Immune modulation and tolerance induction by RelB-silenced dendritic cells through RNA interference.
Dendritic cells (DC), the most potent APCs, can initiate the immune response or help induce immune tolerance, depending upon their level of maturation. DC maturation is associated with activation of the NF-kappaB pathway, and the primary NF-kappaB protein involved in DC maturation is RelB, which coordinates RelA/p50-mediated DC differentiation. In this study, we show that silencing RelB using small interfering RNA results in arrest of DC maturation with reduced expression of the MHC class II, CD80, and CD86. Functionally, RelB-silenced DC inhibited MLR, and inhibitory effects on alloreactive immune responses were in an Ag-specific fashion. RelB-silenced DC also displayed strong in vivo immune regulation. An inhibited Ag-specific response was seen after immunization with keyhole limpet hemocyanin-pulsed and RelB-silenced DC, due to the expansion of T regulatory cells. Administration of donor-derived RelB-silenced DC significantly prevented allograft rejection in murine heart transplantation. This study demonstrates for the first time that transplant tolerance can be induced by means of RNA interference using in vitro-generated tolerogenic DC.
Li
Mu
M
Department of Surgery, University of Western Ontario, London Health Sciences Centre-University Campus, 339 Windermere Road, London, Ontario, Canada.
Zhang
Xusheng
X
Zheng
Xiufen
X
Lian
Dameng
D
Zhang
Zhu-Xu
ZX
Ge
Weiwen
W
Yang
Jinming
J
Vladau
Costin
C
Suzuki
Motohiko
M
Chen
Dong
D
Zhong
Robert
R
Garcia
Bertha
B
Jevnikar
Anthony M
AM
Min
Wei-Ping
WP
D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation; D007165:Immunosuppression Therapy / Q000379:methods*; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051841:Transcription Factor RelB / Q000037:antagonists & inhibitors* / Q000235:genetics; D023001:Transplantation Tolerance / Q000235:genetics*
D034741:RNA, Small Interfering; C497594:Relb protein, mouse; D051841:Transcription Factor RelB