Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4.
In this study, we demonstrate that genetically modified bone marrow-derived dendritic cells (DC) and exosomes derived from the DC, expressing either secreted IL-4 or membrane-bound IL-4, can reduce the severity and the incidence of established collagen-induced arthritis and inhibit inflammation of delayed-type hypersensitivity (DTH) in mice. The ability of the DC and DC-derived exosomes to suppress the DTH response was MHC class II and, in part, Fas ligand/Fas dependent. The DC-derived exosomes were internalized by CD11c(+) DC in the dermis at the site of injection and in the draining lymph node as well as by CD11c(+) DC and F4/80(+) macrophages in the spleen. Moreover, adoptive transfer of CD11c(+) or CD3(+) splenic cells from mice treated with exosomes showed significant reduction of footpad swelling in the DTH model. These results demonstrate that administration of DC/IL-4 or exosomes derived from DC/IL-4 are able to modulate the activity of APC and T cells in vivo through a MHC class II and partly Fas ligand/Fas-dependent mechanism, resulting in effective treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. Thus, APC-derived exosomes could be used therapeutically for the treatment of autoimmune disease and inflammatory disorders.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
Seon Hee
SH
Kim
Nicole R
NR
Bianco
William J
WJ
Shufesky
Adrian E
AE
Morelli
Paul D
PD
Robbins
D019264:Adoptive Transfer; D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D001854:Bone Marrow Cells / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D020405:Dermis / Q000276:immunology; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000628:therapy; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D018949:Antigens, CD1; D017252:CD3 Complex; D000949:Histocompatibility Antigens Class II; D015847:Interleukin-4