IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

A Molecular Mucosal Adjuvant To Enhance Immunity Against Pneumococcal Infection In The Elderly

  • Fukuyama, Yoshiko (Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo) ;
  • Ikeda, Yorihiko (Department of Pediatric Dentistry, The University of Alabama at Birmingham) ;
  • Ohori, Junichiro (Department of Pediatric Dentistry, The University of Alabama at Birmingham) ;
  • Sugita, Gen (Department of Pediatric Dentistry, The University of Alabama at Birmingham) ;
  • Aso, Kazuyoshi (Department of Pediatric Dentistry, The University of Alabama at Birmingham) ;
  • Fujihashi, Keiko (Department of Pediatric Dentistry, The University of Alabama at Birmingham) ;
  • Briles, David E. (Department of Microbiology, The University of Alabama at Birmingham) ;
  • McGhee, Jerry R. (Department of Pediatric Dentistry, The University of Alabama at Birmingham) ;
  • Fujihashi, Kohtaro (Department of Pediatric Dentistry, The University of Alabama at Birmingham)
  • Received : 2015.01.16
  • Accepted : 2015.02.11
  • Published : 2015.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Streptococcus pneumoniae (the pneumococcus) causes a major upper respiratory tract infection often leading to severe illness and death in the elderly. Thus, it is important to induce safe and effective mucosal immunity against this pathogen in order to prevent pnuemocaccal infection. However, this is a very difficult task to elicit protective mucosal IgA antibody responses in older individuals. A combind nasal adjuvant consisting of a plasmid encoding the Flt3 ligand cDNA (pFL) and CpG oligonucleotide (CpG ODN) successfully enhanced S. pneumoniae-specific mucosal immunity in aged mice. In particular, a pneumococcal surface protein A-based nasal vaccine given with pFL and CpG ODN induced complete protection from S. pneumoniae infection. These results show that nasal delivery of a combined DNA adjuvant offers an attractive potential for protection against the pneumococcus in the elderly.

Keywords

References

  1. Fujihashi, K., P. N. Boyaka, and J. R. McGhee. 2013. Host defenses at mucosal surfaces. In Clinical Immunology. R.T. Rich, T.A. Fleisher, W.T. Shearer, H.W. Schroeder, A.J. Frew, and C.M. Weyand, editors. Elsevier, Philadelphia, p. 239-251.
  2. Kiyono, H., J. Kunisawa, J. R. McGhee, and J. Mestecky. 2008. The Mucosal Immune System. In Fundamental Immunology. W.E. Paul, editor Lippincott Williams & Wilkins, Philadelphia, p. 983-1030.
  3. Campbell, D. J., and E. C. Butcher. 2002. Rapid acquisition of tissue-specific homing phenotypes by $CD4^+$ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195: 135-141. https://doi.org/10.1084/jem.20011502
  4. Campbell, J. J., C. E. Brightling, F. A. Symon, S. Qin, K. E. Murphy, M. Hodge, D. P. Andrew, L. Wu, E. C. Butcher, and A. J. Wardlaw. 2001. Expression of chemokine receptors by lung T cells from normal and asthmatic subjects. J. Immunol. 166: 2842-2848. https://doi.org/10.4049/jimmunol.166.4.2842
  5. Csencsits, K. L., N. Walters, and D. W. Pascual. 2001. Cutting edge: dichotomy of homing receptor dependence by mucosal effector B cells: $\alpha$(E) versus L-selectin. J. Immunol. 167: 2441-2445. https://doi.org/10.4049/jimmunol.167.5.2441
  6. Fujihashi, K., and H. Kiyono. 2009. Mucosal immunosenescence: new developments and vaccines to control infectious diseases. Trends Immunol. 30: 334-343. https://doi.org/10.1016/j.it.2009.04.004
  7. Fujihashi, K., and J. R. McGhee. 2004. Mucosal immunity and tolerance in the elderly. Mech. Ageing Dev. 125: 889-898. https://doi.org/10.1016/j.mad.2004.05.009
  8. Fukuyama, S., T. Hiroi, Y. Yokota, P. D. Rennert, M. Yanagita, N. Kinoshita, S. Terawaki, T. Shikina, M. Yamamoto, Y. Kurono, and H. Kiyono. 2002. Initiation of NALT organogenesis is independent of the IL-7R, $LT{\beta}R$, and NIK signaling pathways but requires the Id2 gene and $CD3^-CD4^+CD45^+$ cells. Immunity 17: 31-40. https://doi.org/10.1016/S1074-7613(02)00339-4
  9. Hagiwara, Y., J. R. McGhee, K. Fujihashi, R. Kobayashi, N. Yoshino, K. Kataoka, Y. Etani, M. N. Kweon, S. Tamura, T. Kurata, Y. Takeda, H. Kiyono, and K. Fujihashi. 2003. Protective mucosal immunity in aging is associated with functional $CD4^+$ T cells in nasopharyngeal-associated lymphoreticular tissue. J. Immunol. 170: 1754-1762. https://doi.org/10.4049/jimmunol.170.4.1754
  10. Kantele, A., J. Zivny, M. Hakkinen, C. O. Elson, and J. Mestecky. 1999. Differential homing commitments of antigen- specific T cells after oral or parenteral immunization in humans. J. Immunol. 162: 5173-5177.
