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Cytokines as potential vaccine adjuvants

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Biotherapy

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Abstract

There is a compelling clinical need for adjuvants suitable for human use to enhance the efficacy of vaccines in the prevention of life-threatening infection. Candidate populations for such vaccine-adjuvant strategies include normal individuals at the two extremes of life, as well as the ever increasing population of immunocompromised individuals. In addition, adjuvants that would increase the efficiency of vaccination with such vaccines as those directed against hepatitis B andStreptococcus pneumoniae would have an even greater general use. Cytokines, as natural peptides intimately involved in the normal immune response, have great appeal as potential adjuvants. An increasing body of work utilizing recombinant versions of interleukin-1, -2, -3, -6, -12, gamma-interferon, tumor necrosis factor, and granulocyte-monocyte-colony stimulating factor has shown that cytokines do have vaccine adjuvant activity. However, in order to optimize adjuvant effect and minimize systemic toxicity, strategies in which the cytokine is fused to the antigen, or the cytokine is presented within liposomes or microspheres appear to be necessary to make this a practical approach suitable for human use. There is much promise in this approach, but there is much work to be accomplished in order to optimize the pharmacokinetics of cytokine administration as well as its side effect profile.

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Abbreviations

IL:

interleukin

TNF:

tumor necrosis factor

NK:

natural killer

pIL-1:

interleukin-1 peptide

LPS:

lipopolysaccharide

r:

recombinant

HSV-2:

herpes simplex virus 2

γ :

gamma

References

  1. Hibberd PL, Rubin RH. Approach to immunization in the immunosuppressed host. Infectious Disease Clinics of North America 1990; 4: 123–142.

    PubMed  Google Scholar 

  2. Fauci AS, Rosenberg SA, Sherwin SA,et al. Immunomodulators in clinical medicine. Ann Intern Med 1987; 106: 421–433.

    PubMed  Google Scholar 

  3. Warren HS, Chedid LA. Future prospects for vaccine adjuvants. CRC Crit Rev Immunol 1988; 8: 83–101.

    Google Scholar 

  4. Afonso LCC, Scharton JM, Vierira LQ, et al. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 1994; 263: 235–237.

    PubMed  Google Scholar 

  5. Heath AW, Devey ME, Brown IN, et al. Interferon-gamma as an adjuvant in immunocompromised mice. Immunology 1989; 67: 520–524.

    PubMed  Google Scholar 

  6. Wood DD, Cameron PM. Relationship between bacterial endotoxin and human B -cell activating factor. J Immunol 1978; 121: 53–60.

    PubMed  Google Scholar 

  7. Oppenheim JJ, Togawa A, Chedid L, et al. Components of mycobacteria and muramyl dipeptide with adjuvant activity induce lymphocyte factor. Cell Immunol 1980; 50: 71–81.

    PubMed  Google Scholar 

  8. Skopinska E. Some effects of E. coli endotoxin on the graftversus-host-reaction in ice. Transplant 1972; 14: 432–437.

    Google Scholar 

  9. Lowy I, Bona C, Chedid L. Target cells for the activity of the synthetic adjuvant: Muramyl dipeptide. Cell Immunol 1977; 29: 195–199.

    PubMed  Google Scholar 

  10. Staruch MJ, Wood DD. The adjuventicity of interleukin 1 in vivo. J Immunol 1983; 130: 2191–2194.

    PubMed  Google Scholar 

  11. Nencioni L, Villa L, Tagliabue A, et al. In vivo immunostimulatory activity of the 163–171 peptide of human IL-lb. J Immunol 1987; 139: 800–804.

    PubMed  Google Scholar 

  12. Rao KVS, Nayak AR. Enhanced immunogenicity of a sequence derived from hepatitis B virus surface antigen in a composite peptide that includes the immunostimulatory region from interleukin 1. Proc Natl Acad Sci U S A 1990; 87: 5519–5522.

