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Immune Modulation and Tolerance Induction by RelB-Silenced Dendritic Cells through RNA Interference¹

Mu Li^2,*, Xusheng Zhang^2,*, Xiufen Zheng^*, Dameng Lian^*, Zhu-Xu Zhang^*, Weiwen Ge^¶, Jinming Yang^||, Costin Vladau^*, Motohiko Suzuki^*, Dong Chen^*, Robert Zhong^*,,,, Bertha Garcia^*,, Anthony M. Jevnikar^*,,, and Wei-Ping Min^3,*,,,

^* Department of Surgery, Department of Pathology, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Robarts Research Institute, London, Ontario, Canada; ^¶ Advanced Proteomics Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07107; and ^|| Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232

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-B pathway, and the primary NF-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Heart and Stroke Foundation of Canada, the Roche Organ Transplantation Research Foundation, the Canadian Institutes of Health Research, and the Multi-Organ Transplant Program at the London Health Sciences Centre.

² M.L. and X.Zha. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Wei-Ping Min, C9-136, London Health Sciences Centre-University Campus, 339 Windermere Road, London, Ontario, Canada N6A 5A5. E-mail address: weiping.min{at}uwo.ca

⁴ Abbreviations used in this paper: DC, dendritic cell; imDC, immature DC; mDC, mature DC; RNAi, RNA interference; siRNA, small interfering RNA; Treg, regulatory T cell; KLH, keyhole limpet hemocyanin.

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