Synthetic immunological niche reveals early immune dysregulation and stratifies therapeutic response in type 1 diabetes

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Abstract

In Type 1 Diabetes (T1D), disease onset and immunotherapy responses vary widely, reflecting heterogeneous stage-specific immune dysregulation that remains undefined. To investigate this heterogeneity, we engineered microporous polycaprolactone scaffolds that form synthetic immunological niches (INs) subcutaneously and capture tissue-associated systemic immune changes. Building on our prior demonstration of IN-based longitudinal T1D monitoring, we use multimodal IN profiling to define the immune changes underlying divergent disease trajectories and immunotherapy responses. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN identified early myeloid associated changes, followed by increasing T cell-associated dysregulation that distinguished progressors from non-progressors. An early-stage IN-based T1D gene signature stratified NOD progressors from non-progressors by 6 weeks of age and was conserved across human T1D tissues, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not in peripheral blood. Signature-based stratification revealed macrophage-associated TNFα pathway enrichment in pancreas of NOD progressors, which was validated in human T1D islets. Given the heterogeneous response to anti-TNFα therapy, IN profiling identified genesets associated with anti-TNFα efficacy and generated a response score that prospectively distinguished treatment-sensitive from resistant mice. These findings establish IN as a platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.

Authors

Jyotirmoy Roy, Yifei Jiang, Runbo Mao, Jessica L. King, Amod Talekar, Donglin Liu, Lillian Holman, Haoxuan Zeng, Xin Luo, Laila M. Rad, Peter Sajjakulnukit, Brianna Ha, Kai Liu, Elizabeth J. Bealer, Bryan Wonski, Kathryn Kang, Sean T. Carey, Luke F. Bugada, Brooke M. Smiley, Shahzad Sohail, Antonio D. Holmes, Dominik Awad, Aaron H. Morris, Costas A. Lyssiotis, Jie Liu, Lonnie D. Shea