Vaccine Adjuvants pp 287-309

Part of the Methods in Molecular Biology book series (MIMB, volume 626) | Cite as

Adjuvant Activity of Cytokines

Protocol

Abstract

The activity of several potent adjuvants, including incomplete Freund’s adjuvant, CpG oligodeoxynucleotides, and alum, has been shown to be due at least in part to the induction of cytokines, including type I interferons (IFNs), IFN-γ, interleukin-2 (IL-2), and IL-12, that play key roles in the regulation of innate and adaptive immunity. The relatively short half-life of recombinant homologues of cytokines has limited their use as vaccine adjuvants. These difficulties have been overcome by encapsulation into liposomes and the use of cytokine expression vectors co-administered with DNA vaccines. Although a number of cytokines including IFN-α, IFN-γ, IL-2, IL-12, IL-15, IL-18, IL-21, GM-CSF, and Flt-3 ligand have been shown to potentiate the immune response to vaccination in various experimental models, the full potential of cytokines as vaccine adjuvants remains to be established.

Key words

Adjuvant cytokines interferons interleukins adaptive immunity innate immunity Toll-like receptors 

References

  1. 1.
    Mutwiri, G., Benjamin, P., Soita, H., Babiuk, L. A. (2008) Co-administration of polyphosphazenes with CpG oligodeoxynucleotides strongly enhances immune responses in mice immunized with Hepatitis B virus surface antigen. Vaccine 26, 2680–2688.PubMedCrossRefGoogle Scholar
  2. 2.
    Eisenbarth, S. C., Colegio, O. R., O‘Connor, W., Sutterwala, F. S., Flavell, R. A. (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126.PubMedCrossRefGoogle Scholar
  3. 3.
    Le Bon, A., Schiavoni, G., D‘Agostino, G., Gresser, I., Belardelli, F., Tough, D. F. (2001) Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14, 461–470.PubMedCrossRefGoogle Scholar
  4. 4.
    Leibundgut-Landmann, S., Osorio, F., Brown, G. D., Reis e Sousa, C. (2008) Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood 112, 4971–4980.PubMedCrossRefGoogle Scholar
  5. 5.
    Benko, S., Philpott, D. J., Girardin, S. E. (2008) The microbial and danger signals that activate Nod-like receptors. Cytokine 43, 368–373.PubMedCrossRefGoogle Scholar
  6. 6.
    Koyama, S., Ishii, K. J., Coban, C., Akira, S. (2008) Innate immune response to viral infection. Cytokine 43, 336–341.PubMedCrossRefGoogle Scholar
  7. 7.
    Takaoka, A., Wang, Z., Choi, M. K., Yanai, H., Negishi, H., Ban, T., Lu, Y., Miyagishi, M., Kodama, T., Honda, K., et al.(2007) DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505.PubMedCrossRefGoogle Scholar
  8. 8.
    Weaver, C. T., Hatton, R. D., Mangan, P. R., Harrington, L. E. (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25, 821–852.PubMedCrossRefGoogle Scholar
  9. 9.
    Masci, P., Olencki, T., Wood, L., Rybicki, L., Jacobs, B., Williams, B., Faber, P., Bukowski, R., Tong, K., Borden, E. C. (2007) Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family. Clin Pharmacol Ther 81, 354–361.PubMedCrossRefGoogle Scholar
  10. 10.
    Ank, N., West, H., Paludan, S. R. (2006) IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res 26, 373–379.PubMedCrossRefGoogle Scholar
  11. 11.
    Uematsu, S., Akira, S. (2007) Toll-like receptor and innate immunity. Seikagaku 79, 769–776.PubMedGoogle Scholar
  12. 12.
    Perry, A. K., Chow, E. K., Goodnough, J. B., Yeh, W. C., Cheng, G. (2004) Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. J Exp Med 199, 1651–1658.PubMedCrossRefGoogle Scholar
  13. 13.
    Hemmi, H., Takeuchi, O., Sato, S., Yamamoto, M., Kaisho, T., Sanjo, H., Kawai, T., Hoshino, K., Takeda, K., Akira, S. (2004) The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med 199, 1641–1650.PubMedCrossRefGoogle Scholar
  14. 14.
    Yoneyama, M., Fujita, T. (2007) Function of RIG-I-like receptors in antiviral innate immunity. J Biol Chem 282, 15315–15318.PubMedCrossRefGoogle Scholar
  15. 15.
    Kumar, H., Koyama, S., Ishii, K. J., Kawai, T., Akira, S. (2008) Cutting edge: cooperation of IPS-1- and TRIF-dependent pathways in poly IC-enhanced antibody production and cytotoxic T cell responses. J Immunol 180, 683–687.PubMedGoogle Scholar
  16. 16.
    Steinman, R. M., Hemmi, H. (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311, 17–58.PubMedCrossRefGoogle Scholar
  17. 17.
    Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., Reis e Sousa, C. (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531.PubMedCrossRefGoogle Scholar
  18. 18.
    Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., Bauer, S. (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529.PubMedCrossRefGoogle Scholar
  19. 19.
    Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745.PubMedCrossRefGoogle Scholar
  20. 20.
    de Veer, M. J., Holko, M., Frevel, M., Walker, E., Der, S., Paranjape, J. M., Silverman, R. H., Williams, B. R. (2001) Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 69, 912–920.PubMedGoogle Scholar
  21. 21.