    PubMed  Google Scholar 

  13. McCune CS, Marquis MM. Interleukin 1 as an adjuvant for active specific immunotherapy in a murine tumor model Cancer Res 1990; 50: 1212–1215.

    Google Scholar 

  14. Piera M, De Bolos C, Castro R, et al. Cytokines as adjuvants: Effect on the immunogenicity of NeuAca2-6GalNAcaO-Ser/Thr(SIALYL-Tn). Int J Cancer 1993; 55: 148–152.

    PubMed  Google Scholar 

  15. van der Meer JWM. Defect in host defense mechanisms. In: Rubin RH, Young LS (ed.): Clinical Approach for Infection in the Compromised Host, New York, Plenum Medical Book Co, Third Edition, 1994.

    Google Scholar 

  16. Tagliabue A, Boraschi D. Cytokines as vaccine adjuvants: Interleukin 1 and its synthetic peptide 163–171. Vaccine 1993; 11: 594–595.

    PubMed  Google Scholar 

  17. Dinarello CA. Interleukin-1. FASEB J 1988; 2: 108–115.

    PubMed  Google Scholar 

  18. Kuziel WA, Green WC. Interleukin-2. In: Thomson A (ed.): The Cytokine Handbook, Academic Press, London, 1991, 83–102.

    Google Scholar 

  19. Anderson G, Urbano O, Fedorka-Cray P, et al. Interleukin 2 and protective immunity in Hemophilus pleuropneumoniae. Preliminary studies. In: Vaccines, Cold Spring Harbor Press, 1987, 22–25.

  20. Weinberg A, Merigan TC. Recombinant interleukin 2 as an adjuvant for vaccine-induced protection: Immunization of guinea pigs with herpes simplex virus subunit vaccines. J Immunol 1988; 140: 294–299.

    PubMed  Google Scholar 

  21. Nurnberg JH, Doyle MV, York SM, et al. Interleukin 2 acts as an adjuvant to increase the potency of inactivated rabies virus vaccine. Proc Natl Acad Sci U S A 1989; 86: 4240–4243.

    PubMed  Google Scholar 

  22. Kimoto M, Kindler V, Higaki M, et al. Recombinant murine IL-3 fails to stimulate T or B lymphopoiesis in vivo, but enhances immune immune responses to T cell-dependent antigens. J Immunol 1988; 140: 1889–1894.

    PubMed  Google Scholar 

  23. Takatsuki F, Okano A, Suzuki C, et al. Human recombinant IL6/B cell stimulatory factor 2 augments murine antigenspecific antibody responses in vitro and in vivo. J Immunol 1988; 141: 3072–3077.

    PubMed  Google Scholar 

  24. Hsieh CS, Macatonia SE, Tripp CS et al. Development of TH1 CD4+ cells through IL-12 produced by Listeria-induced macrophages. Science 1993; 260: 547–549.

    PubMed  Google Scholar 

  25. D'Andrea A, Rengaraju M, Valiante NM, et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med 1992; 176: 1387–98.

    PubMed  Google Scholar 

  26. Ghiara P, Boraschi D, Nencioni L, et al. Enhancement of in vivo immune response by tumor necrosis factor. J Immunol 1987; 139: 3676–3679.

    PubMed  Google Scholar 

  27. Playfair JHL, DeSouza JB. Recombinant gamma interferon is a potent adjuvant for a malaria vaccine in mice. Clin Exp Immunol 1987; 6: 5–10.

    Google Scholar 

  28. Anderson KP, Fennie EH, Yilma T. Enhancement of a secondary antibody response to a vescicular stomatitis virus “G” protein by IFN-g treatment at primary immunization. J Immunol 1988; 140: 3500–3604.

    Google Scholar 

  29. Heath AW, Playfair JHL. Conjugation of interferon-gamma to antigen enhances its adjuvanticity. Immunology 1990; 71: 454–456.

