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

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

Published in

The Journal of clinical investigation. Nov 03, 2026. Epub Nov 03, 2026.

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.

PMID:
42975959
Bibliographic data and abstract were imported from PubMed on 04 Nov 2026.

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