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 coo...

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Bibliographic Details
Published in:Journal of Immunology 2007-05, Vol.178 (9), p.5480-5487
Main Authors: Li, Mu, Zhang, Xusheng, Zheng, Xiufen, Lian, Dameng, Zhang, Zhu-Xu, Ge, Weiwen, Yang, Jinming, Vladau, Costin, Suzuki, Motohiko, Chen, Dong, Zhong, Robert, Garcia, Bertha, Jevnikar, Anthony M, Min, Wei-Ping
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Dendritic Cells - drug effects
Dendritic Cells - immunology
Dendritic Cells - transplantation
Graft Rejection - prevention & control
Heart Transplantation
Immunosuppression - methods
Lymphocyte Activation
Mice
Mice, Inbred Strains
RNA Interference
RNA, Small Interfering - pharmacology
T-Lymphocytes, Regulatory - immunology
Transcription Factor RelB - antagonists & inhibitors
Transcription Factor RelB - genetics
Transplantation Tolerance - genetics
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Summary: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.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.178.9.5480