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-kappaB 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 Talpha(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.
Zhang
Yong
Y
Department of Neurology, Xiangya Hosptial, Central South University, Changsha, Hunan 410008, PR China.
Yang
Huan
H
Xiao
Bo
B
Wu
Minghua
M
Zhou
Wenbing
W
Li
Jing
J
Li
Guiyuan
G
Christadoss
Premkumar
P
D000818:Animals; D000906:Antibodies / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D016219:Immunotherapy, Adoptive; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000628:therapy*; D041681:NIH 3T3 Cells; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011950:Receptors, Cholinergic / Q000276:immunology* / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics* / Q000276:immunology; D014161:Transduction, Genetic
D000906:Antibodies; D010455:Peptides; D034741:RNA, Small Interfering; D011950:Receptors, Cholinergic; C497594:Relb protein, mouse; D051841:Transcription Factor RelB