Immune Netw.  2013 Aug;13(4):157-162. 10.4110/in.2013.13.4.157.

Targeted Delivery of VP1 Antigen of Foot-and-mouth Disease Virus to M Cells Enhances the Antigen-specific Systemic and Mucosal Immune Response

• Kim SH
• Lee HY
• Jang YS

• KMID: 2150781
• DOI: http://doi.org/10.4110/in.2013.13.4.157

Abstract

Application of vaccine materials through oral mucosal route confers great economical advantage in animal farming industry due to much less vaccination cost compared with that of injection-based vaccination. In particular, oral administration of recombinant protein antigen against foot-and-mouth disease virus (FMDV) is an ideal strategy because it is safe from FMDV transmission during vaccine production and can induce antigen-specific immune response in mucosal compartments, where FMDV infection has been initiated, which is hardly achievable through parenteral immunization. Given that effective delivery of vaccine materials into immune inductive sites is prerequisite for effective oral mucosal vaccination, M cell-targeting strategy is crucial in successful vaccination since M cells are main gateway for luminal antigen influx into mucosal lymphoid tissue. Here, we applied previously identified M cell-targeting ligand Co1 to VP1 of FMDV in order to test the possible oral mucosal vaccination against FMDV infection. M cell-targeting ligand Co1-conjugated VP1 interacted efficiently with M cells of Peyer's patch. In addition, oral administration of ligand-conjugated VP1 enhanced the induction of VP1-specific IgG and IgA responses in systemic and mucosal compartments, respectively, in comparison with those from oral administration of VP1 alone. In addition, the enhanced VP1-specific immune response was found to be due to antigen-specific Th2-type cytokine production. Collectively, it is suggested that the M cell-targeting strategy could be applied to develop efficient oral mucosal vaccine against FMDV infection.

Keyword

Foot-and-mouth disease virus; M cell; Mucosal immunity; Systemic immunity

MeSH Terms

Administration, Oral
Animals
Foot-and-Mouth Disease
Foot-and-Mouth Disease Virus
Imidazoles
Immunity, Mucosal
Immunization
Immunoglobulin A
Immunoglobulin G
Lymphoid Tissue
Nitro Compounds
Phenobarbital
Vaccination
Imidazoles
Immunoglobulin A
Immunoglobulin G
Nitro Compounds
Phenobarbital

Figure

• 

  Figure 1 Co1-mediated in vitro M cell-targeting of VP1 antigen of FMDV into mouse ileal PPs. In whole-mount ileal PPs, in vitro interactions between VP1 antigen and M cells were monitored by CLSM. VP1 or VP1-Co1 was detected by using anti-FMDV antibody and then by using FITC-conjugated secondary antibody (green). M cells were distinguished from enterocytes through interaction with UEA-1 (red) but not with WGA (blue). Whole-mount images were created using slices from z-stacks into one slice along the χ-turning axes by using an LSM image browser. Each scale bar represents 50µm.

• 

  Figure 2 Enhancement of Co1-mediated VP1-specific IgA response in the mucosal compartment. (A) The VP1-specific IgA level in the fecal extract of mice orally primed with each indicated antigen and then challenged with VP1 alone was measured through ELISA. The results were calculated as the reciprocal of the geometric mean log2 titer. (B) The number of VP1-specific IgA SCs in LP was analyzed by ELISPOT. Results are expressed as mean±SE per 106 cells of 5 mice per group. *p<0.05 indicates significant difference compared with the control VP1-immunized group.

• 

  Figure 3 Characterization of the cytokine expression pattern of lymphocytes after in vitro VP1 stimulation prepared from the mice orally immunized with each indicated antigen. The number of each indicated cytokine SC was analyzed by ELISPOT in PP (A) and LP (B) prepared at 10 days after systemic challenge with VP1 alone as described in Materials and Methods. *p<0.05 and ***p<0.001 indicate significant differences compared with the control VP1-immunized group.

