T1D occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of pancreatic beta-cells which is primarily mediated by autoreactive T-cells. The disease process results in loss of insulin secretion and life-long insulin-dependence. At present there is no treatment that fully interdicts islet autoimmunity. Our long-range scientific goals are to understand the natural history of T1D and its molecular basis and implement clinical trials evaluating new strategies to prevent or ameliorate this disease. The objectives of this proposal are twofold: 1) to remain an active participant in the research network. Type 1 Diabetes TrialNet, involved in the design and implementation of new intervention strategies;and 2) to propose a novel intervention strategy with alefacept in individuals with recent onset T1D. Our central hypothesis is that alefacept will have therapeutic value in T1D, and temper the perpetuation of the destructive autoimmune process resulting in T1D, preserving beta-cells and their insulin-secreting capacity. There is a solid rationale for attempting new trials to target memory T cells in T1D: growing evidence links memory T cells with diabetes development, and alefacept specifically targets these cells. It is FDA-approved for the treatment of adult patients with moderate to severe chronic plaque psoriasis, which is also an immune-mediated disease. Importantly, alefacept has an excellent safety profile without the typical side effects of other immunosuppressive agents, which makes it ideally suited for potential chronic treatment of immune-mediated diseases. We propose a phase l/ll double-masked, randomized, placebo-controlled trial to test the hypothesis that alefacept will preserve C-peptide secretion in patients with recent onset T1D. Importantly, there is growing evidence for a role of memory T cells in T1D, and the memory compartment is likely to be enriched in islet-specific autoreactive T cells. We propose two treatment courses during a 1-year period and follow-up for an additional year. The primary metabolic outcome will be stimulated insulin secretion as assessed by C-peptide levels after the mixed meal tolerance test. The primary immunological outcome will be a 50-60% reduction in the frequency of memory T cells during the treatment phases.

Public Health Relevance

Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells, resulting in loss of insulin secretion and life-long insulin dependence, and unfortunately often affects children and adolescents. Previous clinical trials have shown that it is possible to interfere with this autoimmune destructive process. If treatment with alefacept safely stops or slows this destructive process, it would be a major advance toward the prevention of a lifelong disease associated with significant morbid complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK085499-03
Application #
8073929
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Leschek, Ellen W
Project Start
2009-09-30
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$680,318
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Ismail, Heba M; Xu, Ping; Libman, Ingrid M et al. (2018) The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes. Diabetologia 61:84-92
Culina, Slobodan; Lalanne, Ana Ines; Afonso, Georgia et al. (2018) Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol 3:
Vecchio, Federica; Lo Buono, Nicola; Stabilini, Angela et al. (2018) Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight 3:
Redondo, Maria J; Steck, Andrea K; Sosenko, Jay et al. (2018) Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes. Diabetes Care 41:2480-2486
Sanda, Srinath; Type 1 Diabetes TrialNet Study Group (2018) Increasing ICA512 autoantibody titers predict development of abnormal oral glucose tolerance tests. Pediatr Diabetes 19:271-276
Yeo, Lorraine; Woodwyk, Alyssa; Sood, Sanjana et al. (2018) Autoreactive T effector memory differentiation mirrors ? cell function in type 1 diabetes. J Clin Invest 128:3460-3474
Redondo, Maria J; Geyer, Susan; Steck, Andrea K et al. (2018) A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care 41:1887-1894
Greenbaum, Carla J; Speake, Cate; Krischer, Jeffrey et al. (2018) Strength in Numbers: Opportunities for Enhancing the Development of Effective Treatments for Type 1 Diabetes-The TrialNet Experience. Diabetes 67:1216-1225
Haller, Michael J; Schatz, Desmond A; Skyler, Jay S et al. (2018) Low-Dose Anti-Thymocyte Globulin (ATG) Preserves ?-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care 41:1917-1925
Redondo, Maria J; Geyer, Susan; Steck, Andrea K et al. (2018) TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes. Diabetes Care 41:311-317

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