Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Tetanus antigen modulates the gene expression profile of aluminum phosphate adjuvant in spleen lymphocytes in vivo

The Pharmacogenomics Journal volume 2, pages 57–64 (2002)Cite this article

An Erratum to this article was published on 19 November 2002

Abstract

Adjuvants play an important role in stimulation of the immune response to antigens. Very little is known about the molecular mechanisms of this stimulation. Here we address this issue by studying gene expression profiles from spleen lymphocytes after in vivoimmunization of mice with a clinically relevant vaccine, tetanus toxoid formulated with aluminum phosphate as adjuvant (TTADJ), or the adjuvant alone (ADJ). The Th1/Th2 response to TTADJ was obtained from a combination of up- and downstream markers to conventional cytokines, which were in good agreement with cytokine protein levels. A clustering algorithm revealed that ADJ elicited expression of 47 genes active in cytotoxic lymphocytes, inflammation, oncogenesis, stress, toxicity and cell cycle regulation. In TTADJ these adjuvant-elicited genes were expressed at lower levels and a compensatory onset of protective and inhibitory genes was observed. We conclude that the antigen, to a larger extent than previously recognized, modulates the molecular mechanism of the aluminum phosphate adjuvant and that the identified genes may serve as predictive biomarkers in the development of new adjuvants and vaccines.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Aderem A, Ulevitch RJ . Toll-like receptors in the induction of the innate immune response Nature 2000 406: 782–787

    Article  CAS  Google Scholar 

  2. Medzhitov R, Janeway CA Jr . Innate immunity: the virtues of a nonclonal system of recognition Cell 1997 91: 295–298

    Article  CAS  Google Scholar 

  3. Edelman R . Vaccine adjuvants Rev Infect Dis 1980 2: 370–383

    Article  CAS  Google Scholar 

  4. Ross JS, Smith NP, White IR . Role of aluminium sensitivity in delayed persistent immunisation reactions J Clin Pathol 1991 44: 876–877

    Article  CAS  Google Scholar 

  5. Malakoff D . Public health. Aluminum is put on trial as a vaccine booster Science 2000 288: 1323–1324

    Article  CAS  Google Scholar 

  6. Bussiere JL, McCormick GC, Green JD . In: Powell MF, Newman MJ (eds) Vaccine Design: The Subunit and Adjuvant Approach Plenum Press: New York 1995 pp 61–79

    Book  Google Scholar 

  7. Teague TK, Hildeman D, Kedl RM, Mitchell T, Rees W, Schaefer BC et al . Activation changes the spectrum but not the diversity of genes expressed by T cells Proc Natl Acad Sci USA 1999 96: 12691–12696

    Article  CAS  Google Scholar 

  8. Gutgemann A, Golob M, Muller S, Buettner R, Bosserhoff AK . Isolation of invasion-associated cDNAs in melanoma Arch Dermatol Res 2001 293: 283–290

    Article  CAS  Google Scholar 

  9. Bucy RP, Panoskaltsis-Mortari A, Huang GQ, Li J, Karr L, Ross M et al . Heterogeneity of single cell cytokine gene expression in clonal T cell populations J Exp Med 1994 180: 1251–1262

    Article  CAS  Google Scholar 

  10. Finn PW, Kara CJ, Douhan J 3rd, Van TT, Folsom V, Glimcher LH . Interferon gamma regulates binding of two nuclear protein complexes in a macrophage cell line Proc Natl Acad Sci USA 1990 87: 914–918

    Article  CAS  Google Scholar 

  11. Marsters SA, Pennica D, Bach E, Schreiber RD, Ashkenazi A . Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain Proc Natl Acad Sci USA 1995 92: 5401–5405

    Article  CAS  Google Scholar 

  12. Musso T, Johnston JA, Linnekin D, Varesio L, Rowe TK, O'Shea JJ et al . Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7 J Exp Med 1995 181: 1425–1431

    Article  CAS  Google Scholar 

  13. Baggiolini M . Chemokines and leukocyte traffic Nature 1998 392: 565–568

    Article  CAS  Google Scholar 

  14. Zheng W, Flavell RA . The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells Cell 1997 89: 587–596

    Article  CAS  Google Scholar 

  15. Yin Z, Zhang DH, Welte T, Bahtiyar G, Jung S, Liu L et al . Dominance of IL-12 over IL-4 in gamma delta T cell differentiation leads to default production of IFN-gamma: failure to down-regulate IL- 12 receptor beta 2-chain expression J Immunol 2000 164: 3056–3064

    Article  CAS  Google Scholar 

  16. Takatsu K . Interleukin 5 and B cell differentiation Cytokine Growth Factor Rev 1998 9: 25–35

    Article  CAS  Google Scholar 

  17. Xu-Amano J, Kiyono H, Jackson RJ, Staats HF, Fujihashi K, Burrows PD et al . Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues J Exp Med 1993 178: 1309–1320

    Article  CAS  Google Scholar 

  18. Cheng AM, Negishi I, Anderson SJ, Chan AC, Bolen J, Loh DY et al . The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling Proc Natl Acad Sci USA 1997 94: 9797–9801

    Article  CAS  Google Scholar 

  19. Carter LL, Zhang X, Dubey C, Rogers P, Tsui L, Swain SL . Regulation of T cell subsets from naive to memory J Immunother 1998 21: 181–187

    Article  CAS  Google Scholar 

  20. Rolink AG, Schaniel C, Andersson J, Melchers F . Selection events operating at various stages in B cell development Curr Opin Immunol 2001 13: 202–207

