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Calcineurin Inhibitors Block MHC-Restricted Antigen Presentation In Vivo¹

Young-Hee Lee^*, Young-Ran Lee^*, Sun-A Im^*, Sun-Im Park^*, Ki-Hyang Kim^*, Turmunkh Gerelchuluun^*, Sukgil Song^*, Kyungjae Kim and Chong-Kil Lee^2,*

^* College of Pharmacy, Chungbuk National University, Cheongju, and Department of Pharmacy, SahmYook University, Seoul, South Korea

APCs, like T cells, are affected by calcineurin inhibitors. In this study, we show that calcineurin inhibitors efficiently block MHC-restricted exogenous Ag presentation in vivo. Mice were injected with clinical doses of tacrolimus (FK-506) followed by soluble OVA, and dendritic cells (DCs) were isolated from lymph nodes and spleens. The efficacy of OVA peptide presentation by DCs was evaluated using OVA-specific CD8 and CD4 T cells. Tacrolimus inhibited both class I- and class II-restricted DC presentation of OVA to T cells. Tacrolimus also inhibited both class I- and class II-restricted presentation of OVA in peritoneal macrophages isolated from mice injected with tacrolimus followed by soluble OVA. Tacrolimus-treated peritoneal macrophages, however, were able to present synthetic OVA peptide, SIINFEKL. Inclusion of cyclosporine A to biodegradable microspheres containing OVA greatly reduced their capacity to induce OVA-specific CTL response in mice. These findings provide novel insight into the mode of action of calcineurin inhibitors and have important implications for clinical immunosuppression regimens.

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 research was supported by Korean Science and Engineering Foundation (Grant no. R01–2004-000–10184–0) and a Korean Research Foundation Grant funded by the Korean Government (Ministry of Education and Human Resources Development; Regional Research Universities Program/Chungbuk BIT Research-oriented University Consortium).

² Address correspondence and reprints to Dr. Chong-Kil Lee, College of Pharmacy, Chungbuk National University, Cheongju, South Korea. E-mail address: cklee{at}chungbuk.ac.kr

³ Abbreviations used in this paper: CsA, cyclosporin A; DC, dendritic cell.