Skip to main content

Cytokines As Vaccine Adjuvants: The Use of Interleukin-2

  • Protocol
Vaccine Adjuvants

Part of the book series: Methods in Molecular Medicine™ ((MIMM,volume 42))

Abstract

Live attenuated virus and bacterial vaccines are generally more potent than subunit or nucleic acid vaccines because of the host’s vigorous inflammatory response to them. The challenge to building effective subunit or nucleic acid vaccines is incorporating those factors in the regimen that mimic an infection, resulting in a robust and protective immune response. Numerous cytokines have been shown to significantly modulate the inflammatory process, including interleukin-12 (IL-12), granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-2 (IL-2), (reviewed in 1 and 2). The addition of recombinant or nucleic acid-derived cytokine(s) to a vaccine regimen can therefore enhance the endogenous immune response to the vaccine antigen.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Heath, W. W. and Playfair, J. H. L. (1992) Cytokines as immunological adjuvants. Vaccine 10, 427–434.

    Article  PubMed  CAS  Google Scholar 

  2. Hughes, H. P. A. and Babiuk, L. A. (1992) The adjuvant potential of cytokines. Biotechnol. Therapeut. 3, 101–117.

    CAS  Google Scholar 

  3. Heath, A. W. (1995) Cytokines as adjuvants, in Vaccine Design: The Subunit and Adjuvant Approach (Pavell, M. F. and Neuman, M. J., eds.), Plenum, New York.

    Google Scholar 

  4. Wolf, S. F., Sieburth, D., and Sypek, J. (1994) Interleukin 12: a key modulator of immune function. Stem Cells 12, 154–168.

    Article  PubMed  CAS  Google Scholar 

  5. Germann, T., Gately, M. K., Schoenhaut, D. S., Lohoff, M., Mattner, F., Fischer, S., et al. (1993) Interleukin-12/T cell stimulating factor: a cytokine with multiple effects on T helper type 1 (TH1) but not on TH2 cells. Europ. J. Immunol. 23, 1762–1770.

    Article  CAS  Google Scholar 

  6. Afonso, L. C., Scharton, T. M., Vieira, L. Q., Wysocka, T., Trinchieri, G., and Scott, P. (1994) IL-12 functions as an effective adjuvant in a vaccine against Leish-mania major by directing the development of leishmanial specific CD4+ T h1 cells. Science 263, 235–237.

    Article  PubMed  CAS  Google Scholar 

  7. Letscher-Bru, V., Villard, O., Risse, B., Sauke, M., Klein, J.-P., and Kien, T. T. (1998) Protective effect of vaccination with a combination of recombinant surface antigen 1 and interleukin-12 against Toxoplasmosis in mice. Infec. Immun. 66, 4503–4506.

    CAS  Google Scholar 

  8. Kim, J. J., Ayyavoo, B., Bagarazzi, M. L., Chattergoon, M. A., Dang, K., Wang, B., et al. (1997) In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J. Immunol. 158, 816–826.

    PubMed  CAS  Google Scholar 

  9. Kursawa, H., Wysocka, M., Aruga, E., Chang, A. E., Trinchieri, G., and Lee, W. M. F. (1998) Recombinant interleukin-12 enhances cellular immune response to vaccination only after a period of suppression. Cancer Res. 58, 491–499.

    Google Scholar 

  10. Rodolfo, M., Silocchi, C., Melani, C., Cappetti, B., Arioli, I., Parmiani, G., and Colombo, M. P. (1996) Immunotherapy of experimental metastases by vaccination with interleukin-12 gene-transduced adenocarcinoma cells sharing tumor-associated antigens. J. Immunol. 157, 5536–5542.

    PubMed  CAS  Google Scholar 

  11. Tahara, H., Zitvogel, L., Storkus, W. J., Zeh, H. J., McKinney, T. G., Schreiber, R. D., et al. (1995) Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. J. Immunol. 154, 6466–6474.

