Journal Article

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

Suzanne Bertera, Massimo Trucco, Paul D. Robbins, Lianfu Wang, Nick Giannoukakis, John J. Fung, Lina Lu, Jennifer E. Woodward, Linlin Ma, Xiaoyan Liang, Shiguang Qian

2003

Overview

Prevention of Diabetes in NOD Mice by Administration of Dendritic Cells Deficient in Nuclear Transcription Factor-κB Activity Linlin Ma 1 , Shiguang Qian 1 , Xiaoyan Liang 1 , Lianfu Wang 1 , Jennifer E. Woodward 1 , Nick Giannoukakis 2 , Paul D. Robbins 3 , Suzanne Bertera 4 , Massimo Trucco 4 , John J. Fung 1 and Lina Lu 1 1 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 2 Diabetes Institute, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 3 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 4 Division of Immunogenetics, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania 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 × 10 6 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. APC, antigen-presenting cell CTL, cytotoxic T-lymphocyte DC, dendritic cell ELISA, enzyme-linked immunosorbent assay EMSA, electrophoretic mobility shift assay FITC, fluorescein isothiocyanate GM-CSF, granulocyte-macrophage colony-stimulating factor IFN, interferon IκB, inhibitor of κB IL, interleukin iNOS, inducible nitric oxide synthetase LPS, lipopolysaccharide mAb, monoclonal antibody MHC, major histocompatibility complex MLR, mixed leukocyte reaction NF-κB, nuclear transcription factor-κB ODN, oligodeoxyribonucleotide TNF, tumor necrosis factor TUNEL, transferase-mediated dUTP nick-end labeling Footnotes Accepted May 16, 2003. Received August 16, 2002. DIABETES

• Publisher: American Diabetes Association
• Subject: Autoimmune diseases / Biological and medical sciences / Dendritic cells / Diabetes. Impaired glucose tolerance / Drug therapy / Drug use / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Medical sciences / Prevention / Type 1 diabetes