Responses to Hybrid Insulin Peptides as Biomarkers of Disease Activity in Human Type 1 Diabetes

Abstract: T Cell Responses to Hybrid Insulin Peptides as Biomarkers of Disease Activity in
Type 1 Diabetes
An important objective in T1D research is the investigation of autoantigens that activate effector T cells
and trigger the inflammatory process in islet beta-cells. We recently identified Hybrid Insulin Peptides
(HIPs) as a new class of autoantigens in type 1 diabetes (T1D). These neoantigens are created by the
fusion of insulin fragments with peptides from other secretory granule proteins such as chromogranin
A (ChgA), islet amyloid polypeptide (IAPP), neuropeptide Y (NPY) or insulin itself. Because insulin is
present only in pancreatic beta cells, this discovery might provide an explanation for organ-specific
autoimmunity in T1D. Importantly, CD4 T cells responding to HIPs have been isolated from the islets
of deceased T1D patients, demonstrating the relevance of these autoantigens to the human disease.
We hypothesize that T cells reactive to HIPs can serve as biomarkers of disease. Our goals in this
project are (1) to characterize T cell responses to HIPs in the PBMCs of T1D and controls; (2) to
determine the extent of reactivity to insulin B:9-23 Hybrid Insulin Peptides in recent onset T1D patients;
(3) Investigate the presence and phenotype of HIP-reactive T cells in the natural history of T1D.

Grant Number: 5R01AI146202-05
NIH Institute/Center: NIH
Principal Investigator: Rocky Baker