    PubMed  CAS  Google Scholar 

  12. Metcalf, D. (1985) The granulocyte-macrophage colony-stimulating factors. Science 229, 16–22.

    Article  PubMed  CAS  Google Scholar 

  13. Tarr, P. E., Lin, R., Mueller, E. A., Kovarik, M., Guillaume, M., and Jones, T. C. (1996) Evaluation of tolerability and antibody response after recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and a single dose of recombinant hepatitis B vaccine. Vaccine 14, 1199–1204.

    Article  PubMed  CAS  Google Scholar 

  14. Callard, R. and Gearing, A. eds. (1994) GM-CSF, in Cytokine Facts Book. Academic, New York, pp. 139–143.

    Google Scholar 

  15. Disis, M. L., Bernhard, H., Shiota, F. M., Hand, S. L., Gralow, J. R., Huseby, E. S., et al. (1996) Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 88, 202–210.

    PubMed  CAS  Google Scholar 

  16. Weiss, W. R., Ishii, K. J., Hedstrom, R. C., Sedegah, M., Ichino, M., Barnhart, K., et al. (1998) A plasmid encoding murine granulocyte-macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine. J. Immunol. 161, 2325–2332.

    PubMed  CAS  Google Scholar 

  17. Dranoff, G., Jaffee, E., Lazenby, A., Golumbek, P., Levitsky, H., Brose, K., et al. (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl. Acad. Sci. USA 90, 3539–3543.

    Article  PubMed  CAS  Google Scholar 

  18. Morgan, D. A., Ruscetti, F. W., and Gallo, R. (1976) Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193, 1007–1008.

    Article  PubMed  CAS  Google Scholar 

  19. Mier, J. W. and Gall, R. C. (1985) The purification and properties of human T cell growth factor. J. Immunol. 128, 1122–1127.

    Google Scholar 

  20. Atkins, M. B. and Mier, J. W., eds. (1993) Therapeutic Applications of Interleukin-2. Marcel Dekker, New York.

    Google Scholar 

  21. Schumann, R. R., Nakaral, T., Gruss, H. J., Brach, M. A., Vanm Arnim, U., Kirschning, C., et al. (1996) Transcript synthesis and surface expression of the 294 interleukin-2 receptor (alpha-, beta-, and gamma chain) by normal and malignant myeloid cells. Blood 87, 2419–2427.

    PubMed  CAS  Google Scholar 

  22. Bartlett, Y. (1998) Potential monitoring value of functional interleukin-2 receptors on human neutrophils. Clinic. Diagnos. Lab. Immunol. 5, 270.

    CAS  Google Scholar 

  23. Taniguchi, T. and Minami, Y. (1993) The IL-2/IL-2 receptor system: a current overview. Cell 73, 5–8.

    Article  PubMed  CAS  Google Scholar 

  24. de Jong, J. L., Farner, N. L., Widmer, M. B., Giri, J. G., and Sondel, P. M. (1996) Interaction of IL-15 with the shared IL-2 receptor beta and gamma c subunits: the IL-15/beta/gamma c receptor-ligand complex is less stable than the IL-2/beta/ gamma c receptor-ligand complex. J. Immunol. 156, 1339–1248.

    PubMed  Google Scholar 

  25. Callard, R. and Gearing, A., eds. (1994) IL-2 and IL-2R, in The Cytokine Facts Book. Academic, London and New York, pp. 39–45.

    Google Scholar 

  26. Caligiuri, M. A. (1993) Low-dose recombinant interleukin-2 therapy: rationale and potential clinical applications. Seminars in Oncol. 20,suppl. 9, 3–10.

    CAS  Google Scholar 

  27. David, D., Bani, L., Moreau, J-L., Demaison, C., Sun, K., Salvucci, O., et al. (1998) Further analysis of interleukin-2 receptor subunit expression on the different human peripheral blood mononuclear cell subsets. Blood 91, 165–172.

    PubMed  CAS  Google Scholar 

  28. McElrath, M. J., Kaplan, G., Burkhardt, R. A., and Cohn, Z. A. (1990) Cutaneous responses to recombinant interleukin-2 in human immunodeficiency virus-1 seropositive individuals. Proc. Natl. Acad. Sci. USA 87, 5783–5787.

