Targeted Delivery of Immunogen to Primate M Cells with Tetragalloyl Lysine Dendrimer

Abstract

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 M Cell-Targeting Ligand Promotes Antigen Delivery and Induces Antigen-Specific Immune Responses in Mucosal Vaccination

“…Phage display libraries are powerful tools to obtain specific ligands against small molecules, cells, and even tissues (31,(55)(56)(57)(58). Previously, this method has been used to identify M celltargeting ligands using rat PPs, although the identified peptides showed high binding affinity only to mucosa and Caco-2 cells (46).…”

A Neonatal Fc Receptor-Targeted Mucosal Vaccine Strategy Effectively Induces HIV-1 Antigen-Specific Immunity to Genital Infection

“…One example is antigen targeting to differentiated microfold (M) cells that normally pass antigens along to underlying DCs and macrophages within mucosal tissues (33,37). Unfortunately, M cells are relatively uncommon compared with the number of less-differentiated columnar epithelial cells that constitute the majority of mucosal surfaces.…”

Royal jelly enhances antigen‐specific mucosal IgA response

“…As shown in Misumi et al. (2009), immunofluorescence analysis demonstrated that M‐like cells in the model showed costaining of an FITC‐labeled tetragalloyl‐ d ‐lysine dendrimer (TGDK) (green) and an anti‐gp2 antibody (red) (Fig. 1b), suggesting that TGDK specifically bound to human M‐like cells.…”

“…(2009). The monolayers including M‐like cells or Caco‐2 control monolayers were incubated with FluoSpheres ® carboxylate‐modified microspheres (Life Technologies Corporation, Grand Island, NY).…”