    Le Bon, A., Etchart, N., Rossmann, C., Ashton, M., Hou, S., Gewert, D., Borrow, P., Tough, D. F. (2003) Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol 4, 1009–1015.PubMedCrossRefGoogle Scholar
  22. 22.
    Le Bon, A., Durand, V., Kamphuis, E., Thompson, C., Bulfone-Paus, S., Rossmann, C., Kalinke, U., Tough, D. F. (2006) Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming. J Immunol 176, 4682–4689.PubMedGoogle Scholar
  23. 23.
    Beignon, A. S., Skoberne, M., Bhardwaj, N. (2003) Type I interferons promote cross-priming: more functions for old cytokines. Nat Immunol 4, 939–941.PubMedCrossRefGoogle Scholar
  24. 24.
    Jego, G., Palucka, A. K., Blanck, J. P., Chalouni, C., Pascual, V., Banchereau, J. (2003) Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234.PubMedCrossRefGoogle Scholar
  25. 25.
    Proietti, E., Bracci, L., Puzelli, S., Di Pucchio, T., Sestili, P., De Vincenzi, E., Venditti, M., Capone, I., Seif, I., De Maeyer, E., et al. (2002) Type I IFN as a natural adjuvant for a protective immune response: lessons from the influenza vaccine model. J Immunol 169, 375–383.PubMedGoogle Scholar
  26. 26.
    Litinskiy, M. B., Nardelli, B., Hilbert, D. M., He, B., Schaffer, A., Casali, P., Cerutti, A. (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3, 822–829.PubMedCrossRefGoogle Scholar
  27. 27.
    Marrack, P., Kappler, J., Mitchell, T. (1999) Type I interferons keep activated T cells alive. J Exp Med 189, 521–530.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang, X., Sun, S., Hwang, I., Tough, D. F., Sprent, J. (1998) Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591–599.PubMedCrossRefGoogle Scholar
  29. 29.
    Kawamura, K., Kadowaki, N., Kitawaki, T., Uchiyama, T. (2006) Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells. Blood 107, 1031–1038.PubMedCrossRefGoogle Scholar
  30. 30.
    Levings, M. K., Sangregorio, R., Galbiati, F., Squadrone, S., de Waal Malefyt, R., Roncarolo, M. G. (2001) IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 166, 5530–5539.PubMedGoogle Scholar
  31. 31.
    Dikopoulos, N., Bertoletti, A., Kroger, A., Hauser, H., Schirmbeck, R., Reimann, J. (2005) Type I IFN negatively regulates CD8+ T cell responses through IL-10-producing CD4+ T regulatory 1 cells. J Immunol 174, 99–109.PubMedGoogle Scholar
  32. 32.
    Blachere, N. E., Darnell, R. B., Albert, M. L. (2005) Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation. PLoS Biol 3, e185.PubMedCrossRefGoogle Scholar
  33. 33.
    Epperson, D. E., Arnold, D., Spies, T., Cresswell, P., Pober, J. S., Johnson, D. R. (1992) Cytokines increase transporter in antigen processing-1 expression more rapidly than HLA class I expression in endothelial cells. J Immunol 149, 3297–3301.PubMedGoogle Scholar
  34. 34.
    Marques, L., Brucet, M., Lloberas, J., Celada, A. (2004) STAT1 regulates lipopolysaccharide- and TNF-alpha-dependent expression of transporter associated with antigen processing 1 and low molecular mass polypeptide 2 genes in macrophages by distinct mechanisms. J Immunol 173, 1103–1110.PubMedGoogle Scholar
  35. 35.
    Der, S. D., Zhou, A., Williams, B. R., Silverman, R. H. (1998) Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA 95, 15623–15628.PubMedCrossRefGoogle Scholar
  36. 36.
    White, L. C., Wright, K. L., Felix, N. J., Ruffner, H., Reis, L. F., Pine, R., Ting, J. P. (1996) Regulation of LMP2 and TAP1 genes by IRF-1 explains the paucity of CD8+ T cells in IRF-1–/– mice. Immunity 5, 365–376.PubMedCrossRefGoogle Scholar
  37. 37.
    Gowda, A., Roda, J., Hussain, S. R., Ramanunni, A., Joshi, T., Schmidt, S., Zhang, X., Lehman, A., Jarjoura, D., Carson, W. E., et al. (2008) IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro. Blood 111, 4723–4730.PubMedCrossRefGoogle Scholar
  38. 38.
    Lallemand, C., Blanchard, B., Palmieri, M., Lebon, P., May, E., Tovey, M. G. (2007) Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB. Oncogene 26, 328–338.PubMedCrossRefGoogle Scholar
  39. 39.
    Sun, S., Zhang, X., Tough, D. F., Sprent, J. (1998) Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med 188, 2335–2342.PubMedCrossRefGoogle Scholar
  40. 40.
    Cartner, S. C., Lindsey, J. R., Gibbs-Erwin, J., Cassell, G. H., Simecka, J. W. (1998) Roles of innate and adaptive immunity in respiratory mycoplasmosis. Infect Immun 66, 3485–3491.PubMedGoogle Scholar
  41. 41.
    Reuman, P. D., Keely, S. P., Schiff, G. M. (1990) Rapid recovery in mice after combined nasal/oral immunization with killed respiratory syncytial virus. J Med Virol 32, 67–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Akbari, O., DeKruyff, R. H., Umetsu, D. T. (2001) Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2, 725–731.PubMedCrossRefGoogle Scholar
  43. 43.
