Immunosuppressive exosomes: a new approach for treating arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease and one of the leading causes of disability in the USA. Although certain biological therapies, including protein and antibodies targeting inflammatory factors such as the tumor necrosis factor, are effective in reducing symptoms of RA, these treatments do not reverse disease. Also, although novel gene therapy approaches have shown promise in preclinical and clinical studies to treat RA, it is still unclear whether gene therapy can be readily and safely applied to treat the large number of RA patients. Recently, nanosized, endocytic-derived membrane vesicles "exosomes" were demonstrated to function in cell-to-cell communication and to possess potent immunoregulatory properties. In particular, immunosuppressive DC-derived exosomes and blood plasma- or serum-derived exosomes have shown potent therapeutic effects in animal models of inflammatory and autoimmune disease including RA. This paper discusses the current knowledge on the production, efficacy, mechanism of action, and potential therapeutic use of immunosuppressive exosomes for arthritis therapy.

Figure 1

Exosome biogenesis and molecular composition. (a) Exosomes are small membrane vesicles formed by invagination of the multivesicular bodies (MVBs) in the late endocytic compartment. They are released upon the fusion of MVBs with the plasma membrane. (b) Exosomes are typically enriched in certain molecules including targeting/adhesion molecules, membrane trafficking molecules, cytoskeleton molecules, proteins involved in MVB formation, chaperones, cytoplasmic enzymes, signal transduction proteins, and functional mRNA and microRNA populations. *APC-derived exosomes contain antigen-presenting molecules including MHC class I, MHC class II, and co-stimulatory molecules. **Exosomes also contain cell-specific antigens (e.g., tumor antigens in tumor-derived exosomes). ***Immunosuppressive molecules such as FasL, TRAIL, or TGF-β  are present on certain APC or tumor-derived exosomes.

Figure 2

Transmission electronic micrograph of (a) exosomes isolated from murine BMDC culture [36]. Copyright 2005. The American Association of Immunologists, Inc. and (b) exosomes isolated from murine blood plasma [37]. Copyright 2007. The American Association of Immunologists, Inc.