  11. Kato, H., K. Fujihashi, R. Kato, T. Dohi, K. Fujihashi, Y. Hagiwara, K. Kataoka, R. Kobayashi, and J. R. McGhee. 2003. Lack of oral tolerance in aging is due to sequential loss of Peyer's patch cell interactions. Int. Immunol. 15: 145-158. https://doi.org/10.1093/intimm/dxg011
  12. Koga, T., J. R. McGhee, H. Kato, R. Kato, H. Kiyono, and K. Fujihashi. 2000. Evidence for early aging in the mucosal immune system. J. Immunol. 165: 5352-5359. https://doi.org/10.4049/jimmunol.165.9.5352
  13. Kunisawa, J., T. Nochi, and H. Kiyono. 2008. Immunological commonalities and distinctions between airway and digestive immunity. Trends Immunol. 29: 505-513. https://doi.org/10.1016/j.it.2008.07.008
  14. Macpherson, A. J., K. D. McCoy, F. E. Johansen, and P. Brandtzaeg. 2008. The immune geography of IgA induction and function. Mucosal Immunol. 1: 11-22. https://doi.org/10.1038/mi.2007.6
  15. Pascual, D. W., C. Riccardi, and K. Csencsits-Smith. 2008. Distal IgA immunity can be sustained by ${\alpha}E{\beta}7^+$ B cells in L-selectin-/- mice following oral immunization. Mucosal Immunol. 1: 68-77. https://doi.org/10.1038/mi.2007.2
  16. Rennert, P. D., J. L. Browning, R. Mebius, F. Mackay, and P. S. Hochman. 1996. Surface lymphotoxin ${\alpha}/{\beta}$ complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184: 1999-2006. https://doi.org/10.1084/jem.184.5.1999
  17. Yoshida, H., K. Honda, R. Shinkura, S. Adachi, S. Nishikawa, K. Maki, K. Ikuta, and S. I. Nishikawa. 1999. IL-7 receptor $alpha^+$ CD3(-) cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11: 643-655. https://doi.org/10.1093/intimm/11.5.643
  18. Kurebayashi, S., E. Ueda, M. Sakaue, D. D. Patel, A. Medvedev, F. Zhang, and A. M. Jetten. 2000. Retinoid-related orphan receptor $\gamma$ (ROR$\gamma$) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl. Acad. Sci. U. S. A. 97: 10132-10137. https://doi.org/10.1073/pnas.97.18.10132
  19. Sun, Z., D. Unutmaz, Y. R. Zou, M. J. Sunshine, A. Pierani, S. Brenner-Morton, R. E. Mebius, and D. R. Littman. 2000. Requirement for ROR$\gamma$ in thymocyte survival and lymphoid organ development. Science 288: 2369-2373. https://doi.org/10.1126/science.288.5475.2369
  20. Yokota, Y., A. Mansouri, S. Mori, S. Sugawara, S. Adachi, S. Nishikawa, and P. Gruss. 1999. Development of peripheral lymphoid organs and natural killer cells depends on the helix- loop-helix inhibitor Id2. Nature 397: 702-706. https://doi.org/10.1038/17812
  21. Arulanandam, B. P., J. M. Lynch, D. E. Briles, S. Hollingshead, and D. W. Metzger. 2001. Intranasal vaccination with pneumococcal surface protein A and interleukin- 12 augments antibody-mediated opsonization and protective immunity against Streptococcus pneumoniae infection. Infect. Immun. 69: 6718-6724. https://doi.org/10.1128/IAI.69.11.6718-6724.2001
