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 Blood, 30 April 2009, Vol. 113, No. 18, pp. 4262-4272.
Prepublished online as a Blood First Edition Paper on January 22, 2009; DOI 10.1182/blood-2008-08-176446.

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IMMUNOBIOLOGY

Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity

Shin-ichiro Fujii1, Akira Goto1, and Kanako Shimizu1,2

1 Research Unit for Cellular Immunotherapy and 2 Research Unit for Therapeutic Model, The Institute of Physical and Chemical Research (RIKEN), Research Center for Allergy and Immunology (RCAI), Yokohama, Japan

The maturation of dendritic cells (DCs) in situ by danger signals plays a central role in linking innate and adaptive immunity. We previously demonstrated that the activation of invariant natural killer T (iNKT) cells by administration of {alpha}-galactosylceramide ({alpha}-GalCer)–loaded tumor cells can act as a cellular adjuvant through the DC maturation. In the current study, we used allogeneic fibroblasts loaded with {alpha}-GalCer and transfected with antigen-encoding mRNA, thus combining the adjuvant effects of iNKT-cell activation with delivery of antigen to DCs in vivo. We found that these cells produce antigen protein and activate NK and iNKT cells. When injected into major histocompatibility complex (MHC)–mismatched mice, they elicited antigen-specific T-cell responses and provided tumor protection, suggesting that these immune responses depend on host DCs. In addition, antigen-expressing fibroblasts loaded with {alpha}-GalCer lead to a more potent T-cell response than those expressing NK cell ligands. Thus, glycolipid-loaded, mRNA-transfected allogeneic fibroblasts act as cellular vectors to provide iNKT-cell activation, leading to DC maturation and T-cell immunity. By harnessing the innate immune system and generating an adaptive immune response to a variety of antigens, this unique tool could prove clinically beneficial in the development of immunotherapies against malignant and infectious diseases.


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