    Article  CAS  Google Scholar 

  21. Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dmitrovsky E et al . Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation Proc Natl Acad Sci USA 1999 96: 2907–2912

    Article  CAS  Google Scholar 

  22. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns Proc Natl Acad Sci USA 1998 95: 14863–14868

    Article  CAS  Google Scholar 

  23. Vito P, Lacana E, D'Adamio L . Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3 Science 1996 271: 521–525

    Article  CAS  Google Scholar 

  24. Sherr CJ . Cancer cell cycles Science 1996 274: 1672–1677

    Article  CAS  Google Scholar 

  25. Li XC, Demirci G, Ferrari-Lacraz S, Groves C, Coyle A, Malek TR et al . IL-15 and IL-2: a matter of life and death for T cells in vivo Nat Med 2001 7: 114–118

    Article  CAS  Google Scholar 

  26. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP . CTLA-4-Mediated inhibition of early events of T cell proliferation J Immunol 1999 162: 5813–5820

    CAS  PubMed  Google Scholar 

  27. Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW . Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4 Science 1996 272: 1170–1173

    Article  CAS  Google Scholar 

  28. Meager A . Cytokine regulation of cellular adhesion molecule expression in inflammation Cytokine Growth Factor Rev 1999 10: 27–39

    Article  CAS  Google Scholar 

  29. Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK . Adjuvants—a balance between toxicity and adjuvanticity Vaccine 1993 11: 293–306

    Article  CAS  Google Scholar 

  30. Heller RA, Schena M, Chai A, Shalon D, Bedilion T, Gilmore J et al . Discovery and analysis of inflammatory disease-related genes using cDNA microarrays Proc Natl Acad Sci USA 1997 94: 2150–2155

    Article  CAS  Google Scholar 

  31. Beiqing L, Chen M, Whisler RL . Sublethal levels of oxidative stress stimulate transcriptional activation of c-jun and suppress IL-2 promoter activation in Jurkat T cells J Immunol 1996 157: 160–169

    CAS  PubMed  Google Scholar 

  32. Chatta GS, Spies AG, Chang S, Mize GJ, Linsley PS, Ledbetter JA et al . Differential regulation of proto-oncogenes c-jun and c-fos in T lymphocytes activated through CD28 J Immunol 1994 153: 5393–5401

    CAS  PubMed  Google Scholar 

  33. Su B, Jacinto E, Hibi M, Kallunki T, Karin M, Ben-Neriah Y . JNK is involved in signal integration during costimulation of T lymphocytes Cell 1994 77: 727–736

    Article  Google Scholar 

  34. Surh CD, Sprent J . T-cell apoptosis detected in situ during positive and negative selection in the thymus Nature 1994 372: 100–103

    Article  CAS  Google Scholar 

  35. Crispe IN . Death and destruction of activated T lymphocytes Immunol Res 1999 19: 143–157

    Article  CAS  Google Scholar 

  36. Suzuki I, Fink PJ . The dual functions of fas ligand in the regulation of peripheral CD8+ and CD4+ T cells Proc Natl Acad Sci USA 2000 97: 1707–1712

    Article  CAS  Google Scholar 

  37. Williams O, Gil-Gomez G, Norton T, Kioussis D, Brady HJ . Activation of Cdk2 is a requirement for antigen-mediated thymic negative selection Eur J Immunol 2000 30: 709–713

    Article  CAS  Google Scholar 

  38. Rebollo A, Dumoutier L, Renauld JC, Zaballos A, Ayllon V, Martinez AC . Bcl-3 expression promotes cell survival following interleukin-4 deprivation and is controlled by AP1 and AP1-like transcription factors Mol Cell Biol 2000 20: 3407–3416

    Article  CAS  Google Scholar 

  39. Mitchell TC, Hildeman D, Kedl RM, Teague TK, Schaefer BC, White J et al . Immunological adjuvants promote activated T cell survival via induction of Bcl-3 Nat Immunol 2001 2: 397–402

    Article  CAS  Google Scholar 

  40. Matzinger P . An innate sense of danger Semin Immunol 1998 10: 399–415

    Article  CAS  Google Scholar 

  41. Janeway CA Jr . Approaching the asymptote? Evolution and revolution in immunology Cold Spring Harb Symp Quant Biol 1989 54: 1–13

    Article  CAS  Google Scholar 

  42. Gallucci S, Matzinger P . Danger signals: SOS to the immune system Curr Opin Immunol 2001 13: 114–119

    Article  CAS  Google Scholar 

  43. Hendriksen CF, vd Gun JW, Nagel J, Kreeftenberg JG . The toxin binding inhibition test as a reliable in vitro alternative to the toxin neutralization test in mice for the estimation of tetanus antitoxin in human sera J Biol Stand 1988 16: 287–297

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Martha Granström, Karolinska Hospital, Stockholm, Sweden for the Ab determinations and SBL Vaccin, Solna, Sweden for the generous vaccine gift. This work was supported by the Swedish Board for Technical Development Grant p11381–1 and the Swedish National Network for Drug Development Grant B 6 3368/98.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Uppsala University, Uppsala, Sweden

    K Regnström, E G E Ragnarsson, N Rydell, I Sjöholm & P Artursson

Authors
  1. K Regnström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E G E Ragnarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Rydell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Sjöholm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Artursson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Regnström.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Regnström, K., Ragnarsson, E., Rydell, N. et al. Tetanus antigen modulates the gene expression profile of aluminum phosphate adjuvant in spleen lymphocytes in vivo. Pharmacogenomics J 2, 57–64 (2002). https://doi.org/10.1038/sj.tpj.6500080

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500080

Keywords

This article is cited by

Search

Advanced search

Quick links