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Research article

References

  1. Holmgren J, Czerkinsky C. 2005. Mucosal immunity and vaccines. Nat. Med. 11: S45-S53.
    Pubmed CrossRef
  2. Willimann K, Legler DF, Loetscher M, Roos RS, Delgado MB, Clark-Lewis I, et al. 1998. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur. J. Immunol. 28: 2025-2034.
    CrossRef
  3. van Ginkel FW, Nguyen HH, McGhee JR. 2000. Vaccines for mucosal immunity to combat emerging infectious diseases. Emerg. Infect. Dis. 6: 123-132.
    Pubmed PMC CrossRef
  4. Commins SP. 2015. Mechanisms of oral tolerance. Pediatr. Clin. North Am. 62: 1523-1529.
    Pubmed PMC CrossRef
  5. da Hora VP, Conceicao FR, Dellagostin OA, Doolan DL. 2011. Non-toxic derivatives of LT as potent adjuvants. Vaccine 29: 1538-1544.
    Pubmed CrossRef
  6. Isaka M, Yasuda Y, Mizokami M, Kozuka S, Taniguchi T, Matano K, et al. 2001. Mucosal immunization against hepatitis B virus by intranasal co-administration of recombinant hepatitis B surface antigen and recombinant cholera toxin B subunit as an adjuvant. Vaccine 19: 1460–1466.
    CrossRef
  7. Langridge W, Denes B, Fodor I. 2010. Cholera toxin B subunit modulation of mucosal vaccines for infectious and autoimmune diseases. Curr. Opin. Investig. Drugs 11: 919-928.
    Pubmed
  8. Lee CH, Nawar HF, Mandell L, Liang S, Hajishengallis G, Connell TD. 2010. Enhanced antigen uptake by DCs induced by the B pentamer of the type II heat-labile enterotoxin LTIIa requires engagement of TLR2. Vaccine 28: 3696-3705.
    Pubmed PMC CrossRef
  9. Boberg A, Gaunitz S, Brave A, Wahren B, Carlin N. 2008. Enhancement of epitope-specific cellular immune responses by immunization with HIV-1 peptides genetically conjugated to the B-subunit of recombinant cholera toxin. Vaccine 26:5079-5082.
    Pubmed CrossRef
  10. Harrod T, Martin M, Russell MW. 2001. Long-term persistence and recall of immune responses in aged mice after mucosal immunization. Oral Microbiol. Immunol. 16: 170-177.
    Pubmed CrossRef
  11. Lee CH, Masso-Welch P, Hajishengallis G, Connell TD. 2011. TLR2-dependent modulation of dendritic cells by LT IIa-B5, a novel mucosal adjuvant derived from a type II heat-labile enterotoxin. J. Leukoc. Biol. 90: 911-921.
    Pubmed PMC CrossRef
  12. Murph y KM, Heimberger A B, L oh DY. 1 990. I nduction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250: 1720-1723.
  13. Saeki H, Moore AM, Brown MJ, Hwang ST. 1999. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature DCs from the skin to regional lymph nodes. J. Immunol. 162: 2472-2475.
    Pubmed
  14. Gouwy M, Struyf S, Berghmans N, Vanormelingen C, Schols D, Van Damme J. 2011. CXCR4 and CCR5 ligands cooperate in monocyte and lymphocyte migration and in inhibition of dual-tropic (R5/X4) HIV-1 infection. Eur. J. Immunol. 41:963-973.
    Pubmed CrossRef
  15. Leitner J, Grabmeier-Pfistershammer K, Steinberger P. 2010. Receptors and ligands implicated in human T cell costimulatory processes. Immunol. Lett. 128: 89-97.
    Pubmed CrossRef
  16. Lundgren A, Leach S, Tobias J, Carlin N, Gustafsson B, Jertborn M, et al. 2013. Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein. Vaccine 31: 1163-1170.
    Pubmed CrossRef
  17. Miller T, Fanton M, Nickelson S, Mason H, Webb S. 2012. Safety and immunogenicity of bacterial and tobacco plant cell line derived recombinant native and mutant Escherichia coli heat-labile toxin in chickens. Avian Pathol. 41: 441-449.
    Pubmed CrossRef
  18. Sun M, He C, Cong Y, Liu Z. 2015. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 8: 969-978.
    Pubmed PMC CrossRef
  19. Markey KA, Gartlan KH, Kuns RD, MacDonald KP, Hill GR. 2015. Imaging the immunological synapse between DCs and T cells. J. Immunol. Methods 423: 40-44.
    Pubmed CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2017; 27(4): 709-717

Published online April 28, 2017 https://doi.org/10.4014/jmb.1611.11072

Copyright © The Korean Society for Microbiology and Biotechnology.

