Successfully delaying or preventing type 1 diabetes (T1D) will depend heavily on distinguishing those individuals that will progress to T1D among those individuals possessing high risk major histocompatibility complex alleles and/or titers for islet cell auto-antibodies (AA). Towards this goal, we have developed and applied a sensitive bioassay that measures the effect of serum or plasma on induced transcript levels in a well- controlled """"""""reporter"""""""" peripheral blood mononuclear cell (PBMC) population. With this approach we have defined a recent onset (RO) T1D signature that includes genes regulated by interleukin-1, a cytokine that induces pancreatic ?-cell apoptosis in vitro and co-stimulates T-cells. This response is modulated by blocking IL-1 receptor in cultures and is distinct from that induced by samples of unrelated healthy controls, long- standing T1D patients, or patients possessing other diseases. So far, we have examined longitudinal samples of 9 progressors to T1D;in all cases the RO T1D signature was evident prior to onset. Importantly, this signature was detected in 3/3 cases where samples were available prior to AA development. Our data support the hypothesis that the dilute cytokine milieu associated with autoimmunity towards the pancreatic ?-cells is sufficient to induce a unique T1D-specific transcriptional profile;this signature reflects active autoimmunity, is disease specific, and may improve disease prediction beyond AA. In response to Program Announcement """""""" Response to PAR-11-350: Research Using Biosamples From Selected Type 1 Diabetes Clinical Studies (DP3)"""""""" we propose this collaborative, multicenter study where the following aims will be perused to refine this mechanistically informative biomarker and define its predictive potential and utility: 1) Define the signature as a quantitative early biomarker for staging T1D progression. 2) Define disease-specificity of the T1D-signature.
Many inflammatory diseases, including T1D become evident only after tissue damage has progressed. New approaches are needed. Completion of these aims has the potential to reveal predictive biomarkers reflective of T1D pathophysiology.