    Jones, H. P., Hodge, L. M., Fujihashi, K., Kiyono, H., McGhee, J. R., Simecka, J. W. (2001) The pulmonary environment promotes Th2 cell responses after nasal-pulmonary immunization with antigen alone, but Th1 responses are induced during instances of intense immune stimulation. J Immunol 167, 4518–4526.PubMedGoogle Scholar
  44. 44.
    Bracci, L., Canini, I., Puzelli, S., Sestili, P., Venditti, M., Spada, M., Donatelli, I., Belardelli, F., Proietti, E. (2005) Type I IFN is a powerful mucosal adjuvant for a selective intranasal vaccination against influenza virus in mice and affects antigen capture at mucosal level. Vaccine 23, 2994–3004.PubMedCrossRefGoogle Scholar
  45. 45.
    Tovey, M. G., Maury, C. (1999) Oromucosal interferon therapy: marked antiviral and antitumor activity. J Interferon Cytokine Res 19, 145–155.PubMedCrossRefGoogle Scholar
  46. 46.
    Tovey, M. G., Lallemand, C., Meritet, J. F., Maury, C. (2006) Adjuvant activity of interferon alpha: mechanism(s) of action. Vaccine 24(Suppl 2), S2–S46.PubMedGoogle Scholar
  47. 47.
    Grob, P. J., Joller-Jemelka, H. I., Binswanger, U., Zaruba, K., Descoeudres, C., Fernex, M. (1984) Interferon as an adjuvant for hepatitis B vaccination in non- and low-responder populations. Eur J Clin Microbiol 3, 195–198.PubMedCrossRefGoogle Scholar
  48. 48.
    Goldwater, P. N. (1994) Randomized comparative trial of interferon-alpha versus placebo in hepatitis B vaccine non-responders and hyporesponders. Vaccine 12, 410–414.PubMedCrossRefGoogle Scholar
  49. 49.
    Rizza, P., Capone, I., Urbani, F., Montefiore, E., Rapicetta, M., Chionne, P., Candido, A., Tosti, M. E., Grimaldi, M., Palazzini, E., et al. (2008) Evaluation of the effects of human leukocyte IFN-alpha on the immune response to the HBV vaccine in healthy unvaccinated individuals. Vaccine 26, 1038–1049.PubMedCrossRefGoogle Scholar
  50. 50.
    Tannir, N. M., Cohen, L., Wang, X., Thall, P., Mathew, P. F., Jonasch, E., Siefker-Radtke, A., Pagliaro, L. C., Ng, C. S., Logothetis, C. (2006) Improved tolerability and quality of life with maintained efficacy using twice-daily low-dose interferon-alpha-2b: results of a randomized phase II trial of low-dose versus intermediate-dose interferon-alpha-2b in patients with metastatic renal cell carcinoma. Cancer 107, 2254–2261.PubMedCrossRefGoogle Scholar
  51. 51.
    Sirohi, B., Powles, R., Lawrence, D., Treleaven, J., Kulkarni, S., Leary, A., Rudin, C., Horton, C., Morgan, G. (2007) An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-alpha2b in patients with multiple myeloma maintained on a steady dose of interferon-alpha2b. Ann Oncol 18, 1388–1394.PubMedCrossRefGoogle Scholar
  52. 52.
    Launay, O., Grabar, S., Bloch, F., Desaint, C., Jegou, D., Lallemand, C., Erickson, R., Lebon, P., Tovey, M. G. (2008) Effect of sublingual administration of interferon-alpha on the immune response to influenza vaccination in institutionalized elderly individuals. Vaccine 26, 4073–4079.PubMedCrossRefGoogle Scholar
  53. 53.
    Schoenborn, J. R., Wilson, C. B. (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96, 41–101.PubMedCrossRefGoogle Scholar
  54. 54.
    Quiroga, J. A., Castillo, I., Porres, J. C., Casado, S., Saez, F., Gracia Martinez, M., Gomez, M., Inglada, L., Sanchez-Sicilia, L., Mora, A., et al. (1990) Recombinant gamma-interferon as adjuvant to hepatitis B vaccine in hemodialysis patients. Hepatology 12, 661–663.PubMedCrossRefGoogle Scholar
  55. 55.
    Iida, T., Kuwata, T., Ui, M., Suzuki, H., Miura, T., Ibuki, K., Takahashi, H., Yamamoto, T., Imanishi, J., Hayami, M., et al. (2004) Augmentation of antigen-specific cytokine responses in the early phase of vaccination with a live-attenuated simian/human immunodeficiency chimeric virus expressing IFN-gamma. Arch Virol 149, 743–757.PubMedCrossRefGoogle Scholar
  56. 56.
    Kaneyasu, K., Kita, M., Ohkura, S., Yamamoto, T., Ibuki, K., Enose, Y., Sato, A., Kodama, M., Miura, T., Hayami, M. (2005) Protective efficacy of nonpathogenic nef-deleted SHIV vaccination combined with recombinant IFN-gamma administration against a pathogenic SHIV challenge in rhesus monkeys. Microbiol Immunol 49, 1083–1094.PubMedGoogle Scholar
  57. 57.
    Playfair, J. H., De Souza, J. B. (1987) Recombinant gamma interferon is a potent adjuvant for a malaria vaccine in mice. Clin Exp Immunol 67, 5–10.PubMedGoogle Scholar
  58. 58.
