Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1992 Sep;89(3):347–350. doi: 10.1111/j.1365-2249.1992.tb06960.x

Protective effects of cyclophosphamide, cyclosporin A and FK506 against antigen-induced lung eosinophilia in guinea-pigs.

A A Norris 1, D M Jackson 1, R P Eady 1
PMCID: PMC1554467  PMID: 1381297

Abstract

A close association has been recognized between activated T cells and eosinophils in asthma, albeit circumstantial. The present study attempted to investigate this relationship in an animal model of lung eosinophilia using the new generation of T cell-selective immunosuppressants, cyclosporin A and FK506, compared with the myelotoxic immunosuppressive agent cyclophosphamide. Antigen challenge of ovalbumin-sensitized guinea-pigs resulted in a lung eosinophilia which was assessed by bronchoalveolar lavage. All three agents caused a marked suppression of lung eosinophilia at 24 h post-challenge when the compounds were administered at the time of sensitization but not when administered for 3 days before lavage. However, the lung eosinophilia at 72 h post-challenge was reduced significantly by FK506 and by cyclophosphamide, but not by cyclosporin A, when the drugs were administered for 3 days, before lavage. These results strongly suggest the involvement of T cells in antigen-induced late phase (72 h) eosinophilia in guinea-pigs but not at 24 h. The effects of cyclophosphamide were always associated with a reduction in circulating white cell counts, whereas cyclosporin A and FK506 showed no myelotoxic properties. These results suggest the potential therapeutic use of selective, non-cytotoxic immunosuppressive agents in asthma.

Full text

PDF
347

Selected References

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

  1. Azzawi M., Bradley B., Jeffery P. K., Frew A. J., Wardlaw A. J., Knowles G., Assoufi B., Collins J. V., Durham S., Kay A. B. Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1407–1413. doi: 10.1164/ajrccm/142.6_Pt_1.1407. [DOI] [PubMed] [Google Scholar]
  2. Borel J. F., Feurer C., Gubler H. U., Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976 Jul;6(4):468–475. doi: 10.1007/BF01973261. [DOI] [PubMed] [Google Scholar]
  3. Bousquet J., Chanez P., Lacoste J. Y., Barnéon G., Ghavanian N., Enander I., Venge P., Ahlstedt S., Simony-Lafontaine J., Godard P. Eosinophilic inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033–1039. doi: 10.1056/NEJM199010113231505. [DOI] [PubMed] [Google Scholar]
  4. Corrigan C. J., Hartnell A., Kay A. B. T lymphocyte activation in acute severe asthma. Lancet. 1988 May 21;1(8595):1129–1132. doi: 10.1016/s0140-6736(88)91951-4. [DOI] [PubMed] [Google Scholar]
  5. Corrigan C. J., Kay A. B. CD4 T-lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am Rev Respir Dis. 1990 Apr;141(4 Pt 1):970–977. doi: 10.1164/ajrccm/141.4_Pt_1.. [DOI] [PubMed] [Google Scholar]
  6. Denburg J. A., Dolovich J., Harnish D. Basophil mast cell and eosinophil growth and differentiation factors in human allergic disease. Clin Exp Allergy. 1989 May;19(3):249–254. doi: 10.1111/j.1365-2222.1989.tb02379.x. [DOI] [PubMed] [Google Scholar]
  7. Durham S. R., Kay A. B. Eosinophils, bronchial hyperreactivity and late-phase asthmatic reactions. Clin Allergy. 1985 Sep;15(5):411–418. doi: 10.1111/j.1365-2222.1985.tb02290.x. [DOI] [PubMed] [Google Scholar]
  8. Etienne A., Soulard C., Thonier F., Braquet P. Modulation by drugs of eosinophil recruitment induced by immune challenge in the rat. Possible roles of interleukin 5 and platelet-activating factor. Int Arch Allergy Appl Immunol. 1989;88(1-2):216–221. doi: 10.1159/000234790. [DOI] [PubMed] [Google Scholar]
  9. Frew A. J., Kay A. B. The relationship between infiltrating CD4+ lymphocytes, activated eosinophils, and the magnitude of the allergen-induced late phase cutaneous reaction in man. J Immunol. 1988 Dec 15;141(12):4158–4164. [PubMed] [Google Scholar]
  10. Frew A. J., Moqbel R., Azzawi M., Hartnell A., Barkans J., Jeffery P. K., Kay A. B., Scheper R. J., Varley J., Church M. K. T lymphocytes and eosinophils in allergen-induced late-phase asthmatic reactions in the guinea pig. Am Rev Respir Dis. 1990 Feb;141(2):407–413. doi: 10.1164/ajrccm/141.2.407. [DOI] [PubMed] [Google Scholar]
  11. Gonzalez M. C., Diaz P., Galleguillos F. R., Ancic P., Cromwell O., Kay A. B. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma. Relative increases in OKT8 cells in single early responders compared with those in late-phase responders. Am Rev Respir Dis. 1987 Sep;136(3):600–604. doi: 10.1164/ajrccm/136.3.600. [DOI] [PubMed] [Google Scholar]
  12. Gulbenkian A. R., Fernandez X., Kreutner W., Minnicozzi M., Watnick A. S., Kung T., Egan R. W. Anaphylactic challenge causes eosinophil accumulation in bronchoalveolar lavage fluid of guinea pigs. Modulation by betamethasone, phenidone, indomethacin, WEB 2086, and a novel antiallergy agent, SCH 37224. Am Rev Respir Dis. 1990 Sep;142(3):680–685. doi: 10.1164/ajrccm/142.3.680. [DOI] [PubMed] [Google Scholar]
  13. Hutson P. A., Church M. K., Clay T. P., Miller P., Holgate S. T. Early and late-phase bronchoconstriction after allergen challenge of nonanesthetized guinea pigs. I. The association of disordered airway physiology to leukocyte infiltration. Am Rev Respir Dis. 1988 Mar;137(3):548–557. doi: 10.1164/ajrccm/137.3.548. [DOI] [PubMed] [Google Scholar]
  14. Kimura I., Moritani Y., Tanizaki Y. Basophils in bronchial asthma with reference to reagin-type allergy. Clin Allergy. 1973 Jun;3(2):195–202. doi: 10.1111/j.1365-2222.1973.tb01321.x. [DOI] [PubMed] [Google Scholar]
  15. Kings M. A., Chapman I., Kristersson A., Sanjar S., Morley J. Human recombinant lymphokines and cytokines induce pulmonary eosinophilia in the guinea pig which is inhibited by ketotifen and AH 21-132. Int Arch Allergy Appl Immunol. 1990;91(4):354–361. doi: 10.1159/000235141. [DOI] [PubMed] [Google Scholar]
  16. Kino T., Hatanaka H., Miyata S., Inamura N., Nishiyama M., Yajima T., Goto T., Okuhara M., Kohsaka M., Aoki H. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987 Sep;40(9):1256–1265. doi: 10.7164/antibiotics.40.1256. [DOI] [PubMed] [Google Scholar]
  17. Lopez A. F., Sanderson C. J., Gamble J. R., Campbell H. D., Young I. G., Vadas M. A. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med. 1988 Jan 1;167(1):219–224. doi: 10.1084/jem.167.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Martinet Y., Pinkston P., Saltini C., Spurzem J., Müller-Quernheim J., Crystal R. G. Evaluation of the in vitro and in vivo effects of cyclosporine on the lung T-lymphocyte alveolitis of active pulmonary sarcoidosis. Am Rev Respir Dis. 1988 Nov;138(5):1242–1248. doi: 10.1164/ajrccm/138.5.1242. [DOI] [PubMed] [Google Scholar]
  19. Mullarkey M. F., Blumenstein B. A., Andrade W. P., Bailey G. A., Olason I., Wetzel C. E. Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study. N Engl J Med. 1988 Mar 10;318(10):603–607. doi: 10.1056/NEJM198803103181004. [DOI] [PubMed] [Google Scholar]
  20. Mullarkey M. F., Webb D. R., Pardee N. E. Methotrexate in the treatment of steroid-dependent asthma. Ann Allergy. 1986 Apr;56(4):347–350. [PubMed] [Google Scholar]
  21. Ohtoshi T., Vancheri C., Cox G., Gauldie J., Dolovich J., Denburg J. A., Jordana M. Monocyte-macrophage differentiation induced by human upper airway epithelial cells. Am J Respir Cell Mol Biol. 1991 Mar;4(3):255–263. doi: 10.1165/ajrcmb/4.3.255. [DOI] [PubMed] [Google Scholar]
  22. Owen W. F., Jr, Rothenberg M. E., Silberstein D. S., Gasson J. C., Stevens R. L., Austen K. F., Soberman R. J. Regulation of human eosinophil viability, density, and function by granulocyte/macrophage colony-stimulating factor in the presence of 3T3 fibroblasts. J Exp Med. 1987 Jul 1;166(1):129–141. doi: 10.1084/jem.166.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pacheco Y., Marechal C., Marechal F., Biot N., Perrin Fayolle M. Azathioprine treatment of chronic pulmonary sarcoidosis. Sarcoidosis. 1985 Sep;2(2):107–113. [PubMed] [Google Scholar]
  24. Rothenberg M. E., Owen W. F., Jr, Silberstein D. S., Woods J., Soberman R. J., Austen K. F., Stevens R. L. Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin 3. J Clin Invest. 1988 Jun;81(6):1986–1992. doi: 10.1172/JCI113547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Touvay C., Vilain B., Lejeune V., Mencia-Huerta J. M., Braquet P. Effect of cyclosporin A and the platelet-activating factor (PAF) antagonist, BN 52021, on PAF- and antigen- induced bronchoconstriction in the guinea-pig. Biochem Biophys Res Commun. 1989 Aug 30;163(1):118–123. doi: 10.1016/0006-291x(89)92107-4. [DOI] [PubMed] [Google Scholar]
  26. Yamaguchi Y., Hayashi Y., Sugama Y., Miura Y., Kasahara T., Kitamura S., Torisu M., Mita S., Tominaga A., Takatsu K. Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival. IL-5 as an eosinophil chemotactic factor. J Exp Med. 1988 May 1;167(5):1737–1742. doi: 10.1084/jem.167.5.1737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yoshimura N., Matsui S., Hamashima T., Oka T. Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. I. Inhibition of expression of alloantigen-activated suppressor cells, as well as induction of alloreactivity. Transplantation. 1989 Feb;47(2):351–356. doi: 10.1097/00007890-198902000-00034. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES