免疫教育の誘導における1型糖尿病の同種異種膵島拒絶の制御：発症時の単施設非盲検パイロットスタディ

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.

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.

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.

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.

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.