Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models.
OBJECTIVE
We have demonstrated previously that dendritic cells (DCs) modified with immunosuppressive cytokines, and exosomes derived from DCs can suppress the onset of murine collagen-induced arthritis (CIA) and reduce the severity of established arthritis. Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme that is important for immune regulation and tolerance maintenance. DCs expressing functional IDO can inhibit T cells by depleting them of essential tryptophan and/or by producing toxic metabolites, as well as by generating Treg cells. This study was undertaken to examine the immunosuppressive effects of bone marrow (BM)-derived DCs genetically modified to express IDO, and of exosomes derived from IDO-positive DCs.


METHODS
BM-derived DCs were adenovirally transduced with IDO or CTLA-4Ig (an inducer of IDO), and the resulting DCs and exosomes were tested for their immunosuppressive ability in the CIA and delayed-type hypersensitivity (DTH) murine models.


RESULTS
Both DCs and exosomes derived from DCs overexpressing IDO had an antiinflammatory effect in CIA and DTH murine models. The suppressive effects were partially dependent on B7 costimulatory molecules. In addition, gene transfer of CTLA-4Ig to DCs resulted in induction of IDO in the DCs and in exosomes able to reduce inflammation in an IDO-dependent manner.


CONCLUSIONS
These results demonstrate that both IDO-expressing DCs and DC-derived exosomes are immunosuppressive and antiinflammatory, and are able to reverse established arthritis. Therefore, exosomes from IDO-positive DCs may represent a novel therapy for rheumatoid arthritis.
Bianco
Nicole R
NR
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Kim
Seon Hee
SH
Ruffner
Melanie A
MA
Robbins
Paul D
PD
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D001854:Bone Marrow Cells; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D055354:Exosomes / Q000235:genetics / Q000276:immunology / Q000637:transplantation*; D005260:Female; D018014:Gene Transfer Techniques; D022761:Gene Transfer, Horizontal; D006968:Hypersensitivity, Delayed / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase