Related Experiment Video
Updated: Jan 8, 2026
Bioluminescent Monitoring of Graft Survival in an Adoptive Transfer Model of Autoimmune Diabetes in Mice
Published on: November 18, 2022
Induction of immune education in type 1 diabetes through controlled allogeneic islet rejection at onset: a
Lorenzo Piemonti1,2, Andrea Mario Bolla3, Amelia Caretto3
1Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy.
Background:
Current immunotherapies for type 1 diabetes (T1D) have shown limited success in durably preserving β-cell function. We tested a novel strategy that repurposes allogeneic islet transplantation not for metabolic replacement, but as a platform for antigen-specific immune education.
Methods:
In this monocentric, open-label pilot study (April 2015-April 2023), six patients with recent-onset T1D received a minimal islet mass (median 3452 IEQ/kg; range 2980-4050) combined with short-term immunomodulation (ATG, transient mTOR inhibition, and G-CSF). The transplanted islet mass was intentionally insufficient for metabolic replacement. The primary endpoint was the change in stimulated 2-h C-peptide AUC at 52 weeks. Exploratory endpoints included immune cell phenotyping, cytokine/chemokine profiling, miR-375 release kinetics, analysis of islet-related autoantibodies, and monitoring of donor-specific HLA antibodies. ClinicalTrials.gov Identifier: NCT02505893.
Findings:
The protocol was safe and well-tolerated. At 12 months, the median stimulated C-peptide AUC was preserved at 91-100% of baseline with all participants achieving a partial clinical remission (IDAA1c ≤ 9). At 5 years, median C-peptide AUC declined to 44-56% of baseline, with 2 patients maintaining stable secretion and 2 retaining ∼50% of initial function. Exploratory analyses demonstrated a structured pattern of immune resetting, with early lymphodepletion followed by memory and regulatory T-cell expansion; transient increases in IL-2 and IL-10; sustained early elevation of sCD25; biphasic miR-375 peaks indicating early β-cell stress; transient increases in autoantibodies without epitope spreading; and donor-specific class I HLA antibodies in five patients, with persistent class II DSA in two. No expansion of CD3+CD8+ T cells specific for GAD65 was detected.
Interpretation:
This study introduces a paradigm shift in the use of islet transplantation-transforming it from a metabolic intervention into a tolerogenic stimulus through controlled antigen exposure. Further potentiation with stem-cell-derived islets may enable improved matching, graft modification, and iterative antigen delivery.
Funding:
Supported by Fondazione Italiana Diabete (FID). The funder had no role in study design, data collection, data analysis, interpretation, manuscript preparation, or decision to publish.
