Dendritic cells transduced with lentiviral-mediated RelB-specific ShRNAs inhibit the development of experimental autoimmune myasthenia gravis

Dendritic cells (DC) are professional APC that are able to modulate immune response in either a positive or negative manner depending upon their lineage and state of maturation. RelB is a NF-kappa B family member which plays a key role in the differentiation and maturation of DC. In this study, we constructed lentiviral vector expressing RelB-specific short hairpin RNAs (ShRNAs) that efficiently silenced the RelB gene in bone marrow-derived dendritic cells (BMDCs). These RelB-silenced BMDCs were maturation resistant and could functionally decrease antigen-specific T cells proliferation. We tested the therapeutic effect of RelB-silenced BMDCs in C57BL/6 mice with experimental autoimmune myasthenia gravis (EAMG). Injection i.v.. with RelB-silenced BMDCs plused with Torpedo acetylcholine receptor (TAChR) dominant peptide T alpha(146-162) on days 3, 33, and 63 after first immunization decreased the incidence and severity of clinical EAMG with suppressed IFN-gamma production and increased IL-10 and IL-4 production in vitro and in vivo, and also leads to a decreased serum anti-AChR IgG, IgG1, IgG2b Ab levels. Furthermore, RelB-silenced BMDCs promoted regulatory T cell profiles as indicated by a marked increase of FoxP3 in splenocyte. Our data suggested that lentiviral-mediated RNAi targeting RelB was effective methods to inhibit the maturation of BMDCs, thus possess therapeutic potential to prevent autoimmune disorders such as EAMG or human MG. (C) 2008 Elsevier Ltd. All rights reserved.