title: Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis.
abstract: Our previous studies demonstrated that adoptive transfer of dendritic cells (DC) prevents diabetes in young nonobese diabetic (NOD) mice by inducing regulatory T(H)2 cells. In this report, as a means of treating NOD mice with more advanced insulitis, we infected DC with adenoviral vectors expressing interleukin (IL)-4 (Ad.IL-4), eGFP (Ad.eGFP), or empty vector (Ad psi 5). DC infected with any of the Ad vectors expressed higher levels of CD40, CD80, and CD86 molecules than uninfected DC and Ad.IL-4 DC produced IL-4 after lipopolysaccharide (LPS) and interferon (IFN)-gamma stimulation. Ad-infected DC efficiently stimulated allogeneic T cells, and cultures of T cells with Ad.IL-4 DC produced lower levels of IFN-gamma and marginally higher levels of IL-4. In vivo studies demonstrated that the Ad.eGFP DC trafficked to the pancreatic lymph nodes within 24 hr of intravenous administration, and could be visualized in the T cell areas of the spleen. The intrapancreatic IFN-gamma:IL-4 or IFN-gamma:IL-10 cytokine ratios were lower in 10-week-old mice treated with Ad.IL-4 DC, and these mice were significantly protected from disease. These results demonstrate, for the first time, that genetically modified DC can prevent diabetes in the context of advanced insulitis.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. mah37@pitt.edu
authors.forename: Maryam
authors.initials: M
authors.lastname: Feili-Hariri
authors.forename: Dewayne H
authors.initials: DH
authors.lastname: Falkner
authors.forename: Andrea
authors.initials: A
authors.lastname: Gambotto
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Papworth
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Morel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology* / Q000821:virology; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000628:therapy*; D019047:Phantoms, Imaging; D013154:Spleen / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D018418:Th2 Cells / Q000378:metabolism / Q000502:physiology; D014161:Transduction, Genetic
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D015847:Interleukin-4; D007371:Interferon-gamma