Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis

• Published in: Human gene therapy Vol. 14; no. 1; p. 13
• Main Authors: Feili-Hariri, Maryam, Falkner, Dewayne H, Gambotto, Andrea, Papworth, Glenn D, Watkins, Simon C, Robbins, Paul D, Morel, Penelope A
• Format: Journal Article
• Language: English
• Published: United States 01-01-2003
• Subjects: Adenoviridae - genetics; Animals; Antigens, CD - metabolism; B7-1 Antigen - metabolism; B7-2 Antigen; CD40 Antigens - metabolism; Cells, Cultured; Cytokines - metabolism; Dendritic Cells - drug effects; Dendritic Cells - physiology; Dendritic Cells - virology; Diabetes Mellitus, Experimental - prevention & control; Female; Genetic Therapy - methods; Interferon-gamma - pharmacology; Interleukin-4 - genetics; Interleukin-4 - metabolism; Lymph Nodes - cytology; Lymph Nodes - metabolism; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred NOD; Pancreas - metabolism; Pancreatitis - therapy; Phantoms, Imaging; Spleen - immunology; Spleen - physiology; T-Lymphocytes - physiology; Th2 Cells - metabolism; Th2 Cells - physiology; Transduction, Genetic
• ISSN: 1043-0342
• DOI: 10.1089/10430340360464679

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.