T-cell responses to hybrid insulin peptides prior to type 1 diabetes development

Abstract

T-cell responses to posttranslationally modified self-antigens are associated with many autoimmune disorders. In type 1 diabetes, hybrid insulin peptides (HIPs) are implicated in the T-cell–mediated destruction of insulin-producing β-cells within pancreatic islets. The natural history of the disease is such that it allows for the study of T-cell reactivity prior to the onset of clinical symptoms. We hypothesized that CD4 T-cell responses to posttranslationally modified islet peptides precedes diabetes onset. In a cohort of genetically at-risk individuals, we measured longitudinal T-cell responses to native insulin and hybrid insulin peptides. Both proinflammatory (interferon-γ) and antiinflammatory (interluekin-10) cytokine responses to HIPs were more robust than those to native peptides, and the ratio of such responses oscillated between pro- and antiinflammatory over time. However, individuals who developed islet autoantibodies or progressed to clinical type 1 diabetes had predominantly inflammatory T-cell responses to HIPs. Additionally, several HIP T-cell responses correlated to worsening measurements of blood glucose, highlighting the relevance of T-cell responses to posttranslationally modified peptides prior to autoimmune disease development.

Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

“…The CDI for PI was also greater in AB-positive children than in participants with T1D > 3 months. For PI [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] , CDIs were significantly higher in AB-negative pre-diabetic FDR than in healthy controls, and a similar trend was observed for PI . The overall trend towards higher responses to hEL:A-chain, hEGGG:C-peptide and hEGGG:IAPP2 in participants with T1D ≤ 3 months and AB-positive FDR compared to healthy controls and T1D > 3 months was similar to that of PI 33-63 , but there was greater heterogeneity in the response (Figure 2).…”

“…In a recent analysis of PB cytokine responses to a partially overlapping set of islet epitopes (PI 40-52 , hEL:A-chain and hEGGG:IAPP2) using ELISPOT in FDR, the IFNg/IL-10 ratio in response to certain HIPs correlated with clinical parameters of progression to T1D, including islet AB titres and evidence of glucose intolerance. 48 Given that HIPspecific proliferative responses correlated with PI 33-63 -specific responses and that a PI 33-63 CDI ≥ 3 predicted survival in honeymoon after T1D onset, it will be of interest to determine whether PI 33-63 CDI also stratifies the risk of developing T1D, adding new insights into the classification of presymptomatic T1D. 49 Further work is also needed to characterise the phenotype and function of the proliferating PI 33-63 -specific CD4 + T cells, and to map changes in progressors and nonprogressors to T1D, and in individuals with sustained remission in clinical trials of immunotherapy.…”

Noncontiguous T cell epitopes in autoimmune diabetes: From mice to men and back again

“…In humans, HIP-reactive T cells are not limited to at-risk individuals and patients with T1D but are found in class II MHC-matched normal controls as well ( 26 , 28 ). However, a combined evaluation of T cell number and function for multiple HIP-reactive T cell populations may allow a disease-specific profile to be elucidated ( 26 , 28 , 98 ). Future essential work will ideally uncover HIP reactivities that are more confined to the disease state.…”

Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes

“…The Endotope platform shifts the focus from a single antigen to selected epitopes that can encompass multiple antigens and to which T cell reactivity is well documented. Important disease-driving epitopes now include various neoepitopes (6,7,9,34), which can be incorporated in the Endotope design. Mimotopes can also be used to mimic certain PTMs (e.g.…”