  22. Wright, A. K., I. Christopoulou, B. S. El, J. Limer, and S. B. Gordon. 2011. rhIL-12 as adjuvant augments lung cell cytokine responses to pneumococcal whole cell antigen. Immunobiology 216: 1143-1147. https://doi.org/10.1016/j.imbio.2011.04.003
  23. Nguyen, C. T., S. Y. Kim, M. S. Kim, S. E. Lee, and J. H. Rhee. 2011. Intranasal immunization with recombinant PspA fused with a flagellin enhances cross-protective immunity against Streptococcus pneumoniae infection in mice. Vaccine 29: 5731-5739. https://doi.org/10.1016/j.vaccine.2011.05.095
  24. Bitsaktsis, C., B. V. Iglesias, Y. Li, J. Colino, C. M. Snapper, S. K. Hollingshead, G. Pham, D. R. Gosselin, and E. J. Gosselin. 2012. Mucosal immunization with an unadjuvanted vaccine that targets Streptococcus pneumoniae PspA to human Fc$\gamma$ receptor type I protects against pneumococcal infection through complement- and lactoferrin-mediated bactericidal activity. Infect. Immun. 80: 1166-1180. https://doi.org/10.1128/IAI.05511-11
  25. Xu, J., W. Dai, Z. Wang, B. Chen, Z. Li, and X. Fan. 2011. Intranasal vaccination with chitosan-DNA nanoparticles expressing pneumococcal surface antigen a protects mice against nasopharyngeal colonization by Streptococcus pneumoniae. Clin. Vaccine Immunol. 18: 75-81. https://doi.org/10.1128/CVI.00263-10
  26. Kong, I. G., A. Sato, Y. Yuki, T. Nochi, H. Takahashi, S. Sawada, M. Mejima, S. Kurokawa, K. Okada, S. Sato, D. E. Briles, J. Kunisawa, Y. Inoue, M. Yamamoto, K. Akiyoshi, and H. Kiyono. 2013. Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by Streptococcus pneumoniae. Infect. Immun. 81: 1625-1634. https://doi.org/10.1128/IAI.00240-13
  27. Hernani, M. L., P. C. Ferreira, D. M. Ferreira, E. N. Miyaji, P. L. Ho, and M. L. Oliveira. 2011. Nasal immunization of mice with Lactobacillus casei expressing the pneumococcal surface protein C primes the immune system and decreases pneumococcal nasopharyngeal colonization in mice. FEMS Immunol. Med. Microbiol. 62: 263-272. https://doi.org/10.1111/j.1574-695X.2011.00809.x
  28. Muralinath, M., M. J. Kuehn, K. L. Roland, and R. Curtiss, III. 2011. Immunization with Salmonella enterica serovar Typhimurium-derived outer membrane vesicles delivering the pneumococcal protein PspA confers protection against challenge with Streptococcus pneumoniae. Infect. Immun. 79: 887-894. https://doi.org/10.1128/IAI.00950-10
  29. Xu, X., H. Wang, Y. Liu, Y. Wang, L. Zeng, K. Wu, J. Wang, F. Ma, W. Xu, Y. Yin, and X. Zhang. 2015. Mucosal immunization with the live attenuated vaccine SPY1 induces humoral and Th2-Th17-regulatory T cell cellular immunity and protects against pneumococcal infection. Infect. Immun. 83: 90-100. https://doi.org/10.1128/IAI.02334-14