    Article  PubMed  CAS  Google Scholar 

  29. Murray, H. W., DePamphilis, J., Schooley, R. T., and Hirsch, M. S. (1988) Circulating Interferon gamma in AIDS patients treated with interleukin-2. N. Engl. J. Med. 318, 1538–1539.

    Article  PubMed  CAS  Google Scholar 

  30. Murray, H. W., Welte, K., Jacobs, J. L., Rubin, B. Y., Mertelsmann, R., and Roberts, R. B. (1985) Production of and in vitro response to interleukin 2 in the acquired immunodeficiency syndrome. J. Clinic. Investig. 76, 1959–1964.

    Article  CAS  Google Scholar 

  31. Bykovskaja, S. N., Buffo, S. J., Bunker, M., Shang, H., Majors, A., Herbert, M., et al. (1998) Interleukin-2 induces development of dendritic cells from cord blood CD34+cells. J. Leukocyte Biology 63, 620–630.

    CAS  Google Scholar 

  32. Benedetto, N., Auriault C., Darcy F., Lando D., Watier H., and Capron, A. (1991) Effect of rIFNγ and IL-2 treatments in mouse and nude rat infections with Toxo-plasma gondii. Europ. Cytokine Net. 2, 107–114.

    CAS  Google Scholar 

  33. Jeevan, A. and Asherson, G. L. (1988) Recombinant interleukin-2 limits the replication of Mycobacterium lepraemurium and Mycobacterium bovis BCG in mice. Lymphokine Res. 7, 129–140.

    PubMed  CAS  Google Scholar 

  34. Reddehase, M. J., Mutter, W., and Koszinowski, U. H. (1987) In vivo application of recombinant interleukin 2 in the immunotherapy of established cytomegalovi-rus infection. J. Exp. Med. 165, 650–656.

    Article  PubMed  CAS  Google Scholar 

  35. Bonavida, B., Katz, J., and Gottlieb, M. (1986) Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J. Immunol. 137, 1157–1163.

    PubMed  CAS  Google Scholar 

  36. Toosi, Z., Kleinhenz, M. E., Ellner, J. J. (1986) Defective interleukin-2 production and responsiveness in human pulmonary tuberculosis. J. Exp. Med. 163, 1162–1172.

    Article  Google Scholar 

  37. Sheridan, J. F., Aurelian, L., Sonnenberg, A. D., and Quinn, T. C. (1984) Cell-mediated immunity to cytomegalovirus (CMV) and herpes simplex virus (HSV) antigens in the acquired immunodeficiency syndrome: interleukin-1 and interleukin-2 modify in vitro responses. J. Clinic. Immunol. 4, 304–311.

    Article  CAS  Google Scholar 

  38. Dix, R. D., Giedlin, M., and Cousins, S. W. (1997) Systemic cytokine immuno-therapy for experimental cytomegalovirus retinitis in mice with retrovirus-induced immunodeficiency. Investigat. Opthalmol. Visual Sci. 38, 1411–1417.

    CAS  Google Scholar 

  39. Connors, M., Kovacs, J. A., Kreva, S., Gea-Banacloche J. C., Sneller, M. C., Flanigan, M., et al. (1997) HIV infection induces changes in CD4+T-cell pheno-type and depletions within the CD4+T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nature Med. 3, 533–540.

    Article  PubMed  CAS  Google Scholar 

  40. Fei, P. C., Solmone, M., Viora, M., Vanacore, P., Pugliese, O., Giglio, A., et al. (1994) Apoptosis in HIV infection: protective role of IL-2. J. Biolog. Regulators Homerostatic Agents 8, 60–64.

    Google Scholar 

  41. Bell, S. J. D., Cooper, D. A., Kemp, B. E., Doherty, R. R., and Penny, R. (1992) Heterogenous effects of exogenous IL-2 on HIV-specific cell-mediated immunity (CMI). Clinic. Exp. Immunol. 90, 6–12.

    Article  CAS  Google Scholar 

  42. Barker, E., Mackewicz, C. E., and Levy, J. A. (1995) Effects of TH1 and TH2 cytokines on CD8+T-cell response against human immunodeficiency virus: implications for long-term survival. Proc. Natl. Acad. Sci. USA 92, 11,135–11,139.

