Exosomes Derived from IL-10-Treated Dendritic Cells Can Suppress Inflammation and Collagen-Induced Arthritis

Abstract

We have demonstrated previously that local, adenoviral-mediated gene transfer of viral IL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. This contralateral effect is mediated in part by APCs able to traffic from the treated joint to lymph nodes as well as to untreated joints. Moreover, injection of dendritic cells (DC) genetically modified to express IL-4 or Fas ligand was able to reverse established murine arthritis. To examine the ability of exosomes derived from immunosuppressive DCs to reduce inflammation and autoimmunity, murine models of delayed-type hypersensitivity and collagen-induced arthritis were used. In this study, we demonstrate that periarticular administration of exosomes purified from either bone marrow-derived DCs transduced ex vivo with an adenovirus expressing viral IL-10 or bone marrow-derived DCs treated with recombinant murine IL-10 were able to suppress delayed-type hypersensitivity responses within injected and untreated contralateral joints. In addition, the systemic injection of IL-10-treated DC-derived exosomes was able suppress the onset of murine collagen-induced arthritis as well as reduce severity of established arthritis. Taken together, these data suggest that immature DCs are able to secrete exosomes that are involved in the suppression of inflammatory and autoimmune responses. Thus DC-derived exosomes may represent a novel, cell-free therapy for the treatment of autoimmune diseases.

B cell activation regulates exosomal HLA production

“…On the other hand, exosomes secreted from cancer cells or in malignant effusions possess Fas ligands and mediate apoptosis of T cells [44][45][46]. In addition, placenta-derived exosomes of pregnant women [47][48][49][50] and IL-10-treated dendritic cell-derived exosomes [51] have immunoregulating functions. Based on our observations, the exosomes derived from EBVtransformed B cells showed an immunoregulatory function in vitro, although it remains to be determined whether trace amounts of unknown factors included in our exosomal fractions exert their effect.…”

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…Tolerogenic bone marrow derived DCs can suppress collagen-induced arthritis or prevent hyperglycaemia in NOD mice without inducing generalised immunosuppression [5,7,26]. Intriguingly, EVs derived from in vitro generated immunosuppressive DCs can retain the effects of their parental cells [27,28]. Recently, clinical trials using tolerogenic DC-based therapies have been designed [4,5].…”

Novel MHC Class I Structures on Exosomes

“…For example, peptide-pulsed exosomes from DC can induce tumor rejection in mice (10), while exosomes generated from DC incubated with the immunoregulatory cytokine IL-10 can down-regulate disease activity in a collagen-induced murine model of arthritis (1). This ability of exosomes to act as "cell-free" vaccines has already been tested in phase I clinical trials against melanoma, small-cell lung cancer, and colorectal cancer (11)(12)(13).…”

“…3 (1)(2)(3)(4). A proportion of these MVBs can fuse with the plasma membrane, releasing their internal vesicles to the extracellular environment.…”