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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type 1 Diabetes Targeted Research Award (DP3)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-J (J2))
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Cabrera, Susanne M; Engle, Samuel; Kaldunski, Mary et al. (2018) Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes. Diabetologia 61:2356-2370
Tsai, Susan; McOlash, Laura; Jia, Shuang et al. (2018) A serum-induced transcriptome and serum cytokine signature obtained at diagnosis correlates with the development of early pancreatic ductal adenocarcinoma metastasis. Cancer Epidemiol Biomarkers Prev :
Gao, Shouguo; Wolanyk, Nathaniel; Chen, Ye et al. (2017) Investigation of coordination and order in transcription regulation of innate and adaptive immunity genes in type 1 diabetes. BMC Med Genomics 10:7
Gurram, B; Salzman, N H; Kaldunski, M L et al. (2016) Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease. Clin Exp Immunol 184:36-49
Cabrera, Susanne M; Henschel, Angela M; Hessner, Martin J (2016) Innate inflammation in type 1 diabetes. Transl Res 167:214-27
Cabrera, Susanne M; Chen, Yi-Guang; Hagopian, William A et al. (2016) Blood-based signatures in type 1 diabetes. Diabetologia 59:414-25
Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang et al. (2016) Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset. Eur J Immunol 46:1030-46
Chen, Yi-Guang; Cabrera, Susanne M; Jia, Shuang et al. (2014) Molecular signatures differentiate immune states in type 1 diabetic families. Diabetes 63:3960-73
Chen, Y G; Mordes, J P; Blankenhorn, E P et al. (2013) Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes. Genes Immun 14:387-400