    Van Slooten, M. L., Boerman, O., Romoren, K., Kedar, E., Crommelin, D. J., Storm, G. (2001) Liposomes as sustained release system for human interferon-gamma: biopharmaceutical aspects. Biochim Biophys Acta 1530, 134–145.PubMedCrossRefGoogle Scholar
  59. 59.
    van Slooten, M. L., Hayon, I., Babai, I., Zakay-Rones, Z., Wagner, E., Storm, G., Kedar, E. (2001) Immunoadjuvant activity of interferon-gamma-liposomes co-administered with influenza vaccines. Biochim Biophys Acta 1531, 99–110.PubMedCrossRefGoogle Scholar
  60. 60.
    Segura, S., Gamazo, C., Irache, J. M., Espuelas, S. (2007) Gamma interferon loaded onto albumin nanoparticles: in vitro and in vivo activities against Brucella abortus. Antimicrob Agents Chemother 51, 1310–1314.PubMedCrossRefGoogle Scholar
  61. 61.
    Segura, S., Espuelas, S., Renedo, M. J., Irache, J. M. (2005) Potential of albumin nanoparticles as carriers for interferon gamma. Drug Dev Ind Pharm 31, 271–280.PubMedGoogle Scholar
  62. 62.
    McCormick, A. L., Thomas, M. S., Heath, A. W. (2001) Immunization with an interferon-gamma-gp120 fusion protein induces enhanced immune responses to human immunodeficiency virus gp120. J Infect Dis 184, 1423–1430.PubMedCrossRefGoogle Scholar
  63. 63.
    Kim, J. J., Yang, J. S., Manson, K. H., Weiner, D. B. (2001) Modulation of antigen-specific cellular immune responses to DNA vaccination in rhesus macaques through the use of IL-2, IFN-gamma, or IL-4 gene adjuvants. Vaccine 19, 2496–2505.PubMedCrossRefGoogle Scholar
  64. 64.
    Lena, P., Villinger, F., Giavedoni, L., Miller, C. J., Rhodes, G., Luciw, P. (2002) Co-immunization of rhesus macaques with plasmid vectors expressing IFN-gamma, GM-CSF, and SIV antigens enhances anti-viral humoral immunity but does not affect viremia after challenge with highly pathogenic virus. Vaccine 20(Suppl 4), A69–A79.PubMedCrossRefGoogle Scholar
  65. 65.
    Pertmer, T. M., Oran, A. E., Madorin, C. A., Robinson, H. L. (2001) Th1 genetic adjuvants modulate immune responses in neonates. Vaccine 19, 1764–1771.PubMedCrossRefGoogle Scholar
  66. 66.
    Chow, Y. H., Chiang, B. L., Lee, Y. L., Chi, W. K., Lin, W. C., Chen, Y. T., Tao, M. H. (1998) Development of Th1 and Th2 populations and the nature of immune responses to hepatitis B virus DNA vaccines can be modulated by codelivery of various cytokine genes. J Immunol 160, 1320–1329.PubMedGoogle Scholar
  67. 67.
    Long, J. E., Huang, L. N., Qin, Z. Q., Wang, W. Y., Qu, D. (2005) IFN-gamma increases efficiency of DNA vaccine in protecting ducks against infection. World J Gastroenterol 11, 4967–4973.PubMedGoogle Scholar
  68. 68.
    Lee, S., Gierynska, M., Eo, S. K., Kuklin, N., Rouse, B. T. (2003) Influence of DNA encoding cytokines on systemic and mucosal immunity following genetic vaccination against herpes simplex virus. Microbes Infect 5, 571–578.PubMedCrossRefGoogle Scholar
  69. 69.
    Rosa, D. S., Bastos, K. R., Bargieri, D. Y., Tzelepis, F., Nomizo, A., Russo, M., Soares, I. S., Rodrigues, M. M. (2007) Role of interferon-gamma during CpG oligodeoxynucleotide-adjuvanted immunization with recombinant proteins. Vaccine 25, 6007–6017.PubMedCrossRefGoogle Scholar
  70. 70.
    Shi, T., Liu, W. Z., Gao, F., Shi, G. Y., Xiao, S. D. (2005) Intranasal CpG-oligodeoxynucleotide is a potent adjuvant of vaccine against Helicobacter pylori, and T helper 1 type response and interferon-gamma correlate with the protection. Helicobacter 10, 71–79.PubMedCrossRefGoogle Scholar
  71. 71.
    Wei, F., Liu, Q., Gao, S., Shang, L., Zhai, Y., Men, J., Jiang, L., Zhu, X. Q., Fu, Z., Shi, Y., et al. (2008) Enhancement by IL-18 of the protective effect of a Schistosoma japonicum 26 kDa GST plasmid DNA vaccine in mice. Vaccine 26, 4145–4149.PubMedCrossRefGoogle Scholar
  72. 72.
    Abaitua, F., Rodriguez, J. R., Garzon, A., Rodriguez, D., Esteban, M. (2006) Improving recombinant MVA immune responses: potentiation of the immune responses to HIV-1 with MVA and DNA vectors expressing Env and the cytokines IL-12 and IFN-gamma. Virus Res 116, 11–20.PubMedCrossRefGoogle Scholar
  73. 73.
