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Diabetes. 2019 Jun 7. pii: db190128. doi: 10.2337/db19-0128. [Epub ahead of print]

Hybrid Insulin Peptides are Autoantigens in Type 1 Diabetes.

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Department of Immunology and Microbiology;
Barbara Davis Center for Childhood Diabetes, Univ. of Colorado School of Medicine.
Department of Immunology and Microbiology.
Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado.


We recently established that hybrid insulin peptides (HIPs) are present in human islets and that T cells reactive to HIPs are found in the residual islets of type 1 diabetic (T1D) organ donors. Here we investigate whether HIP-reactive T cells are indicative of ongoing autoimmunity in human T1D patients. We used IFN-γ ELISPOT analyses on peripheral blood mononuclear cells (PBMCs) to determine if new onset T1D or control subjects displayed T cell reactivity to a panel of 16 HIPs. We observed that nearly half of the patients responded to one or more HIPs. Responses to 4 HIPs were significantly elevated in T1D patients but not in control subjects. To characterize the T cells reactive to HIPs, we used a CFSE-based assay to clone T cells from PBMCs. We isolated 6 non-redundant, antigen-specific T cell clones, most of which reacting to their target HIPs in the low nanomolar range. One T cell clone was isolated from the same patient on two different blood draws, indicating persistence of this T cell clone in the peripheral blood. This work suggests that HIPs are important target antigens in human T1D subjects and may play a critical role in disease.


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