Effective Treatment of Inflammatory Disease Models with Exosomes Derived from Dendritic Cells Genetically Modified to Express IL-4

• Published in: Journal of Immunology Vol. 179; no. 4; pp. 2242 - 2249
• Main Authors: Kim, Seon Hee, Bianco, Nicole R, Shufesky, William J, Morelli, Adrian E, Robbins, Paul D
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.08.2007
• Subjects: Adoptive Transfer; Animals; Antigens, CD1 - genetics; Antigens, CD1 - immunology; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - therapy; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - therapy; Bone Marrow Cells - immunology; CD3 Complex - immunology; Dendritic Cells - immunology; Dermis - immunology; Gene Expression; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; Hypersensitivity, Delayed - genetics; Hypersensitivity, Delayed - immunology; Hypersensitivity, Delayed - therapy; Inflammation - genetics; Inflammation - immunology; Inflammation - therapy; Interleukin-4 - genetics; Interleukin-4 - immunology; Mice; Mice, Inbred DBA; Spleen - immunology; T-Lymphocytes - immunology; Transduction, Genetic
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.4.2242

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.