    Yoon, H. A., Aleyas, A. G., George, J. A., Park, S. O., Han, Y. W., Lee, J. H., Kang, H. Y., Kang, S. H., Cho, J. G., Eo, S. K. (2006) Modulation of immune responses induced by DNA vaccine expressing glycoprotein B of Pseudorabies Virus via coadministration of IFN-gamma-associated cytokines. J Interferon Cytokine Res 26, 730–738.PubMedCrossRefGoogle Scholar
  74. 74.
    Smith, K. A. (1988) Interleukin-2: inception, impact, and implications. Science 240, 1169–1176.PubMedCrossRefGoogle Scholar
  75. 75.
    Gillis, S., Smith, K. A. (1977) Long term culture of tumour-specific cytotoxic T cells. Nature 268, 154–156.PubMedCrossRefGoogle Scholar
  76. 76.
    Fontenot, J. D., Rasmussen, J. P., Gavin, M. A., Rudensky, A. Y. (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6, 1142–1151.PubMedCrossRefGoogle Scholar
  77. 77.
    Blattman, J. N., Grayson, J. M., Wherry, E. J., Kaech, S. M., Smith, K. A., Ahmed, R. (2003) Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat Med 9, 540–547.PubMedCrossRefGoogle Scholar
  78. 78.
    Rosenberg, S. A., Lotze, M. T., Muul, L. M., Leitman, S., Chang, A. E., Ettinghausen, S. E., Matory, Y. L., Skibber, J. M., Shiloni, E., Vetto, J. T., et al. (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313, 1485–1492.PubMedCrossRefGoogle Scholar
  79. 79.
    Kovacs, J. A., Vogel, S., Albert, J. M., Falloon, J., Davey, R. T., Jr., Walker, R. E., Polis, M. A., Spooner, K., Metcalf, J. A., Baseler, M., et al. (1996) Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 335, 1350–1356.PubMedCrossRefGoogle Scholar
  80. 80.
    Osorio, Y., Ghiasi, H. (2003) Comparison of adjuvant efficacy of herpes simplex virus type 1 recombinant viruses expressing TH1 and TH2 cytokine genes. J Virol 77, 5774–5783.PubMedCrossRefGoogle Scholar
  81. 81.
    Yang, Y., Leggat, D., Herbert, A., Roberts, P. C., Sundick, R. S. (2009) A novel method to incorporate bioactive cytokines as adjuvants on the surface of virus particles. J Interferon Cytokine Res 29, 9–22.PubMedCrossRefGoogle Scholar
  82. 82.
    Cai, H., Yu, D. H., Tian, X., Zhu, Y. X. (2005) Coadministration of interleukin 2 plasmid DNA with combined DNA vaccines significantly enhances the protective efficacy against Mycobacterium tuberculosis. DNA Cell Biol 24, 605–613.PubMedCrossRefGoogle Scholar
  83. 83.
    Henke, A., Rohland, N., Zell, R., Wutzler, P. (2006) Co-expression of interleukin-2 by a bicistronic plasmid increases the efficacy of DNA immunization to prevent influenza virus infections. Intervirology 49, 249–252.PubMedCrossRefGoogle Scholar
  84. 84.
    Del Vecchio, M., Bajetta, E., Canova, S., Lotze, M. T., Wesa, A., Parmiani, G., Anichini, A. (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13, 4677–4685.PubMedCrossRefGoogle Scholar
  85. 85.
    Lee, K., Overwijk, W. W., O’Toole, M., Swiniarski, H., Restifo, N. P., Dorner, A. J., Wolf, S. F., Sturmhoefel, K. (2000) Dose-dependent and schedule-dependent effects of interleukin-12 on antigen-specific CD8 responses. J Interferon Cytokine Res 20, 589–596.PubMedCrossRefGoogle Scholar
  86. 86.
    Ha, S. J., Park, S. H., Kim, H. J., Kim, S. C., Kang, H. J., Lee, E. G., Kwon, S. G., Kim, B. M., Lee, S. H., Kim, W. B., et al. (2006) Enhanced immunogenicity and protective efficacy with the use of interleukin-12-encapsulated microspheres plus AS01B in tuberculosis subunit vaccination. Infect Immun 74, 4954–4959.PubMedCrossRefGoogle Scholar
  87. 87.
    Uto, T., Wang, X., Sato, K., Haraguchi, M., Akagi, T., Akashi, M., Baba, M. (2007) Targeting of antigen to dendritic cells with poly(gamma-glutamic acid) nanoparticles induces antigen-specific humoral and cellular immunity. J Immunol 178, 2979–2986.PubMedGoogle Scholar
  88. 88.
    Shan, M. M., Liu, K. Z., Fang, H. L., Chen, Z. (2002) DNA immune responses induced by codelivery of IL-12 expression vectors with hepatitis C structural antigens. Hepatobiliary Pancreat Dis Int 1, 553–557.PubMedGoogle Scholar
  89. 89.
    Bodnar, A., Nizsaloczki, E., Mocsar, G., Szaloki, N., Waldmann, T. A., Damjanovich, S., Vamosi, G. (2008) A biophysical approach to IL-2 and IL-15 receptor function: localization, conformation and interactions. Immunol Lett 116, 117–125.PubMedCrossRefGoogle Scholar
  90. 90.
    Johnston, J. A., Bacon, C. M., Finbloom, D. S., Rees, R. C., Kaplan, D., Shibuya, K., Ortaldo, J. R., Gupta, S., Chen, Y. Q., Giri, J. D., et al. (1995) Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci USA 92, 8705–8709.PubMedCrossRefGoogle Scholar
  91. 91.