Dendritic Cell-Mediated Mechanisms Triggered by LT-IIa-B5, a Mucosal Adjuvant Derived from a Type II Heat-Labile Enterotoxin of Escherichia coli

Chang Hoon Lee 1, 2*, George Hajishengallis 3 and Terry D. Connell 4

1Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea, 22Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34114, Republic of Korea, 3Department of Microbiology, School of Dental Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA, 4Department of Microbiology & Immunology and The Witebsky Center for Microbial Pathogenesis and Immunology, The Jacob’s School of Medicine and Biomedical Sciences, The University at Buffalo, State University of New York, Buffalo, NY 14214, USA

Received: November 29, 2016; Accepted: January 31, 2017

Abstract

Mucosal tissues are the initial site through which most pathogens invade. As such, vaccines
and adjuvants that modulate mucosal immune functions have emerged as important agents
for disease prevention. Herein, we investigated the immunomodulatory mechanisms of the B
subunit of Escherichia coli heat-labile enterotoxin type IIa (LT-IIa-B5), a potent non-toxic
mucosal adjuvant. Alternations in gene expression in response to LT-IIa-B5 were identified
using a genome-wide transcriptional microarray that focused on dendritic cells (DC), a type of
cell that broadly orchestrates adaptive and innate immune responses. We found that LT-IIa-B5
enhanced the homing capacity of DC into the lymph nodes and selectively regulated
transcription of pro-inflammatory cytokines, chemokines, and cytokine receptors. These data
are consistent with a model in which directional activation and differentiation of immune cells
by LT-IIa-B5 serve as a critical mechanism whereby this potent adjuvant amplifies mucosal
immunity to co-administered antigens.

Keywords: LT-IIa-B5, mucosal vaccine adjuvant, dendritic cells, immune cell migration, lymph node

References

  1. Holmgren J, Czerkinsky C. 2005. Mucosal immunity and vaccines. Nat. Med. 11: S45-S53.
    Pubmed CrossRef
  2. Willimann K, Legler DF, Loetscher M, Roos RS, Delgado MB, Clark-Lewis I, et al. 1998. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur. J. Immunol. 28: 2025-2034.
    CrossRef
  3. van Ginkel FW, Nguyen HH, McGhee JR. 2000. Vaccines for mucosal immunity to combat emerging infectious diseases. Emerg. Infect. Dis. 6: 123-132.
    Pubmed KoreaMed CrossRef
  4. Commins SP. 2015. Mechanisms of oral tolerance. Pediatr. Clin. North Am. 62: 1523-1529.
    Pubmed KoreaMed CrossRef
  5. da Hora VP, Conceicao FR, Dellagostin OA, Doolan DL. 2011. Non-toxic derivatives of LT as potent adjuvants. Vaccine 29: 1538-1544.
    Pubmed CrossRef
  6. Isaka M, Yasuda Y, Mizokami M, Kozuka S, Taniguchi T, Matano K, et al. 2001. Mucosal immunization against hepatitis B virus by intranasal co-administration of recombinant hepatitis B surface antigen and recombinant cholera toxin B subunit as an adjuvant. Vaccine 19: 1460–1466.
    CrossRef
  7. Langridge W, Denes B, Fodor I. 2010. Cholera toxin B subunit modulation of mucosal vaccines for infectious and autoimmune diseases. Curr. Opin. Investig. Drugs 11: 919-928.
    Pubmed
  8. Lee CH, Nawar HF, Mandell L, Liang S, Hajishengallis G, Connell TD. 2010. Enhanced antigen uptake by DCs induced by the B pentamer of the type II heat-labile enterotoxin LTIIa requires engagement of TLR2. Vaccine 28: 3696-3705.
    Pubmed KoreaMed CrossRef
  9. Boberg A, Gaunitz S, Brave A, Wahren B, Carlin N. 2008. Enhancement of epitope-specific cellular immune responses by immunization with HIV-1 peptides genetically conjugated to the B-subunit of recombinant cholera toxin. Vaccine 26:5079-5082.
    Pubmed CrossRef
  10. Harrod T, Martin M, Russell MW. 2001. Long-term persistence and recall of immune responses in aged mice after mucosal immunization. Oral Microbiol. Immunol. 16: 170-177.
    Pubmed CrossRef
  11. Lee CH, Masso-Welch P, Hajishengallis G, Connell TD. 2011. TLR2-dependent modulation of dendritic cells by LT IIa-B5, a novel mucosal adjuvant derived from a type II heat-labile enterotoxin. J. Leukoc. Biol. 90: 911-921.
    Pubmed KoreaMed CrossRef
  12. Murph y KM, Heimberger A B, L oh DY. 1 990. I nduction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250: 1720-1723.
  13. Saeki H, Moore AM, Brown MJ, Hwang ST. 1999. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature DCs from the skin to regional lymph nodes. J. Immunol. 162: 2472-2475.
    Pubmed
  14. Gouwy M, Struyf S, Berghmans N, Vanormelingen C, Schols D, Van Damme J. 2011. CXCR4 and CCR5 ligands cooperate in monocyte and lymphocyte migration and in inhibition of dual-tropic (R5/X4) HIV-1 infection. Eur. J. Immunol. 41:963-973.
    Pubmed CrossRef
  15. Leitner J, Grabmeier-Pfistershammer K, Steinberger P. 2010. Receptors and ligands implicated in human T cell costimulatory processes. Immunol. Lett. 128: 89-97.
    Pubmed CrossRef
  16. Lundgren A, Leach S, Tobias J, Carlin N, Gustafsson B, Jertborn M, et al. 2013. Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein. Vaccine 31: 1163-1170.
    Pubmed CrossRef
  17. Miller T, Fanton M, Nickelson S, Mason H, Webb S. 2012. Safety and immunogenicity of bacterial and tobacco plant cell line derived recombinant native and mutant Escherichia coli heat-labile toxin in chickens. Avian Pathol. 41: 441-449.
    Pubmed CrossRef
  18. Sun M, He C, Cong Y, Liu Z. 2015. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 8: 969-978.
    Pubmed KoreaMed CrossRef
  19. Markey KA, Gartlan KH, Kuns RD, MacDonald KP, Hill GR. 2015. Imaging the immunological synapse between DCs and T cells. J. Immunol. Methods 423: 40-44.
    Pubmed CrossRef