Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis.
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.
Feili-Hariri
Maryam
M
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. mah37@pitt.edu
Falkner
Dewayne H
DH
Gambotto
Andrea
A
Papworth
Glenn D
GD
Watkins
Simon C
SC
Robbins
Paul D
PD
Morel
Penelope A
PA
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
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