In Pursuit of HIPs and HIP-reactive T cells

Hybrid insulin peptides (HIPs) are a new class of antigens that are targeted by autoreactive T cells isolated from the residual islets of organ donors with type 1 diabetes (T1D). Each HIP consists of a proinsulin fragment that is covalently cross-linked to another protein fragments through a peptide bond. We previously isolated and identified various HIPs in murine beta cell tumors and we demonstrated that several of these HIPs are targeted by a number diabetes-triggering CD4 T cell clones obtained from non-obese diabetic (NOD) mice. We also identified HIP-reactive T cells that were isolated from the residual islets of T1D organ donors, signifying localization of HIPs to the core of the infiltrated pancreatic islets in humans. We are currently applying mass spectrometric methods to determine if HIPs form in human islets. Additionally, we are using ELISPOT analyses to determine if new onset T1D patients have HIP-reactive T cells in their peripheral blood mononuclear cell (PBMCs). Identification of new HIPs in human islets and new HIP-reactive T cell specificities in T1D patients may provide us with reagents to further characterize the T cell mediated attack on beta cells and to test new strategies for antigen-specific tolerance induction.