• 

  Figure 4 Induction of efficient VP1-specific systemic immune response by oral priming of mice with Co1-conjugated VP1. The numbers of VP1-specific IgG SCs (A) and each indicated cytokine SC (B) in SPLs were analyzed by ELISPOT. Results are expressed as mean±SE per 106 cells of 5 mice per group. *p<0.05 indicates significant differences compared with the control VP1-immunized group. (C) Lymphocyte proliferation was measured by tritium incorporation after in vitro stimulation with VP1 antigen 10 days after systemic challenge. Results are expressed as stimulation indices calculated as described in Materials and Methods. *p<0.05 indicates significant differences compared with the control VP1-immunized group.

Reference

1. O'Donnell V, LaRocco M, Duque H, Baxt B. Analysis of foot-and-mouth disease virus internalization events in cultured cells. J Virol. 2005; 79:8506–8518.

2. Rodriguez LL, Grubman MJ. Foot and mouth disease virus vaccines. Vaccine. 2009; 27:Suppl 4. D90–D94.

3. Zhang LJ, Chen HT, Zhou JH, Ma LN, Ding YZ, Liu YS. Research in advance for FMD novel vaccines. Virol J. 2011; 8:268.

4. Cubillos C, de la Torre BG, Jakab A, Clementi G, Borrás E, Bárcena J, Andreu D, Sobrino F, Blanco E. Enhanced mucosal immunoglobulin A response and solid protection against foot-and-mouth disease virus challenge induced by a novel dendrimeric peptide. J Virol. 2008; 82:7223–7230.

5. Mestecky J, Nguyen H, Czerkinsky C, Kiyono H. Oral immunization: an update. Curr Opin Gastroenterol. 2008; 24:713–719.

6. Pasetti MF, Simon JK, Sztein MB, Levine MM. Immunology of gut mucosal vaccines. Immunol Rev. 2011; 239:125–148.

7. Brandtzaeg P. Mucosal immunity: induction, dissemination, and effector functions. Scand J Immunol. 2009; 70:505–515.

8. Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005; 11:4 Suppl. S45–S53.

9. Kim SH, Seo KW, Kim J, Lee KY, Jang YS. The M cell-targeting ligand promotes antigen delivery and induces antigen-specific immune responses in mucosal vaccination. J Immunol. 2010; 185:5787–5795.

10. Kim SH, Jung DI, Yang IY, Kim J, Lee KY, Nochi T, Kiyono H, Jang YS. M cells expressing the complement C5a receptor are efficient targets for mucosal vaccine delivery. Eur J Immunol. 2011; 41:3219–3229.

11. Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Yabashi A, Waguri S, Nakato G, Kimura S, Murakami T, Iimura M, Hamura K, Fukuoka S, Lowe AW, Itoh K, Kiyono H, Ohno H. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2009; 462:226–230.

12. Cerutti A, Chen K, Chorny A. Immunoglobulin responses at the mucosal interface. Annu Rev Immunol. 2011; 29:273–293.

13. Azizi A, Kumar A, Diaz-Mitoma F, Mestecky J. Enhancing oral vaccine potency by targeting intestinal M cells. PLoS Pathog. 2010; 6:e1001147.

14. Kim SH, Lee KY, Jang YS. Mucosal Immune System and M Cell-targeting Strategies for Oral Mucosal Vaccination. Immune Netw. 2012; 12:165–175.

15. Hutber AM, Kitching RP, Fishwick JC, Bires J. Foot-and-mouth disease: the question of implementing vaccinal control during an epidemic. Vet J. 2011; 188:18–23.

16. Cerutti A. The regulation of IgA class switching. Nat Rev Immunol. 2008; 8:421–434.

17. Strugnell RA, Wijburg OL. The role of secretory antibodies in infection immunity. Nat Rev Microbiol. 2010; 8:656–667.

18. Kaetzel CS, Robinson JK, Chintalacharuvu KR, Vaerman JP, Lamm ME. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc Natl Acad Sci USA. 1991; 88:8796–8800.

19. Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012; 12:821–832.

20. Schulz O, Pabst O. Antigen sampling in the small intestine. Trends Immunol. 2013; 34:155–161.