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J Clin Endocrinol Metab. 2014 Aug;99(8):E1418-26. doi: 10.1210/jc.2013-3864. Epub 2014 Feb 14.

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.

Author information

1
Barbara Davis Center for Childhood Diabetes (P.A.G., A.K.A., A.W.M., D.Z.) and Division of Infectious Diseases (C.A.D.), University of Colorado Denver, Aurora, Colorado 80045; Department of Clinical Biochemistry and Pharmacology (E.C.L.), Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel; and Department of Medicine (L.S.), Division of Infectious Diseases, Veterans Affairs Medical Center and University of Colorado Denver, Denver, Colorado 80202.

Abstract

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 α1-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-1β 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-1β 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-1β, 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-1β was observed only 9 and 12 months after treatment but not in untreated diabetics. Improved β-cell function in the 5 AAT-treated individuals correlated with lower frequencies of monocytes and mDCs producing IL-1β 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-1β.

PMID:
24527714
PMCID:
PMC4121034
DOI:
10.1210/jc.2013-3864
[Indexed for MEDLINE]
Free PMC Article

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