    Lin, J. X., Migone, T. S., Tsang, M., Friedmann, M., Weatherbee, J. A., Zhou, L., Yamauchi, A., Bloom, E. T., Mietz, J., John, S., et al. (1995) The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2, 331–339.PubMedCrossRefGoogle Scholar
  92. 92.
    Miyazaki, T., Liu, Z. J., Kawahara, A., Minami, Y., Yamada, K., Tsujimoto, Y., Barsoumian, E. L., Permutter, R. M., Taniguchi, T. (1995) Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell 81, 223–231.PubMedCrossRefGoogle Scholar
  93. 93.
    Schluns, K. S., Williams, K., Ma, A., Zheng, X. X., Lefrancois, L. (2002) Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 168, 4827–4831.PubMedGoogle Scholar
  94. 94.
    Oh, S., Perera, L. P., Terabe, M., Ni, L., Waldmann, T. A., Berzofsky, J. A. (2008) IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis. Proc Natl Acad Sci USA 105, 5201–5206.PubMedCrossRefGoogle Scholar
  95. 95.
    Zheng, X., Wang, Y., Wei, H., Ling, B., Sun, R., Tian, Z. (2008) Bcl-xL is associated with the anti-apoptotic effect of IL-15 on the survival of CD56(dim) natural killer cells. Mol Immunol 45, 2559–2569.PubMedCrossRefGoogle Scholar
  96. 96.
    Li, W., Li, S., Hu, Y., Tang, B., Cui, L., He, W. (2008) Efficient augmentation of a long-lasting immune responses in HIV-1 gag DNA vaccination by IL-15 plasmid boosting. Vaccine 26, 3282–3290.PubMedCrossRefGoogle Scholar
  97. 97.
    Oh, S., Berzofsky, J. A., Burke, D. S., Waldmann, T. A., Perera, L. P. (2003) Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc Natl Acad Sci USA 100, 3392–3397.PubMedCrossRefGoogle Scholar
  98. 98.
    Calarota, S. A., Dai, A., Trocio, J. N., Weiner, D. B., Lori, F., Lisziewicz, J. (2008) IL-15 as memory T-cell adjuvant for topical HIV-1 DermaVir vaccine. Vaccine 26, 5188–5195.PubMedCrossRefGoogle Scholar
  99. 99.
    Kutzler, M. A., Robinson, T. M., Chattergoon, M. A., Choo, D. K., Choo, A. Y., Choe, P. Y., Ramanathan, M. P., Parkinson, R., Kudchodkar, S., Tamura, Y., et al. (2005) Coimmunization with an optimized IL-15 plasmid results in enhanced function and longevity of CD8 T cells that are partially independent of CD4 T cell help. J Immunol 175, 112–123.PubMedGoogle Scholar
  100. 100.
    Bolesta, E., Kowalczyk, A., Wierzbicki, A., Eppolito, C., Kaneko, Y., Takiguchi, M., Stamatatos, L., Shrikant, P. A., Kozbor, D. (2006) Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery. J Immunol 177, 177–191.PubMedGoogle Scholar
  101. 101.
    Halwani, R., Boyer, J. D., Yassine-Diab, B., Haddad, E. K., Robinson, T. M., Kumar, S., Parkinson, R., Wu, L., Sidhu, M. K., Phillipson-Weiner, R., et al. (2008) Therapeutic vaccination with simian immunodeficiency virus (SIV)-DNA + IL-12 or IL-15 induces distinct CD8 memory subsets in SIV-infected macaques. J Immunol 180, 7969–7979.PubMedGoogle Scholar
  102. 102.
    Boyer, J. D., Robinson, T. M., Kutzler, M. A., Vansant, G., Hokey, D. A., Kumar, S., Parkinson, R., Wu, L., Sidhu, M. K., Pavlakis, G. N., et al. (2007) Protection against simian/human immunodeficiency virus (SHIV) 89.6P in macaques after coimmunization with SHIV antigen and IL-15 plasmid. Proc Natl Acad Sci USA 104, 18648–18653.PubMedCrossRefGoogle Scholar
  103. 103.
    Chong, S. Y., Egan, M. A., Kutzler, M. A., Megati, S., Masood, A., Roopchard, V., Garcia-Hand, D., Montefiori, D. C., Quiroz, J., Rosati, M., et al. (2007) Comparative ability of plasmid IL-12 and IL-15 to enhance cellular and humoral immune responses elicited by a SIVgag plasmid DNA vaccine and alter disease progression following SHIV(89.6P) challenge in rhesus macaques. Vaccine 25, 4967–4982.PubMedCrossRefGoogle Scholar
  104. 104.
    Mueller, Y. M., Do, D. H., Altork, S. R., Artlett, C. M., Gracely, E. J., Katsetos, C. D., Legido, A., Villinger, F., Altman, J. D., Brown, C. R., et al. (2008) IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses. J Immunol 180, 350–360.PubMedGoogle Scholar
  105. 105.
    Gursel, M., Gregoriadis, G. (1997) Interleukin-15 acts as an immunological co-adjuvant for liposomal antigen in vivo. Immunol Lett 55, 161–165.PubMedCrossRefGoogle Scholar
  106. 106.
    Villinger, F., Miller, R., Mori, K., Mayne, A. E., Bostik, P., Sundstrom, J. B., Sugimoto, C., Ansari, A. A. (2004) IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques. Vaccine 22, 3510–3521.PubMedCrossRefGoogle Scholar
  107. 107.
