of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK070430-08
Application #
8141988
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O1))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2004-09-30
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$1
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hanley, Patrick; Sutter, Jennifer A; Goodman, Noah G et al. (2017) Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes. Clin Immunol 183:336-343
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
Vallabhajosyula, Prashanth; Korutla, Laxminarayana; Habertheuer, Andreas et al. (2017) Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue. J Clin Invest 127:1375-1391
Rickels, Michael R; Peleckis, Amy J; Markmann, Eileen et al. (2016) Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes. J Clin Endocrinol Metab 101:4421-4430
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
Kolhatkar, Nikita S; Brahmandam, Archana; Thouvenel, Christopher D et al. (2015) Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome. J Exp Med 212:1663-77
Rickels, Michael R; Fuller, Carissa; Dalton-Bakes, Cornelia et al. (2015) Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes. Diabetes 64:1713-8
Choudhary, Pratik; Rickels, Michael R; Senior, Peter A et al. (2015) Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 38:1016-29

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