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* Department of Molecular Genetics and Biochemistry,
Department of Surgery and
Department of Molecular Medicine and
T. E. Starzl Transplantion Institutes, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported in part by Grants AI56374 (to P.D.R.), HL075512 (to A.E.M.), and HL077545 (to A.E.M.) from the National Institutes of Health and Juvenile Diabetes Research Foundation Grant 7-005-1154 (to P.D.R.).
2 Address correspondence and reprint requests to Dr. Paul D. Robbins, Department of Molecular Genetics and Biochemistry, W1246 BST, University of Pittsburgh, Pittsburgh, PA 15261. E-mail address: probb{at}pitt.edu
3 Abbreviations used in this paper: CIA, collagen-induced arthritis; DC, dendritic cell; BM, bone marrow; FasL, Fas ligand; MHC I/II, MHC class I/II; Ad.FasL, adenovirus encoding FasL; DTH, delayed-type hypersensitivity; mbIL-4, membrane-bound IL-4; sIL-4, secreted IL-4; KLH, keyhole limpet hemocyanin; i.d., intradermal(ly); Ad.IL-4, adenovirus encoding IL-4; Ad.mbIL-4, adenovirus encoding mbIL-4; Ad.sIL-4, adenovirus encoding sIL-4.
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