    Article  PubMed  CAS  Google Scholar 

  43. Zerhouni, B., Sanhadji, K., Kehrli, L., Livrozet, J. M., and Touraine, J. L. (1997) Interleukin (IL)-2 deficiency aggravates the defect of natural killer cell activity in AIDS patients. Thymus. 24, 147–156.

    Article  PubMed  CAS  Google Scholar 

  44. Weinberg, A. and Merigan, T. C. (1988) Recombinant interleukin 2 as an adjuvant for vaccine-induced protection. J. Immunol. 140, 294–299.

    PubMed  CAS  Google Scholar 

  45. Nunberg, J. H., Doyle, M. V., and Newell, A. D. (1988) Interleukin-2 as an adjuvant to vaccination, in Technological Advances in Vaccine Development (Lasky, L., ed.), Alan R Liss, New York.

    Google Scholar 

  46. Nunberg, J. H., Doyle, M. V., York, S. M., and York, C. J. (1989) Interleukin 2 acts as an adjuvant to enhance the potency of inactivated rabies virus vaccine. Proc. Natl. Acad. Sci. USA 86, 4240–4243.

    Article  PubMed  CAS  Google Scholar 

  47. Kawamura, H., Rosenberg, S. A., and Berzofsky, J. A. (1985) Immunization with antigen and interleukin 2 in vivo overcomes Ir gene low responsiveness. J. Exp. Med. 162, 381–386.

    Article  PubMed  CAS  Google Scholar 

  48. Good, M. F., Pombo, D., Lunde, M. N., Maloy, W. L., Halenbeck, R., Koths, K., et al. (1988) Recombinant IL-2 overcomes genetic nonresponsiveness to malaria sporozoite peptides: correlation of effect with biological activity of IL-2. J. Immunol. 141, 972–977.

    PubMed  CAS  Google Scholar 

  49. Schijns, V. E. C. J., Claasen, I. J. T. M., Vermeulem, A. A., Horsinek, M. C., and Osterhaus, A. D. M. E. (1994) Modulation of antiviral immune responses by exogenous cytokines: Effects of tumor necrosis factor-α, interleukin-1α, interleukin-2, and interferon-γ on the immunogenicity of an inactivated rabies vaccine. J. General Virol. 75, 55–63.

    Article  CAS  Google Scholar 

  50. Kawashima, K. and Platt, K. B. (1989) The effect of human recombinant interleukin-2 on the porcine immune response to a pseudorabies virus subunit vaccine. Veterin. Immunol. Immunopathol. 22, 345–353.

    Article  CAS  Google Scholar 

  51. Zimmerman, R. J., Aukerman, S. L., Katre, N. V., Winkelhake, J. L., and Young, J. D. (1989) Schedule dependency of the antitumor activity and toxicity of polyethylene glycol-modified interleukin 2 in murine tumor models. Cancer Res. 49, 6521–6528.

    PubMed  CAS  Google Scholar 

  52. Schmidt, W., Schweighoffer, T., Herbst, E., Maass, G., Berger, M., Schilcher, F., et al. (1995). Cancer vaccines: the interleukin 2 dosage effect. Proc. Natl. Acad. Sci. USA 92, 4711–4714.

    Article  PubMed  CAS  Google Scholar 

  53. Delaney, B. and Kaminsky, N. E. (1993) High concentrations of interleukin-2 selectively suppress T-cell dependent humoral immune responses. Immuno-pharmacology 26, 119–127.

    Article  CAS  Google Scholar 

  54. Katre, N. V. (1990) Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J. Immunol. 144, 209–213.

    PubMed  CAS  Google Scholar 

  55. Baldwin, S. L., D’Souza, C., Roberts, A. D., Kelly, B. P., Frank, A. A., Lui, M.A., et al. (1998) Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis. Infec. Immun. 66, 2951–2959.