  30. Rosch, J. W., A. R. Iverson, J. Humann, B. Mann, G. Gao, P. Vogel, M. Mina, K. A. Murrah, A. C. Perez, S. W. Edward, E. I. Tuomanen, and J. A. McCullers. 2014. A live-attenuated pneumococcal vaccine elicits $CD4^+$ T-cell dependent class switching and provides serotype independent protection against acute otitis media. EMBO Mol. Med. 6: 141-154. https://doi.org/10.1002/emmm.201202150
  31. Kim, E. H., S. Y. Choi, M. K. Kwon, T. D. Tran, S. S. Park, K. J. Lee, S. M. Bae, D. E. Briles, and D. K. Rhee. 2012. Streptococcus pneumoniae pep27 mutant as a live vaccine for serotype-independent protection in mice. Vaccine 30: 2008- 2019. https://doi.org/10.1016/j.vaccine.2011.11.073
  32. Janssens, J. P., and K. H. Krause. 2004. Pneumonia in the very old. Lancet Infect. Dis. 4: 112-124. https://doi.org/10.1016/S1473-3099(04)00931-4
  33. Schenkein, J. G., M. H. Nahm, and M. T. Dransfield. 2008. Pneumococcal vaccination for patients with COPD: current practice and future directions. Chest 133: 767-774. https://doi.org/10.1378/chest.07-0996
  34. Shapiro, E. D., A. T. Berg, R. Austrian, D. Schroeder, V. Parcells, A. Margolis, R. K. Adair, and J. D. Clemens. 1991. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N. Engl. J. Med. 325: 1453-1460. https://doi.org/10.1056/NEJM199111213252101
  35. Romero-Steiner, S., D. M. Musher, M. S. Cetron, L. B. Pais, J. E. Groover, A. E. Fiore, B. D. Plikaytis, and G. M. Carlone. 1999. Reduction in functional antibody activity against Streptococcus pneumoniae in vaccinated elderly individuals highly correlates with decreased IgG antibody avidity. Clin. Infect. Dis. 29: 281-288. https://doi.org/10.1086/520200
  36. Rubins, J. B., M. Alter, J. Loch, and E. N. Janoff. 1999. Determination of antibody responses of elderly adults to all 23 capsular polysaccharides after pneumococcal vaccination. Infect. Immun. 67: 5979-5984.
  37. Rubins, J. B., A. K. Puri, J. Loch, D. Charboneau, R. MacDonald, N. Opstad, and E. N. Janoff. 1998. Magnitude, duration, quality, and function of pneumococcal vaccine responses in elderly adults. J. Infect. Dis. 178: 431-440. https://doi.org/10.1086/515644
  38. Briles, D. E., S. K. Hollingshead, J. King, A. Swift, P. A. Braun, M. K. Park, L. M. Ferguson, M. H. Nahm, and G. S. Nabors. 2000. Immunization of humans with recombinant pneumococcal surface protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J. Infect. Dis. 182: 1694-1701. https://doi.org/10.1086/317602
  39. Wu, H. Y., M. H. Nahm, Y. Guo, M. W. Russell, and D. E. Briles. 1997. Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage, pulmonary infection, and sepsis with Streptococcus pneumoniae. J. Infect. Dis. 175: 839-846. https://doi.org/10.1086/513980
  40. Yamamoto, M., D. E. Briles, S. Yamamoto, M. Ohmura, H. Kiyono, and J. R. McGhee. 1998. A nontoxic adjuvant for mucosal immunity to pneumococcal surface protein A. J. Immunol. 161: 4115-4121.
  41. Janoff, E. N., C. Fasching, J. M. Orenstein, J. B. Rubins, N. L. Opstad, and A. P. Dalmasso. 1999. Killing of Streptococcus pneumoniae by capsular polysaccharide-specific polymeric IgA, complement, and phagocytes. J. Clin. Invest. 104: 1139-1147. https://doi.org/10.1172/JCI6310
  42. Ferreira, D. M., M. Darrieux, D. A. Silva, L. C. Leite, J. M. Ferreira, Jr., P. L. Ho, E. N. Miyaji, and M. L. Oliveira. 2009. Characterization of protective mucosal and systemic immune responses elicited by pneumococcal surface protein PspA and PspC nasal vaccines against a respiratory pneumococcal challenge in mice. Clin. Vaccine Immunol. 16: 636-645. https://doi.org/10.1128/CVI.00395-08
  43. Park, S. M., H. J. Ko, D. H. Shim, J. Y. Yang, Y. H. Park, R. Curtiss, III, and M. N. Kweon. 2008. MyD88 signaling is not essential for induction of antigen-specific B cell responses but is indispensable for protection against Streptococcus pneumoniae infection following oral vaccination with attenuated Salmonella expressing PspA antigen. J. Immunol. 181: 6447-6455. https://doi.org/10.4049/jimmunol.181.9.6447
  44. Sun, K., F. E. Johansen, L. Eckmann, and D. W. Metzger. 2004. An important role for polymeric Ig receptor-mediated transport of IgA in protection against Streptococcus pneumoniae nasopharyngeal carriage. J. Immunol. 173: 4576-4581. https://doi.org/10.4049/jimmunol.173.7.4576
  45. Fukuyama, Y., J. D. King, K. Kataoka, R. Kobayashi, R. S. Gilbert, K. Oishi, S. K. Hollingshead, D. E. Briles, and K. Fujihashi. 2010. Secretory-IgA antibodies play an important role in the immunity to Streptococcus pneumoniae. J. Immunol. 185: 1755-1762. https://doi.org/10.4049/jimmunol.1000831
  46. Lu, Y. J., J. Gross, D. Bogaert, A. Finn, L. Bagrade, Q. Zhang, J. K. Kolls, A. Srivastava, A. Lundgren, S. Forte, C. M. Thompson, K. F. Harney, P. W. Anderson, M. Lipsitch, and R. Malley. 2008. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog. 4: e1000159. https://doi.org/10.1371/journal.ppat.1000159
  47. Zhang, Z., T. B. Clarke, and J. N. Weiser. 2009. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J. Clin. Invest. 119: 1899-1909.
  48. Zygmunt, B. M., F. Rharbaoui, L. Groebe, and C. A. Guzman. 2009. Intranasal immunization promotes th17 immune responses. J. Immunol. 183: 6933-6938. https://doi.org/10.4049/jimmunol.0901144
  49. Galli, G., K. Hancock, K. Hoschler, J. DeVos, M. Praus, M. Bardelli, C. Malzone, F. Castellino, C. Gentile, T. McNally, G. G. Del, A. Banzhoff, V. Brauer, E. Montomoli, M. Zambon, J. Katz, K. Nicholson, and I. Stephenson. 2009. Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc. Natl. Acad. Sci. U. S. A. 106: 7962-7967. https://doi.org/10.1073/pnas.0903181106
  50. Jackson, L. A., W. H. Chen, J. T. Stapleton, C. L. Dekker, A. Wald, R. C. Brady, S. Edupuganti, P. Winokur, M. J. Mulligan, H. L. Keyserling, K. L. Kotloff, N. Rouphael, D. L. Noah, H. Hill, and M. C. Wolff. 2012. Immunogenicity and safety of varying dosages of a monovalent 2009 H1N1 influenza vaccine given with and without AS03 adjuvant system in healthy adults and older persons. J. Infect. Dis. 206: 811-820. https://doi.org/10.1093/infdis/jis427
  51. Schneider-Ohrum, K., B. M. Giles, H. K. Weirback, B. L. Williams, D. R. DeAlmeida, and T. M. Ross. 2011. Adjuvants that stimulate TLR3 or NLPR3 pathways enhance the efficiency of influenza virus-like particle vaccines in aged mice. Vaccine 29: 9081-9092. https://doi.org/10.1016/j.vaccine.2011.09.051
  52. Maletto, B., A. Ropolo, V. Moron, and M. C. Pistoresi-Palencia. 2002. CpG-DNA stimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice. J. Leukoc. Biol. 72: 447-454.
  53. Maletto, B. A., A. S. Ropolo, M. V. Liscovsky, D. O. Alignani, M. Glocker, and M. C. Pistoresi-Palencia. 2005. CpG oligodeoxinucleotides functions as an effective adjuvant in aged BALB/c mice. Clin. Immunol. 117: 251-261. https://doi.org/10.1016/j.clim.2005.08.016
  54. Manning, B. M., E. Y. Enioutina, D. M. Visic, A. D. Knudson, and R. A. Daynes. 2001. CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice. Exp. Gerontol. 37: 107-126. https://doi.org/10.1016/S0531-5565(01)00157-7
  55. Qin, W., J. Jiang, Q. Chen, N. Yang, Y. Wang, X. Wei, and R. Ou. 2004. CpG ODN enhances immunization effects of hepatitis B vaccine in aged mice. Cell. Mol. Immunol. 1: 148-152.
