Prevention of diabetes in NOD mice by administration of dendritic cells deficient in nuclear transcription factor-kappaB activity.
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)-kappaB 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-kappaB activity may prevent diabetes. DCs propagated from NOD mouse bone marrow and treated with NF-kappaB-specific oligodeoxyribonucleotide (ODN) in vitro (NF-kappaB 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-kappaB DNA binding by NF-kappaB ODN. The costimulatory molecule expression, interleukin (IL)-12 production, and immunostimulatory capacity in presenting allo- and islet-associated antigens by NF-kappaB ODN DC were significantly suppressed. NF-kappaB ODN renders DCs resistant to lipopolysaccharide stimulation. Administration of 2 x 10(6) NF-kappaB ODN DCs into NOD mice aged 6-7 weeks effectively prevented the onset of diabetes. T-cells from pancreatic lymph nodes of NF-kappaB ODN DC-treated animals exhibited hyporesponsiveness to islet antigens with low production of interferon-gamma and IL-2. These findings provide novel insights into the mechanisms of autoimmune diabetes and may lead to development of novel preventive strategies.
Ma
Linlin
L
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Qian
Shiguang
S
Liang
Xiaoyan
X
Wang
Lianfu
L
Woodward
Jennifer E
JE
Giannoukakis
Nick
N
Robbins
Paul D
PD
Bertera
Suzanne
S
Trucco
Massimo
M
Fung
John J
JJ
Lu
Lina
L
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D004247:DNA