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* Department of Pharmaceutical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;
Shin Nippon Biomedical Laboratories, Kagoshima, Japan; and
Kumamoto Health Science University, Kumamoto, Japan
Effective uptake of Ags by specialized M cells of gut-associated lymphoid tissues is an important step in inducing efficient immune responses after oral vaccination. Although stable nontoxic small molecule mimetics of lectins, such as synthetic multivalent polygalloyl derivatives, may have potential in murine M cell targeting, it remains unclear whether synthetic multivalent polygalloyl derivatives effectively target nonhuman and human M cells. In this study, we evaluated the ability of a tetragalloyl derivative, the tetragalloyl-D-lysine dendrimer (TGDK), to target M cells in both in vivo nonhuman primate and in vitro human M-like cell culture models. TGDK was efficiently transported from the lumen of the intestinal tract into rhesus Peyer’s patches by M cells and then accumulated in germinal centers. Oral administration of rhesus CCR5-derived cyclopeptide conjugated with TGDK in rhesus macaque resulted in a statistically significant increase in stool IgA response against rhesus CCR5-derived cyclopeptide and induced a neutralizing activity against SIV infection. Furthermore, TGDK was specifically bound to human M-like cells and efficiently transcytosed from the apical side to the basolateral side in the M-like cell model. Thus, the TGDK-mediated vaccine delivery system represents a potential approach for enabling M cell-targeted mucosal vaccines in primates.
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 study was supported in part by a Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a health science research grant from the Ministry of Health, Labor, and Welfare of Japan.
2 S.M. and M.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Shozo Shoji, Kumamoto University, Department of Pharmaceutical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, 5-1 Oe-Honmachi, Kumamoto 862-0973, Japan. E-mail address: shoji{at}gpo.kumamoto-u.ac.jp
4 Abbreviations used in this paper: SHIV, simian/HIV; DAPI, 4',6-diamidino-2 phenylindole; DIC, differential interference contrast; DMF, dimethylformamide; EDS, energy-dispersive x-ray spectroscopy; FAE, follicle-associated epithelium; Fmoc, 9-fuorenylmethoxycarbonyl; GC, germinal center; PEG, polyethylene glycol; PP, Peyer’s patch; PV, poliovirus; rcDDR5, rhesus CCR5-derived cyclopeptide; RT, room temperature; SMPD, synthetic multivalent polygalloyl derivative; TEM, transmission electron microscopy; TGDK, tetragalloyl-D-lysine dendrimer; TRITC, tetramethylrhodamine isothiocyanate; UEA-1, Ulex europaeus agglutinin-1; wpim, weeks postinitial immunization.
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