    CAS  Google Scholar 

  56. Ho, R. J. Y., Burke, R. L., and Merigan, T. C. (1992) Liposome-formulated interleukin-2 as an adjuvant of recombinant HSV glycoprotein gD for the treatment of recurrent genital HSV-2 in guinea pigs. Vaccine 10, 209–213.

    Article  PubMed  CAS  Google Scholar 

  57. Hora, M. S., Rana, R. K., Numberg, J. H., Tice, T. R., Gilley, R. M., and Hudsen, M. E. (1990) Controlled release of interleukin-2 from biodegradable microspheres. Biotechnology 8, 755–758.

    Article  PubMed  CAS  Google Scholar 

  58. Arroyo, P. J., Bash, J. A., and Wallack, M. K. (1990) Active immunotherapy with vaccinia colon oncolysate enhances the immunomodulatory and antitumor effects of interleukin-2 and interferon-α in a murine hepatic metastasis model. Cancer Immunol. Immunother. 31, 305–311.

    Article  PubMed  CAS  Google Scholar 

  59. Bronte, V., Tsung, K., Rao, J. B., Chen, P. W., Wang, M., Rosenberg, S. A., and Restifo, N. P. (1995) IL-2 enhances the function of recombinant poxvirus-based vaccines in the treatment of established pulmonary metastases. J. Immunol. 154, 5282–5292.

    PubMed  CAS  Google Scholar 

  60. McLaughlin, J. P., Schlom, J., Kantor, J. S., and Greiner, J. W. (1996) Improved immunotherapy of a recombinant carcinoembryonic antigen vaccinia vaccine when given with interleukin-2. Cancer Res. 56, 2361–2367.

    PubMed  CAS  Google Scholar 

  61. Vondrys, P., Simova, J., Takacova, S. Jandlove, T., and Bubenik, J. (1997) Recombinant interleukin-2 acts as an adjuvant and helps to increase the efficacy of tumor vaccines. Folia Biologica (Praha) 43, 39,40.

    Google Scholar 

  62. Everse, L. A., Bernsen, M. R., Dullens, H. F. J., and Otter, W. D. (1997) Priming of the antitumor response promotes efficacy of interleukin-2 therapy. Cancer Immunol. Immunother. 44, 221–229.

    Article  PubMed  CAS  Google Scholar 

  63. Harada, M., Matsuzaki, G., Shinomiya, Y., Kurosawa, S., Ito, O., Okamoto, T., et al. (1994) Generation of tumor-specific cytotoxic T lymphocytes in vivo by 297 combined treatment with inactivated tumor cells and recombinant interleukin-2. Cancer Immunol. Immunother. 38, 332–338.

    PubMed  CAS  Google Scholar 

  64. Shimiza, K., Fields, R. C., Giedlin, M., Mulé, J. J. (1999) Systemic administration of interleukin-2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines. PNAS(USA) 96, 2268–2273.

    Article  Google Scholar 

  65. Provinciali, M., Di Sefano, G., Colombo, M., Della Croce, F., Gandolfi, M. C., Daghetta, L., et al. (1994) Adjuvant effect of low-dose interleukin-2 on antibody response to influenza virus vaccination in healthy elderly subjects. Mechan. Aging Develop. 77,75-82.

    Google Scholar 

  66. Fagiolo, U., Bordin, M. C., Biselli, R., D’Amelio, R., Zamarchi, R., and Amadori, A. (1997) Effect of rIL-2 treatment on anti-tetanus toxoid response in the elderly. Mechan. Aging Develop. 93, 205–214.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Humana Press Inc.

About this protocol

Cite this protocol

Giedlin, M.A. (2000). Cytokines As Vaccine Adjuvants: The Use of Interleukin-2. In: O’Hagan, D.T. (eds) Vaccine Adjuvants. Methods in Molecular Medicine™, vol 42. Springer, Totowa, NJ. https://doi.org/10.1385/1-59259-083-7:283

Download citation

  • DOI: https://doi.org/10.1385/1-59259-083-7:283

  • Publisher Name: Springer, Totowa, NJ

  • Print ISBN: 978-0-89603-735-9

  • Online ISBN: 978-1-59259-083-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics