Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive

Mol Ther. 2006 Feb;13(2):289-300. doi: 10.1016/j.ymthe.2005.09.015. Epub 2005 Nov 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / metabolism
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Disease Models, Animal
  • Exosomes / genetics*
  • Exosomes / immunology*
  • Exosomes / transplantation
  • Fas Ligand Protein / biosynthesis
  • Fas Ligand Protein / genetics*
  • Gene Expression Regulation / immunology*
  • Hypersensitivity, Delayed / immunology
  • Hypersensitivity, Delayed / prevention & control
  • Immunosuppressive Agents / administration & dosage*
  • Inflammation Mediators / administration & dosage*
  • Inflammation Mediators / physiology
  • Injections, Subcutaneous
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • fas Receptor / metabolism

Substances

  • Fas Ligand Protein
  • Fas protein, mouse
  • Immunosuppressive Agents
  • Inflammation Mediators
  • fas Receptor