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To investigate this heterogeneity, we engineered a microporous polycaprolactone scaffold that forms a synthetic immunological niche (IN) upon subcutaneous implantation, enabling in vivo capture of systemic immune dysregulation. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN-infiltrating cells identified early-stage genes relatively enriched for myeloid cells, followed by progressive increases in T cell-associated dysregulation at later stages that distinguished T1D progressors from non-progressors. We derived an early-stage IN-based T1D gene signature capturing immune alterations. The signature stratified NOD progressors from non-progressors as early as 6 weeks of age and was conserved across human T1D datasets, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not peripheral blood. Signature-based stratification further revealed enrichment of macrophage-associated TNF-\u03b1 pathways in NOD progressors, validated in human T1D islets. Given heterogeneous response to anti-TNF-\u03b1 therapy, IN profiling identified resistance-associated mechanisms and enabled derivation of a pathway score that prospectively distinguished treatment-sensitive from resistant mice prior to therapy, establishing the IN as a minimally invasive platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.<\/jats:p>","DOI":"10.64898\/2026.03.06.710219","type":"posted-content","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T19:40:19Z","timestamp":1773171619000},"source":"Crossref","is-referenced-by-count":2,"title":["Synthetic Immunological Niche Reveals Early Immune Dysregulation and Stratifies Therapeutic Response in Type 1 Diabetes"],"prefix":"10.64898","author":[{"given":"Jyotirmoy","family":"Roy","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runbo","family":"Mao","sequence":"additional","affiliation":[{"name":"Gilbert S. 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