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WIREs Nanomed Nanobiotechnol
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Engineering immunity in the mucosal niche against sexually transmitted infections

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The mucosal surfaces of the genital tract are the site of entry to over 30 different bacterial, parasitic, and viral pathogens that are the cause of sexually transmitted infections (STIs) including HIV. Women and adolescent girls are more severely impacted by STIs than men due in part to a greater biological susceptibility for acquiring infections and differences in disease sequelae. While it is widely accepted that preventative vaccines against the most commonly transmitted STIs would have a major impact on decreasing the global health burden of STIs for women worldwide, several challenges preclude their development. The female genital tract is a complex niche of microflora, hormonal influences, and immune tissues and cells that result in a mucosal immune system that is distinct from other mucosal sites and from our systemic immune system. An appreciation of these differences and their effect on shaping mucosal immunity to sexually transmitted pathogens is an important determinant for the design of effective STI vaccines. Here we describe the anatomy and mucosal immune system of the female reproductive tract, and discuss bioengineering strategies to design mucosal vaccines that overcome delivery challenges and coordinate the presentation kinetics and compartmentalization of antigens and adjuvants to relevant mucosal immune cell subsets. In particular, we describe recent progress in understanding the role of specific mucosal dendritic cell subsets in facilitating immune responses to pathogenic microbes in the genital mucosa. We also discuss the development of pathogen‐mimicking materials that may be useful for engineering protective immunity in this mucosal niche. WIREs Nanomed Nanobiotechnol 2015, 8:107–122. doi: 10.1002/wnan.1359 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease
Unique features of the reproductive tissues include type I and II mucosal epithelium in the upper and lower genital tract, respectively. Type I mucosal tissues include a single layer of columnar epithelial cells while type II mucosal tissues consist of multiple layers of stratified squamous epithelial cells. The luminal side of the genital tract is coated in a layer of mucus, which is constitutively produced in the reproductive tissues. Various immune cells populate the vaginal epithelium and the submucosal tissues including vaginal epithelial dendritic cells (VEDCs), macrophages, and submucosal dendritic cells (SMDCs). The reproductive tissues have mechanisms for bidirectional transcytosis of IgG across the vaginal epithelium by the neonatal Fc receptor (FcRn).
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Nanocarrier platforms have been synthesized for efficient encapsulation of various cargo including protein and peptide antigens, vectors and inactivated microbes, as well as a variety of adjuvants for co‐stimulation of T lymphocytes. These systems can be synthesized from lipids or polymers and range in size to include micelles, nanoparticles, and microparticles. Finally, many of these systems can be surface functionalized with a range of ligands to provide mucus penetration, cell targeting, or endosomal escape.
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Dendritic cells subsets include blood DCs, tissue DCs, and specialized mucosal DCs in the vaginal tract. VEDCs in the reproductive mucosa are identified by cell surface markers MHC II, CD11c, and CD207. Submucosal DCs (MHC II+ CD11c+ CD11b+) play a key role defending against primary infections by sampling antigen and trafficking to draining lymph nodes. During inflammation, circulating undifferentiated monocytes are rapidly recruited into the reproductive tissues to provide response to secondary infection and restimulation of effector T lymphocytes.
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