Reviews suggest less than 200nm (1, 2).
- However, particle size is only one of many considerations necessary for directing uptake to Peyer’s Patch (PP) M cells, which have several possible uptake pathways.
- Species differences are also considerable. For e.g., mouse PPs consist of 10-50% M cells while it’s only ~5% in human PPs (3).
The four most commonly used approaches to target antigen uptake by M cells
1. M cell-specific lectins
- Most well-studied and mostly used in mouse models.
- UEA-1, a lectin that specifically binds alpha-L-fucose residues expressed on the apical (facing the gut lumen) end of mouse M cells (4). No UEA-1 equivalent lectin identified yet for human M cells.
- Targeting these M cell-specific alpha-L-fucose residues by conjugating particle/antigen of choice with UEA-1 works.
- Worked for oral hepatitis B surface antigen (5) and oral birch pollen allergen (6).
- Could impede nutrition.
- Could degrade before reaching M cells (7).
- Glycosylation patterns are different between enterocytes and M cells in different intestinal locations, at different ages, and between species (8). This could influence non-specific uptake.
2. M cell-targeting pathogens
- Mouse M cells specifically express glycoprotein 2 on their apical surface. It selectively binds FimH, an outer membrane type I pili component in Escherichia coli and Salmonella enterica serovar typhimurium (9).
- Mouse M cells specifically express an integrin (cell membrane protein) called beta-1 integrin (10). Yersinia pseudotuberculosis expresses a cell surface molecule called invasin that specifically binds M cell beta-1 integrin.
- Mouse, rat and rabbit M cells express alpha 2,3-salic acid on their apical surface to which the outer capsid protein delta 1 of Reovirus binds (11).
- Claudin 4 is a mouse M cell receptor which binds peptides such as the C-terminal domain of the å enterotoxin of Clostridium perfringens (12).
3. M cell-specific peptides
- Certain peptide sequences bind specifically to M cell-surface receptors.
- They can serve as carriers for antigens.
- Experimental data in in vitro human culture systems (13, 14), rat (15), mouse (16, 17).
4. M cell-specific antibodies
- Even decades later, this is still preliminary territory.
- A few monoclonal antibodies such as 5B11 (for rabbit M cells) and NKM 16-2-4 (for mouse M cells) target M cell-specific molecules and studies show they can serve as M cell antigen delivery vehicles (18, 19).
- Gupta, Prem N. “Mucosal Vaccine Delivery and M Cell Targeting.” Targeted Drug Delivery: Concepts and Design. Springer International Publishing, 2015. 313-337.
- des Rieux, Anne, et al. “Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach.” Journal of controlled release 116.1 (2006): 1-27.
- Giannasca, Paul J., et al. “Human intestinal M cells display the sialyl Lewis A antigen.” Infection and immunity 67.2 (1999): 946-953.
- Clark, M. A., et al. “Differential expression of lectin-binding sites defines mouse intestinal M-cells.” Journal of Histochemistry & Cytochemistry 41.11 (1993): 1679-1687.
- Clark, M. Ann, et al. “Targeting polymerised liposome vaccine carriers to intestinal M cells.” Vaccine 20.1 (2001): 208-217.
- Roth-Walter, Franziska, et al. “Targeting antigens to murine and human M-cells with Aleuria aurantia lectin-functionalized microparticles.” Immunology letters 100.2 (2005): 182-188.
- Devriendt, Bert, et al. “Crossing the barrier: Targeting epithelial receptors for enhanced oral vaccine delivery.” Journal of Controlled Release 160.3 (2012): 431-439.
- Rajapaksa, Thejani E., and David D. Lo. “Microencapsulation of vaccine antigens and adjuvants for mucosal targeting.” Current Immunology Reviews 6.1 (2010): 29-37.
- Hase, Koji, et al. “Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response.”
Nature 462.7270 (2009): 226-230.
- Clark, M. Ann, Barry H. Hirst, and Mark A. Jepson. “M-cell surface β1 integrin expression and invasin-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer’s patch M cells.”
Infection and immunity 66.3 (1998): 1237-1243.
- Helander, Anna, et al. “The viral σ1 protein and glycoconjugates containing α2-3-linked sialic acid are involved in type 1 reovirus adherence to M cell apical surfaces.” Journal of virology 77.14 (2003): 7964-7977.
- Ling, Jun, et al. “Structural constraints for the binding of short peptides to claudin-4 revealed by surface plasmon resonance.” Journal of Biological Chemistry 283.45 (2008): 30585-30595.
- Fievez, Virginie, et al. “In vitro identification of targeting ligands of human M cells by phage display.” International journal of pharmaceutics 394.1 (2010): 35-42.
- Kim, Sae-Hae, et al. “The M cell-targeting ligand promotes antigen delivery and induces antigen-specific immune responses in mucosal vaccination.” The Journal of Immunology 185.10 (2010): 5787-5795.
- Yoo, Mi-Kyong, et al. “Targeted delivery of chitosan nanoparticles to Peyer’s patch using M cell-homing peptide selected by phage display technique.” Biomaterials 31.30 (2010): 7738-7747.
- Higgins, Lisa M., et al. “In vivo phage display to identify M cell-targeting ligands.” Pharmaceutical research 21.4 (2004): 695-705.
- Jiang, Tao, et al. “Targeted oral delivery of BmpB vaccine using porous PLGA microparticles coated with M cell homing peptide-coupled chitosan.” Biomaterials 35.7 (2014): 2365-2373.
- Pappo, J., T. H. Ermak, and H. J. Steger. “Monoclonal antibody-directed targeting of fluorescent polystyrene microspheres to Peyer’s patch M cells.” Immunology 73.3 (1991): 277.
- Nochi, Tomonori, et al. “A novel M cell–specific carbohydrate-targeted mucosal vaccine effectively induces antigen-specific immune responses.” The Journal of experimental medicine 204.12 (2007): 2789-2796.