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.

Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells

Abstract

Allergic asthma is a chronic inflammatory disease and despite the introduction of potent and effective drugs, the prevalence has increased substantially over the past few decades1. The explanation that has attracted the most attention is the 'hygiene hypothesis', which suggests that the increase in allergic diseases is caused by a cleaner environment and fewer childhood infections2,3,4. Indeed, certain mycobacterial strains can cause a shift from T-helper cell 2 (Th2) to Th1 immune responses, which may subsequently prevent the development of allergy in mice5,6,7. Although the reconstitution of the balance between Th1 and Th2 is an attractive theory, it is unlikely to explain the whole story, as autoimmune diseases characterized by Th1 responses can also benefit from treatment with mycobacteria and their prevalence has also increased in parallel to allergies8. Here we show that treatment of mice with SRP299, a killed Mycobacterium vaccae-suspension, gives rise to allergen-specific CD4+CD45RBLo regulatory T cells, which confer protection against airway inflammation. This specific inhibition was mediated through interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), as antibodies against IL-10 and TGF-β completely reversed the inhibitory effect of CD4+CD45RBLo T cells. Thus, regulatory T cells generated by mycobacteria treatment may have an essential role in restoring the balance of the immune system to prevent and treat allergic diseases.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Effect of SRP299 treatment on the OVA-induced eosinophilic inflammation and cytokine production by splenocytes.
Figure 2: Transfer of SRP299-treated cells inhibit the OVA-induced eosinophilic inflammation and bronchial hyperresponsiveness in an allergen-specific manner.
Figure 3: The inhibitory effect of regulatory T cells resides within the CD4+CD45RBLo population and is mediated by IL-10 and TGF-β.

Similar content being viewed by others

References

  1. Bousquet, J., Jeffery, P.K., Busse, W.W., Johnson, M. & Vignola, A.M. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 161, 1720–1745 (2000).

    Article  CAS  Google Scholar 

  2. Martinez, F.D. & Holt, P.G. Role of microbial burden in aetiology of allergy and asthma. Lancet 354 (suppl. 2), 12–15 (1999).

    Article  Google Scholar 

  3. Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J.M. The inverse association between tuberculin responses and atopic disorder. Science, 275, 77–79 (1997).

    Article  CAS  Google Scholar 

  4. Farooqi, I.S. & Hopkin, J.M. Early childhood infection and atopic disorder. Thorax, 53, 927–932 (1998).

    Article  CAS  Google Scholar 

  5. Erb, K.J., Holloway, J.W., Sobeck, A., Moll, H. & Le Gros, G. Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J. Exp. Med. 187, 561–569 (1998).

    Article  CAS  Google Scholar 

  6. Herz, U. et al. BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model. J. Allergy Clin. Immunol. 102: 867–874 (1998).

    Article  CAS  Google Scholar 

  7. Gajewski, T.F. & Fitch, F.W. Anti-proliferative effect of IFN-γ in immune regulation: IFN-γ inhibits the proliferation of Th2 but not Th1 murine helper T-lymphocyte clones. J. Immunol. 140, 4245–4252 (1988).

    CAS  PubMed  Google Scholar 

  8. Stene, L.C. & Nafstad, P. Relation between occurrence of type 1 diabetes and asthma. Lancet 357, 607 (2001).

  9. Wang, C.C. & Rook, G.A.W. Inhibition of an established allergic response to ovalbumin in BALB/c mice by killedMycobacterium vaccae. Immunology 93, 307–313 (1998).

    Article  CAS  Google Scholar 

  10. Roncarolo, M.G. & Levings, M.K. The role of different subsets of T regulatory cells in controlling autoimmunity. Curr. Opin. Immunol. 12, 676–683 (2000).

    Article  CAS  Google Scholar 

  11. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  Google Scholar 

  12. Zuany-Amorim, C. et al. Modulation by IL-10 of antigen-induced IL-5 generation and CD4+ T lymphocyte and eosinophil infiltration into the mouse peritoneal cavity. J. Immunol. 157, 377–384 (1996).

    CAS  PubMed  Google Scholar 

  13. Maloy, K.J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001)

    Article  CAS  Google Scholar 

  14. Thornton, A.M. & Shevack, E.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T-cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).

    Article  CAS  Google Scholar 

  15. Levings, M.K., Sangregorio, R. & Roncarolo, M.G. Human CD25+CD4+ T regulatory cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of function. J. Exp. Med. 193, 1295–1301 (2001).

    Article  CAS  Google Scholar 

  16. Roncarolo, M.G., Levings, M.K. & Traversari, K. Differentiation of T regulatory cells by immature dendritic cells. J. Exp. Med. 193, F5–F10 (2001).

    Article  CAS  Google Scholar 

  17. Cottrez, F., Hurst, S.D., Coffman, R.L. & Groux, H. T regulatory cells 1 inhibit a Th2–specific response in vivo. J. Immunol. 165, 4848–4853 (2000).

    Article  CAS  Google Scholar 

  18. Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).

    Article  CAS  Google Scholar 

  19. Davies, J.D. et al. CD4+CD45RB low-density cells from untreated mice prevent acute allograft rejection. J. Immunol. 163, 5353–5357 (1999).

    CAS  PubMed  Google Scholar 

  20. Hopkins, J.M. Mycobacterial immunization: agents to limit asthma. in New Drugs for Asthma, Allergy and COPD (eds. Hansel, T.T. & Barnes, P.J.) 226–228 (Karger, Basel, Switzerland, 2001).

    Chapter  Google Scholar 

  21. Arkwright, P.D. & David, T.J. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J. Allergy Clin. Immunol. 107, 531–534 (2001).

    Article  CAS  Google Scholar 

  22. Camporota, L. et al. Effects of intradermal injection of SRL172 (killed Mycobacterium vaccae suspension) on allergen-induced airway response and IL-5 generation by PBMC in asthma. Am. J. Resp. Crit. Care Med. 161, A477 (2000).

    Google Scholar 

  23. Shirtcliffe, P.M. et al. The effect of delipidated deglycolipidated (DDMV) and heat-killed Mycobacterium vaccae in asthma. Am. J. Respir. Crit. Care Med. 163, 1410–1414 (2001).

    Article  CAS  Google Scholar 

  24. Zuany-Amorim, C. et al. Requirement for γδ T cells in allergic airway inflammation. Science. 280, 1265–1267 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Lee, A. Nicholls and G. Dubois for technical support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Claudia Zuany-Amorim.

Ethics declarations

Competing interests

L.R.B., G.B. and G.R. are employed by SR Pharma, the company that produces the heat-killed Mycobacterium vaccae.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zuany-Amorim, C., Sawicka, E., Manlius, C. et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8, 625–629 (2002). https://doi.org/10.1038/nm0602-625

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0602-625

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing