Skip to main content
PMC home page
Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 1999 Nov 7;266(1434):2217–2223. doi: 10.1098/rspb.1999.0911

Analysis of cytokine dynamics in corneal allograft rejection.

C C Chan 1, J Stark 1, A J George 1
PMCID: PMC1690347  PMID: 10649636

Abstract

Motivated by the discovery of oscillations in tumour necrosis factor-alpha (TNF-alpha) concentration in the aqueous humour of rabbits undergoing corneal allograft rejection, a simple mathematical model is developed for the regulation of TNF-alpha, which incorporates both negative feedback and amplification pathways. Mathematical analysis reveals a surprisingly rich behavioural repertoire for this simple cytokine pathway, including excitability, threshold behaviour, hysteresis, oscillations and bistability. This suggests new possibilities for experimental demonstration, and reveals the potential contributions of nonlinear dynamics to understanding cytokine regulation.

Full Text

The Full Text of this article is available as a PDF (198.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amiot F., Boussadia O., Cases S., Fitting C., Lebastard M., Cavaillon J. M., Milon G., Dautry F. Mice heterozygous for a deletion of the tumor necrosis factor-alpha and lymphotoxin-alpha genes: biological importance of a nonlinear response of tumor necrosis factor-alpha to gene dosage. Eur J Immunol. 1997 Apr;27(4):1035–1042. doi: 10.1002/eji.1830270434. [DOI] [PubMed] [Google Scholar]
  2. Dallman M. J. Cytokines as mediators of organ graft rejection and tolerance. Curr Opin Immunol. 1993 Oct;5(5):788–793. doi: 10.1016/0952-7915(93)90138-i. [DOI] [PubMed] [Google Scholar]
  3. Ferguson T. A., Fletcher S., Herndon J., Griffith T. S. Neuropeptides modulate immune deviation induced via the anterior chamber of the eye. J Immunol. 1995 Aug 15;155(4):1746–1756. [PubMed] [Google Scholar]
  4. Ferguson T. A., Herndon J. M., Dube P. The immune response and the eye: a role for TNF alpha in anterior chamber-associated immune deviation. Invest Ophthalmol Vis Sci. 1994 Apr;35(5):2643–2651. [PubMed] [Google Scholar]
  5. Fisher C. J., Jr, Agosti J. M., Opal S. M., Lowry S. F., Balk R. A., Sadoff J. C., Abraham E., Schein R. M., Benjamin E. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996 Jun 27;334(26):1697–1702. doi: 10.1056/NEJM199606273342603. [DOI] [PubMed] [Google Scholar]
  6. Griffith T. S., Brunner T., Fletcher S. M., Green D. R., Ferguson T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  7. Heaney M. L., Golde D. W. Soluble cytokine receptors. Blood. 1996 Feb 1;87(3):847–857. [PubMed] [Google Scholar]
  8. Kalden J. R., Breedveld F. C., Burkhardt H., Burmester G. R. Immunological treatment of autoimmune diseases. Adv Immunol. 1998;68:333–418. doi: 10.1016/s0065-2776(08)60564-7. [DOI] [PubMed] [Google Scholar]
  9. Nickerson P., Steiger J., Zheng X. X., Steele A. W., Steurer W., Roy-Chaudhury P., Strom T. B. Manipulation of cytokine networks in transplantation: false hope or realistic opportunity for tolerance? Transplantation. 1997 Feb 27;63(4):489–494. doi: 10.1097/00007890-199702270-00001. [DOI] [PubMed] [Google Scholar]
  10. Niederkorn J. Y. Immune privilege and immune regulation in the eye. Adv Immunol. 1990;48:191–226. doi: 10.1016/s0065-2776(08)60755-5. [DOI] [PubMed] [Google Scholar]
  11. Philip R., Epstein L. B. Tumour necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, gamma-interferon and interleukin-1. Nature. 1986 Sep 4;323(6083):86–89. doi: 10.1038/323086a0. [DOI] [PubMed] [Google Scholar]
  12. Prieur A. M., Roux-Lombard P., Dayer J. M. Dynamics of fever and the cytokine network in systemic juvenile arthritis. Rev Rhum Engl Ed. 1996 Mar;63(3):163–170. [PubMed] [Google Scholar]
  13. Rooney M., David J., Symons J., Di Giovine F., Varsani H., Woo P. Inflammatory cytokine responses in juvenile chronic arthritis. Br J Rheumatol. 1995 May;34(5):454–460. doi: 10.1093/rheumatology/34.5.454. [DOI] [PubMed] [Google Scholar]
  14. Schattner A., Lachmi M., Livneh A., Pras M., Hahn T. Tumor necrosis factor in familial Mediterranean fever. Am J Med. 1991 Apr;90(4):434–438. [PubMed] [Google Scholar]
  15. Streilein J. W., Wilbanks G. A., Cousins S. W. Immunoregulatory mechanisms of the eye. J Neuroimmunol. 1992 Aug;39(3):185–200. doi: 10.1016/0165-5728(92)90253-h. [DOI] [PubMed] [Google Scholar]
  16. Strieter R. M., Kunkel S. L., Bone R. C. Role of tumor necrosis factor-alpha in disease states and inflammation. Crit Care Med. 1993 Oct;21(10 Suppl):S447–S463. doi: 10.1097/00003246-199310001-00006. [DOI] [PubMed] [Google Scholar]
  17. Tracey K. J., Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med. 1994;45:491–503. doi: 10.1146/annurev.med.45.1.491. [DOI] [PubMed] [Google Scholar]
  18. Williams K. A., Coster D. J. Rethinking immunological privilege: implications for corneal and limbal stem cell transplantation. Mol Med Today. 1997 Nov;3(11):495–501. doi: 10.1016/S1357-4310(97)01122-2. [DOI] [PubMed] [Google Scholar]
  19. Williams K. A., Roder D., Esterman A., Muehlberg S. M., Coster D. J. Factors predictive of corneal graft survival. Report from the Australian Corneal Graft Registry. Ophthalmology. 1992 Mar;99(3):403–414. doi: 10.1016/s0161-6420(92)31960-8. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES