News & Research

    Barbara Davis Center University of Colorado Denver, Aurora, Colorado

Immunopathogenesis of Type 1 Diabetes

General Research Subject: Type 1 Diabetes

Focus: Genetics\Type 1 Diabetes, Immunology, Other

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2011

Project End Date: June 30, 2015

Research Description

We and others have generated considerable evidence that insulin is likely the primary target for T cells causing Type 1 diabetes. In the NOD mouse model we can mutate one amino acid of a portion of the insulin molecule (amino acids B: 9-23) and prevent all NOD diabetes. In man, only levels of insulin autoantibodies correlate with the rate with which children progress from development of autoantibodies to overt diabetes. Our studies are aimed at defining exactly how insulin is mistakenly targeted. The 'tip of the spear' for T lymphocytes is a trimolecular complex consisting of the T cell receptor, the target peptide (e.g. piece of insulin) and the molecule that holds the peptide for presentation to T cell receptors. In the past two years we have finally begun to visualize the structure of this trimolecular complex. Such new knowledge has led to development of what are termed tetramers to see with flow cytometry mouse T cells targeting insulin peptide B: 9-23. The main goals of the current proposal are to apply our new knowledge to human T cells, with the first human T cell receptor targeting insulin B: 9-23 in hand. We believe that we will be able to develop improved T cell assays to predict diabetes and perhaps, more important, have the opportunity to discover small molecules that will block the 'tip of the spear'.

Research Profile

Mentor: Eisenbarth, George, MD, PhD  Postdoctoral Fellow: Fuse, Masanori

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

We believe we are finally beginning to understand fundamental molecular determinants of Type 1 diabetes in the NOD mouse model, and similar molecular structures are likely to be key in man. In particular if we mutate a single amino acid of an insulin peptide (amino acids B: 9-23) targeted by NOD T cells we can prevent all diabetes (Nakayama et al Nature 2005). Collaborating with Dr. John Kappler at the National Jewish we now know how this peptide is bound by the mouse HLA-like molecule (termed I-Ag7) and presented to T cells (Stadinski et al PNAS 2010). Given this knowledge we have reagents that allow us to identify the T cells targeting this peptide of the NOD mouse and approximately 4% of the invading CD4 T cells react specifically with the B: 9-23 peptide. Our project seeks to take advantage of this new knowledge and specific reagents, and we are developing assays that will allow us to mark T cells of man genetically targeting insulin peptides. The major genetic determinants of targeting are specific HLA molecules. In addition we are studying small molecules able to block the recognition of specific islet peptides as a major pathway aimed at the prevention of Type 1 diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Approximately 1/300 children in the general population develop Type 1 diabetes, while approximately 1/20 offspring of a patient with Type 1 diabetes develop Type 1 diabetes. If a child is both a relative of a patient with Type 1 diabetes and has inherited certain HLA genes that are common in the general population, but most common in patients with Type 1, the risk of diabetes is much higher. We believe the combination of these HLA genes, and a piece of insulin, recognized by T cells is the fundamental cause of Type 1 diabetes. Our goal is to develop therapies to block this interaction that leads to diabetes. Since we can now predict Type 1 diabetes with autoantibody testing, our hope is that safe therapies can be developed to be applied prior to development of high blood sugars.