Prevention of Diabetes in NOD Mice by Administration of Dendritic Cells Deficient in Nuclear Transcription Factor-κB Activity

  1. Linlin Ma1,
  2. Shiguang Qian1,
  3. Xiaoyan Liang1,
  4. Lianfu Wang1,
  5. Jennifer E. Woodward1,
  6. Nick Giannoukakis2,
  7. Paul D. Robbins3,
  8. Suzanne Bertera4,
  9. Massimo Trucco4,
  10. John J. Fung1 and
  11. Lina Lu1
  1. 1Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
  2. 2Diabetes Institute, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
  3. 3Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
  4. 4Division of Immunogenetics, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  1. Address correspondence and reprint requests to Lina Lu, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, W1556 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261. E-mail: lul{at}msx.upmc.edu

Abstract

Abnormalities of dendritic cells (DCs) have been identified in type 1 diabetic patients and in nonobese diabetic (NOD) mice that are associated with augmented nuclear transcription factor (NF)-κB activity. An imbalance that favors development of the immunogenic DCs may predispose to the disease, and restoration of the balance by administration of DCs deficient in NF-κB activity may prevent diabetes. DCs propagated from NOD mouse bone marrow and treated with NF-κB–specific oligodeoxyribonucleotide (ODN) in vitro (NF-κB ODN DC) were assessed for efficacy in prevention of diabetes development in vivo. Gel shift assay with DC nuclear extracts confirmed specific inhibition of NF-κB DNA binding by NF-κB ODN. The costimulatory molecule expression, interleukin (IL)-12 production, and immunostimulatory capacity in presenting allo- and islet-associated antigens by NF-κB ODN DC were significantly suppressed. NF-κB ODN renders DCs resistant to lipopolysaccharide stimulation. Administration of 2 × 106 NF-κB ODN DCs into NOD mice aged 6–7 weeks effectively prevented the onset of diabetes. T-cells from pancreatic lymph nodes of NF-κB ODN DC–treated animals exhibited hyporesponsiveness to islet antigens with low production of interferon-γ and IL-2. These findings provide novel insights into the mechanisms of autoimmune diabetes and may lead to development of novel preventive strategies.

Footnotes

    • Accepted May 16, 2003.
    • Received August 16, 2002.
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