  56. Sen, G., Q. Chen, and C. M. Snapper. 2006. Immunization of aged mice with a pneumococcal conjugate vaccine combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective immunoglobulin G antipolysaccharide responses and specific $CD4^+$-T-cell priming to young adult levels. Infect. Immun. 74: 2177-2186. https://doi.org/10.1128/IAI.74.4.2177-2186.2006
  57. Sharma, S., A. L. Dominguez, D. B. Hoelzinger, and J. Lustgarten. 2008. CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol. Immunother. 57: 549-561. https://doi.org/10.1007/s00262-007-0393-1
  58. Subramanian, S. and A. N. vya Shree. 2008. Enhanced Th2 immunity after DNA prime-protein boost immunization with amyloid beta (1-42) plus CpG oligodeoxynucleotides in aged rats. Neurosci. Lett. 436: 219-222. https://doi.org/10.1016/j.neulet.2008.03.024
  59. Alignani, D., B. Maletto, M. Liscovsky, A. Ropolo, G. Moron, and M. C. Pistoresi-Palencia. 2005. Orally administered OVA/CpG-ODN induces specific mucosal and systemic immune response in young and aged mice. J. Leukoc. Biol. 77: 898-905. https://doi.org/10.1189/jlb.0604330
  60. Fukuiwa, T., S. Sekine, R. Kobayashi, H. Suzuki, K. Kataoka, R. S. Gilbert, Y. Kurono, P. N. Boyaka, A. M. Krieg, J. R. McGhee, and K. Fujihashi. 2008. A combination of Flt3 ligand cDNA and CpG ODN as nasal adjuvant elicits NALT dendritic cells for prolonged mucosal immunity. Vaccine 26: 4849-4859. https://doi.org/10.1016/j.vaccine.2008.06.091
  61. Fukuyama, Y., J. D. King, K. Kataoka, R. Kobayashi, R. S. Gilbert, S. K. Hollingshead, D. E. Briles, and K. Fujihashi. 2011. A combination of Flt3 ligand cDNA and CpG oligodeoxynucleotide as nasal adjuvant elicits protective secretory-IgA immunity to Streptococcus pneumoniae in aged mice. J. Immunol. 186: 2454-2461. https://doi.org/10.4049/jimmunol.1002837
  62. Haynes, L., P. J. Linton, S. M. Eaton, S. L. Tonkonogy, and S. L. Swain. 1999. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice.J. Exp. Med. 190: 1013-1024. https://doi.org/10.1084/jem.190.7.1013
  63. Fayad, R., H. Zhang, D. Quinn, Y. Huang, and L. Qiao. 2004. Oral administration with papillomavirus pseudovirus encoding IL-2 fully restores mucosal and systemic immune responses to vaccinations in aged mice. J. Immunol. 173: 2692-2698. https://doi.org/10.4049/jimmunol.173.4.2692
  64. Henson, S. M., J. Pido-Lopez, and R. Aspinall. 2004. Reversal of thymic atrophy. Exp. Gerontol. 39: 673-678. https://doi.org/10.1016/j.exger.2003.10.030
  65. Min, D., A. Panoskaltsis-Mortari, O. Kuro, G. A. Hollander, B. R. Blazar, and K. I. Weinberg. 2007. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109: 2529-2537. https://doi.org/10.1182/blood-2006-08-043794
  66. Moretto, M. M., E. M. Lawlor, and I. A. Khan. 2008. Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J. Immunol. 181: 7977-7984. https://doi.org/10.4049/jimmunol.181.11.7977

Cited by

  1. Nasal double DNA adjuvant induces salivary FimA-specific secretory IgA antibodies in young and aging mice and blocks Porphyromonas gingivalis binding to a salivary protein vol.19, pp.1, 2019, https://doi.org/10.1186/s12903-019-0886-2
  2. Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives vol.11, pp.None, 2020, https://doi.org/10.3389/fimmu.2020.00717
  3. Intratracheal inoculation of AHc vaccine induces protection against aerosolized botulinum neurotoxin A challenge in mice vol.6, pp.1, 2015, https://doi.org/10.1038/s41541-021-00349-w