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Exosomes derived from genetically modified dc expressing fasl are anti-inflammatory and immunosuppressive

Academic Article
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Overview

authors

  • Kim, S. H.
  • Bianco, N.
  • Menon, R.
  • Lechman, E. R.
  • Shufesky, W. J.
  • Morelli, A. E.
  • Robbins, Paul D.

publication date

  • February 2006

journal

  • Molecular Therapy  Journal

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.

subject areas

  • Animals
  • Antigens, CD95
  • Arthritis, Experimental
  • Cells, Cultured
  • Dendritic Cells
  • Disease Models, Animal
  • Exosomes
  • Fas Ligand Protein
  • Gene Expression Regulation
  • Hypersensitivity, Delayed
  • Immunosuppressive Agents
  • Inflammation Mediators
  • Injections, Subcutaneous
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
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Research

keywords

  • Fas ligand
  • autoimmune disease
  • dendritic cells
  • exosomes
  • suppression
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Identity

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1016/j.ymthe.2005.09.015

PubMed ID

  • 16275099
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Additional Document Info

start page

  • 289

end page

  • 300

volume

  • 13

issue

  • 2

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