Immune Biomarkers of Islet Transplant Rejection Revealed by Synthetic Immunological Niche

ABSTRACT Islet transplantation can restore glycemic control in type 1 diabetes, yet heterogeneity of immune responses and transplant outcomes necessitates improved graft monitoring. Since transplanted islets are diffusely engrafted within the liver and inaccessible to biopsy, clinical monitoring relies on blood glucose and C‐peptide, which change only after substantial graft injury. Here, we developed a synthetic immunological niche (IN) that captures graft‐associated immune responses through serial subcutaneous biopsy. We evaluated the IN across murine syngeneic, allogeneic, and autoimmune islet transplant models, including CD40/CD154 blockade with anti‐CD40L. The IN identified immune populations and transcriptomic signatures reflective of the graft and distinguished syngeneic from rejecting allografts. In anti‐CD40L‐treated allografts, the IN revealed innate immune programs characterized by macrophage‐ and dendritic cell‐associated signatures linked to acceptance versus rejection, whereas untreated allografts showed stronger adaptive immune signatures. Longitudinal IN profiling detected inflammatory activation in accepted allografts, indicating persistent subclinical risk. Finally, in autoimmune allografts treated with anti‐CD40L plus rapamycin, IN identified a 13‐gene signature that separated early from late rejection and distinguished autoimmune‐ from alloimmune‐associated rejection programs. These findings establish the IN as a platform for identification of early biomarkers of islet graft rejection before overt dysfunction, addressing an unmet need in islet transplant monitoring.