α1-Antitrypsin Therapy Downregulates Toll-Like Receptor-Induced IL-1β Responses in Monocytes and Myeloid Dendritic Cells and May Improve Islet Function in Recently Diagnosed Patients With Type 1 Diabetes

Context: Recent studies have implicated proinflammatory responses in the mechanism of type 1 diabetes (T1D). Objective: Our objective was to evaluate the safety and effects of therapy with the anti-inflammatory serum protein alpha(1)-antitrypsin (AAT) on islet function and innate immunity in recent-onset patients. Design and Setting: This was an open-label phase I trial at the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver. Patients: Twelve recently diagnosed subjects with T1D with detectable C-peptides were included in the study. Intervention: Eight consecutive weekly infusions of 80 mg/kg of AAT were given. Main Outcome Measures: Patients were monitored for adverse effects of AAT therapy, C-peptide responses to a mixed-meal tolerance test, and toll-like receptor (TLR)-induced cellular IL-1 beta in monocytes and myeloid dendritic cells (mDCs). Results: No adverse effects were detected. AAT led to increased, unchanged, or moderately reduced levels of C-peptide responses compared with baseline in 5 patients. The total content of TLR4-induced cellular IL-1 beta in monocytes at 12 months after AAT therapy was 3-fold reduced compared with baseline (P < .05). Furthermore, at baseline, 82% of monocytes produced IL-1 beta, but at 12 months after therapy, the level decreased to 42%. Similar reductions were observed using TLR7/8 and TLR3 agonists in monocytes and mDCs. Unexpectedly, the reduction in cellular IL-1 beta was observed only 9 and 12 months after treatment but not in untreated diabetics. Improved beta-cell function in the 5 AAT-treated individuals correlated with lower frequencies of monocytes and mDCs producing IL-1 beta compared with subjects without improvement of islet function (P < .04 and P < .02, respectively). Conclusions: We hypothesize that AAT may have a beneficial effect on T1D in recently diagnosed patients that is associated with downmodulation of IL-1 beta.