title: Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive.
abstract: We previously have demonstrated the ability of primary murine bone marrow-derived DC (BM-DC), genetically modified by adenoviral infection to express FasL, to inhibit progression of established collagen-induced arthritis (CIA) following systemic delivery. Here we demonstrate that exosomes derived from genetically modified BM-DC expressing FasL are able to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH). Local administration of exosomes derived from DC expressing FasL (Exo/FasL) as well as the parental DC/FasL resulted in a significant reduction in swelling in both the treated and the untreated distal paw. However, both the DC/FasL and the Exo/FasL were unable to suppress the DTH response in lpr (Fas-deficient) mice. Gene transfer of FasL to BM-DC from gld (FasL-deficient) mice resulted in restoration of the ability of DC as well as DC-derived exosomes to suppress DTH. The ability of DC-derived exosomes and DC to suppress DTH responses was antigen specific and MHC class II dependent, but class I independent. The injected exosomes were found to be internalized into CD11c(+) cells at the site of injection and in the draining popliteal lymph node. Systemic injection of exosome/FasL into mice with established CIA resulted in significant disease amelioration. These results demonstrate that both systemic and local administration of exosomes derived from FasL-expressing DC are able to suppress antigen-specific immune responses through an MHC class II-dependent pathway, resulting in effective and sustained treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. These results suggest that DC/FasL-derived exosomes could be used clinically for the treatment of inflammatory and autoimmune diseases.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Nicole
authors.initials: N
authors.lastname: Bianco
authors.forename: Rajasree
authors.initials: R
authors.lastname: Menon
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lechman
authors.forename: William J
authors.initials: WJ
authors.lastname: Shufesky
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D055354:Exosomes / Q000235:genetics* / Q000276:immunology* / Q000637:transplantation; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000502:physiology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D019014:fas Receptor