    Saikh, K. U., Kissner, T. L., Nystrom, S., Ruthel, G., Ulrich, R. G. (2008) Interleukin-15 increases vaccine efficacy through a mechanism linked to dendritic cell maturation and enhanced antibody titers. Clin Vaccine Immunol 15, 131–137.PubMedCrossRefGoogle Scholar
  108. 108.
    Perera, L. P., Waldmann, T. A., Mosca, J. D., Baldwin, N., Berzofsky, J. A., Oh, S. K. (2007) Development of smallpox vaccine candidates with integrated interleukin-15 that demonstrate superior immunogenicity, efficacy, and safety in mice. J Virol 81, 8774–8783.PubMedCrossRefGoogle Scholar
  109. 109.
    Kwissa, M., Kroger, A., Hauser, H., Reimann, J., Schirmbeck, R. (2003) Cytokine-facilitated priming of CD8+ T cell responses by DNA vaccination. J Mol Med 81, 91–101.PubMedCrossRefGoogle Scholar
  110. 110.
    Zhang, W., Dong, S. F., Sun, S. H., Wang, Y., Li, G. D., Qu, D. (2006) Coimmunization with IL-15 plasmid enhances the longevity of CD8 T cells induced by DNA encoding hepatitis B virus core antigen. World J Gastroenterol 12, 4727–4735.PubMedGoogle Scholar
  111. 111.
    Wang, X., Zhang, X., Kang, Y., Jin, H., Du, X., Zhao, G., Yu, Y., Li, J., Su, B., Huang, C., et al. (2008) Interleukin-15 enhance DNA vaccine elicited mucosal and systemic immunity against foot and mouth disease virus. Vaccine 26, 5135–5144.PubMedCrossRefGoogle Scholar
  112. 112.
    Toka, F. N., Rouse, B. T. (2005) Mucosal application of plasmid-encoded IL-15 sustains a highly protective anti-Herpes simplex virus immunity. J Leukoc Biol 78, 178–186.PubMedCrossRefGoogle Scholar
  113. 113.
    Toka, F. N., Gierynska, M., Suvas, S., Schoenberger, S. P., Rouse, B. T. (2005) Rescue of memory CD8+ T cell reactivity in peptide/TLR9 ligand immunization by codelivery of cytokines or CD40 ligation. Virology 331, 151–158.PubMedCrossRefGoogle Scholar
  114. 114.
    Tang, C., Yamada, H., Shibata, K., Maeda, N., Yoshida, S., Wajjwalku, W., Ohara, N., Yamada, T., Kinoshita, T., Yoshikai, Y. (2008) Efficacy of recombinant bacille Calmette-Guerin vaccine secreting interleukin-15/antigen 85B fusion protein in providing protection against mycobacterium tuberculosis. J Infect Dis 197, 1263–1274.PubMedCrossRefGoogle Scholar
  115. 115.
    Min, W., Lillehoj, H. S., Burnside, J., Weining, K. C., Staeheli, P., Zhu, J. J. (2001) Adjuvant effects of IL-1beta, IL-2, IL-8, IL-15, IFN-alpha, IFN-gamma TGF-beta4 and lymphotactin on DNA vaccination against Eimeria acervulina. Vaccine 20, 267–274.PubMedCrossRefGoogle Scholar
  116. 116.
    Khan, I. A., Casciotti, L. (1999) IL-15 prolongs the duration of CD8+ T cell-mediated immunity in mice infected with a vaccine strain of Toxoplasma gondii. J Immunol 163, 4503–4509.PubMedGoogle Scholar
  117. 117.
    Boraschi, D., Dinarello, C. A. (2006) IL-18 in autoimmunity: review. Eur Cytokine Netw 17, 224–252.PubMedGoogle Scholar
  118. 118.
    Ozaki, K., Spolski, R., Feng, C. G., Qi, C. F., Cheng, J., Sher, A., Morse, H. C., 3rd, Liu, C., Schwartzberg, P. L., Leonard, W. J. (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634.PubMedCrossRefGoogle Scholar
  119. 119.
    Habib, T., Nelson, A., Kaushansky, K. (2003) IL-21: a novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses. J Allergy Clin Immunol 112, 1033–1045.PubMedCrossRefGoogle Scholar
  120. 120.
    Casey, K. A., Mescher, M. F. (2007) IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype. J Immunol 178, 7640–7648.PubMedGoogle Scholar
  121. 121.
    Avery, D. T., Bryant, V. L., Ma, C. S., de Waal Malefyt, R., Tangye, S. G. (2008) IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J Immunol 181, 1767–1779.PubMedGoogle Scholar
  122. 122.
    Cui, F. D., Asada, H., Jin, M. L., Kishida, T., Shin-Ya, M., Nakaya, T., Kita, M., Ishii, M., Iwai, M., Okanoue, T., et al. (2005) Cytokine genetic adjuvant facilitates prophylactic intravascular DNA vaccine against acute and latent herpes simplex virus infection in mice. Gene Ther 12, 160–168.PubMedCrossRefGoogle Scholar
  123. 123.
    Dou, J., Tang, Q., Zhao, F., Chu, L., Chen, J., Cao, M., Liu, C., Wang, Y., Li, Y., Li, J. L. (2008) Comparison of immune responses induced in mice by vaccination with DNA vaccine constructs expressing mycobacterial antigen 85A and interleukin-21 and Bacillus Galmette-Guerin. Immunol Invest 37, 113–127.PubMedCrossRefGoogle Scholar
  124. 124.