    PubMed  Google Scholar 

  30. Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocytemacrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 1993; 90: 3539–3543.

    PubMed  Google Scholar 

  31. Leieschke GJ, Maher D, Cebon J, et al. Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy. Ann Intern Med 1989; 110: 357–364.

    PubMed  Google Scholar 

  32. Gerhartz HH, Stern AC, Wolf-Hornung B, et al. Intervention treatment of established neutropenia with human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients undergoing cancer chemotheraphy. Leuk Res 1993; 17: 175–185.

    PubMed  Google Scholar 

  33. Meuer SC, Dumann H, Meyer Zum Buschenfelde KH, et al. Low-dose interleukin-2 induces systemic immune responses against HBsAg in immunodeficient non-responders to hepatitis B vaccination. Lancet 1989; 1: 15–18.

    PubMed  Google Scholar 

  34. Quiroga JA, Castillo I, Poires JC, et al. Rocombinant ginterferon as adjuvant to hepatitis B vaccine in hemodialysis patients. Hepatology 1990; 12: 661–663.

    PubMed  Google Scholar 

  35. Kawamura H, Berzofsky JA, Rosenberg SA. Immunization with antigen and interleukin-2 in vivo overcomes IR gene low responsiveness. J Exp Med 1985; 162: 381–386.

    PubMed  Google Scholar 

  36. Good MF, Pombo D, Lunde MN, et al. Recombinant human IL-2 overcomes genetic nonresponsiveness to malaria sporozoite peptides — correlation of effect with biological activity of IL-2. J Immunol 1988; 141: 972–977.

    PubMed  Google Scholar 

  37. Hazama M, Mayumi-Aono A, Asakawa N, et al. Adjuvantindependent enhanced immune responses to recombinant herpes simplex virus type 1 glycoprotein D by fusion with biologically active interleukin-2. Vaccine 1993; 11: 629–636.

    PubMed  Google Scholar 

  38. Tao M, Levy R. Idiotype/granulocyte-macrophage colonystimulating factor fusion protein as a vaccine for B-cell lymphoma. Nature 1993; 362: 755–758.

    PubMed  Google Scholar 

  39. Mbawuike IN, Wyde PR, Anderson PM. Enhancement of the protective efficacy of inactivated influenza A virus vaccine in aged mice by IL-2 liposomes. Vaccine 1990; 8: 347–352.

    PubMed  Google Scholar 

  40. Duits AJ, van Puijenbroek A, Vermeulen H, et al. Immunoadjuvant activity of aliposomal IL-6 formulation. Vaccine 1993; 11: 777–781.

    PubMed  Google Scholar 

  41. Sing-Hora M, Rana RK, Nunberg JH, et al. Controlled release of interleukin-2 from biodergradable microspheres. Biotechnology 1990; 8: 755–758.

    PubMed  Google Scholar 

  42. Heath AW, Playfair JHL. Early administration of interferongamma as an adjuvant: an effect on a T-helper subpopulation ? Vaccine 1991; 91: 351–354.

    Google Scholar 

  43. Heath AW, Playfair JHL. Cytokines as immunological adjuvants. Vaccine 1992; 10: 427–434.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Experimental Pharmacology and Therapeutics, Harvard- M.I.T., Division of Health Sciences and Technology, 02142, Cambridge, Massachusetts

    Anju Nohria &  Robert H. Rubin (Director)

  2. HST Center for Experimental Pharmacology and Therapeutics, Massachusetts Institute of Technology, Clinical Research Center, 40 Ames Street, Building E18-435, 02142-1308, Cambridge, Massachusetts

    Robert H. Rubin (Director)

Authors
  1. Anju Nohria
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  2. Robert H. Rubin
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Nohria, A., Rubin, R.H. Cytokines as potential vaccine adjuvants. Biotherapy 7, 261–269 (1994). https://doi.org/10.1007/BF01878491

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