title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was an open-label phase I trial at the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver.
  
  
  METHODS
  Twelve recently diagnosed subjects with T1D with detectable C-peptides were included in the study.
  
  
  METHODS
  Eight consecutive weekly infusions of 80 mg/kg of AAT were given.
  
  
  METHODS
  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.
authors: 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.
authors: Peter A
authors: PA
authors: Gottlieb
authors: Aimon K
authors: AK
authors: Alkanani
authors: Aaron W
authors: AW
authors: Michels
authors: Eli C
authors: EC
authors: Lewis
authors: Leland
authors: L
authors: Shapiro
authors: Charles A
authors: CA
authors: Dinarello
authors: Danny
authors: D
authors: Zipris
mesh_terms: D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D051193:Toll-Like Receptors; D000515:alpha 1-Antitrypsin