    Fabrizi, F., Ganeshan, S. V., Dixit, V., Martin, P. (2006) Meta-analysis: the adjuvant role of granulocyte macrophage-colony stimulating factor on immunological response to hepatitis B virus vaccine in end-stage renal disease. Aliment Pharmacol Ther 24, 789–796.PubMedCrossRefGoogle Scholar
  125. 125.
    Yoon, H. A., Aleyas, A. G., George, J. A., Park, S. O., Han, Y. W., Lee, J. H., Cho, J. G., Eo, S. K. (2006) Cytokine GM-CSF genetic adjuvant facilitates prophylactic DNA vaccine against pseudorabies virus through enhanced immune responses. Microbiol Immunol 50, 83–92.PubMedGoogle Scholar
  126. 126.
    Robinson, H. L., Montefiori, D. C., Villinger, F., Robinson, J. E., Sharma, S., Wyatt, L. S., Earl, P. L., McClure, H. M., Moss, B., Amara, R. R. (2006) Studies on GM-CSF DNA as an adjuvant for neutralizing Ab elicited by a DNA/MVA immunodeficiency virus vaccine. Virology 352, 285–294.PubMedCrossRefGoogle Scholar
  127. 127.
    Tenbusch, M., Kuate, S., Tippler, B., Gerlach, N., Schimmer, S., Dittmer, U., Uberla, K. (2008) Coexpression of GM-CSF and antigen in DNA prime-adenoviral vector boost immunization enhances polyfunctional CD8+ T cell responses, whereas expression of GM-CSF antigen fusion protein induces autoimmunity. BMC Immunol 9, 13.PubMedCrossRefGoogle Scholar
  128. 128.
    McNeel, D. G., Knutson, K. L., Schiffman, K., Davis, D. R., Caron, D., Disis, M. L. (2003) Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant. J Clin Immunol 23, 62–72.PubMedCrossRefGoogle Scholar
  129. 129.
    Xu, R., Megati, S., Roopchand, V., Luckay, A., Masood, A., Garcia-Hand, D., Rosati, M., Weiner, D. B., Felber, B. K., Pavlakis, G. N., et al. (2008) Comparative ability of various plasmid-based cytokines and chemokines to adjuvant the activity of HIV plasmid DNA vaccines. Vaccine 26, 4819–4829.PubMedCrossRefGoogle Scholar
  130. 130.
    Encke, J., Bernardin, J., Geib, J., Barbakadze, G., Bujdoso, R., Stremmel, W. (2006) Genetic vaccination with Flt3-L and GM-CSF as adjuvants: Enhancement of cellular and humoral immune responses that results in protective immunity in a murine model of hepatitis C virus infection. World J Gastroenterol 12, 7118–7125.PubMedGoogle Scholar
  131. 131.
    Sang, H., Pisarev, V. M., Munger, C., Robinson, S., Chavez, J., Hatcher, L., Parajuli, P., Guo, Y., Talmadge, J. E. (2003) Regional, but not systemic recruitment/expansion of dendritic cells by a pluronic-formulated Flt3-ligand plasmid with vaccine adjuvant activity. Vaccine 21, 3019–3029.PubMedCrossRefGoogle Scholar
  132. 132.
    Pisarev, V. M., Parajuli, P., Mosley, R. L., Chavez, J., Zimmerman, D., Winship, D., Talmadge, J. E. (2002) Flt3 ligand and conjugation to IL-1beta peptide as adjuvants for a type 1, T-cell response to an HIV p17 gag vaccine. Vaccine 20, 2358–2368.PubMedCrossRefGoogle Scholar
  133. 133.
    Williams, J. G., Jurkovich, G. J., Maier, R. V. (1993) Interferon-gamma: a key immunoregulatory lymphokine. J Surg Res 54, 79–93.PubMedCrossRefGoogle Scholar
  134. 134.
    Covic, A., Maftei, I. D., Mardare, N. G., Ionita-Radu, F., Totolici, C., Tuta, L., Golea, O., Covic, M., Volovat, C., Gusbeth-Tatomir, P., et al. (2006) Analysis of safety and efficacy of pegylated-interferon alpha-2a in hepatitis C virus positive hemodialysis patients: results from a large, multicenter audit. J Nephrol 19, 794–801.PubMedGoogle Scholar
  135. 135.
    Wright, A. K., Briles, D. E., Metzger, D. W., Gordon, S. B. (2008) Prospects for use of interleukin-12 as a mucosal adjuvant for vaccination of humans to protect against respiratory pneumococcal infection. Vaccine 26, 4893–4903.PubMedCrossRefGoogle Scholar
  136. 136.
    Walsh, G. M., Williamson, M. L, Symon, F. A., Willars, G. B., Wardlaw A. J. (1996) Ligation of CD69 induces apoptosis and cell death in human eosinophils cultured with granulocyte-macrophage colony-stimulating factor. Blood 87, 2815–2821.Google Scholar
  137. 137.
    Eid, P., Meritet, J. F., Maury, c., Lasfar, A., Tovey, M. G. (1999) Oromucosal interferon therapy: Pharmacokinetics and pharmacodynamics. J. Interferon Cytokin Res. 19, 157–169.Google Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratory of Viral Oncology, FRE2937 CNRSInstitut André LwoffVillejuifFrance

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