Rheumatoid arthritis (RA) is a systemic autoimmune disease distinguished by chronic pathology of the joint including inflammatory cell infiltration and synovial hyperplasia that contribute to the progressive degradation of cartilage and bone. Although progress has been made in improving certain arthritis-associated pathologies, no therapy has been effective in reversing disease progression. Recently the Robbins laboratory has demonstrated the ability of genetically modified immature dendritic cells (DC) expressing IL-4 or FasL to reverse established murine collagen induced arthritis following a single systemic injection for extended periods of time. Recently, exosomes derived from DC and B cells, which are small (40-100nm) secreted membrane vesicles of endocytic origin, have been shown to regulate the immune system in an antigen-dependent manner. Preliminary studies from the Robbins laboratory have shown that exosomes from immunosuppressive DC are able to prevent an antigen-specific delayed-type hypersensitivity response (DTH) and suppress and even reverse induced murine arthritis for extended periods of time after a single systemic injection. Interestingly, with both immunosuppressive DC and exosomes, amelioration of disease occurs in the treated as well as the untreated contralateral joints. The underlying hypothesize is that immunosuppressive DC produce exosomes that confer lasting immunosuppressive effects in models of autoimmune and inflammatory disease. This hypothesis will be examined in the following three Specific Aims: 1) To improve the yield and purity of DC-derived exosomes. 2) To determine the DC-derived exosome components responsible for the immunosuppressive effects. 3) To examine the mechanisms through which exosomes confer their therapeutics effects.
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