title: Systemic administration of RANKL overcomes the bottleneck of oral vaccine delivery through microfold cells in ileum.
abstract: A successful delivery of antigen through oral route requires to overcome several barriers, such as enzymatic barrier of gastrointestinal tract and epithelial barrier that constitutes of microfold cells (M cells) for antigen uptake. Although each barrier represents a critical step in determining the final efficiency of antigen delivery, the transcytosis of antigen by M cells in the follicle-associated epithelium (FAE) to Peyer's patches appears to be a major bottleneck. Considering the systemic administration of receptor activator of nuclear factor (NF)-ĸB ligand (RANKL) induces differentiation of receptor activator of nuclear factor (NF)-ĸB (RANK)-expressing enterocytes into M cells, here, we illustrated a promising approach of antigen delivery using full length transmembrane RANKL (mRANKL). The results showed that the intraperitoneal injection of mRANKL increased the population of dendritic cells and macrophages in mesenteric lymph nodes and spleen. Subsequently, systemic administration of mRANKL resulted in significantly higher number of functional GP2(+) M cells leading higher transcytosis of fluorescent beads through them. To corroborate the effect of mRANKL in antigen delivery through M cells, we orally delivered microparticulate antigen to mice treated with mRANKL. Oral immunization induced strong protective IgA and systemic IgG antibody responses against orally delivered antigen in mRANKL-treated mice. The higher antibody responses are attributed to the higher transcytosis of antigens through M cells. Ultimately, the higher memory B cells and effector memory CD4 T cells after oral immunization in RANKL-treated mice confirmed potency of RANKL-mediated antigen delivery. To the best of our knowledge, this is the first study to demonstrate significant induction of mucosal and humoral immune responses to M cell targeted oral vaccines after the systemic administration of RANKL.
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Sushila
authors: S
authors: Maharjan
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Bijay
authors: B
authors: Singh
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Tao
authors: T
authors: Jiang
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: So-Yeon
authors: SY
authors: Yoon
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Hui-Shan
authors: HS
authors: Li
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Girak
authors: G
authors: Kim
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Min Jeong
authors: MJ
authors: Gu
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Soo Ji
authors: SJ
authors: Kim
authors: Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Ok-Jin
authors: OJ
authors: Park
authors: Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Seung Hyun
authors: SH
authors: Han
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute of Eco-friendly Animal Science, Institute of Green-Bio Science and Technology, Seoul National University, Kangwon-Do 232-916, Republic of Korea.
authors: Sang-Kee
authors: SK
authors: Kang
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Cheol-Heui
authors: CH
authors: Yun
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: cyjcow@snu.ac.kr.
authors: Yun-Jaie
authors: YJ
authors: Choi
authors: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: chocs@snu.ac.kr.
authors: Chong-Su
authors: CS
authors: Cho
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000941:Antigens / Q000276:immunology; D001862:Bone Resorption / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D007082:Ileum / Q000166:cytology*; D007114:Immunization; D007070:Immunoglobulin A / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007156:Immunologic Memory / Q000187:drug effects; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008807:Mice, Inbred BALB C; D010316:Particle Size; D010581:Peyer's Patches / Q000166:cytology; D053245:RANK Ligand / Q000008:administration & dosage* / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D057900:Transcytosis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014612:Vaccines / Q000276:immunology*
chemical_list: D000941:Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D053245:RANK Ligand; D014612:Vaccines
keywords: Dendritic cells; M cells; Oral vaccine; Peyer's patches; RANKL