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. 1995 Mar;99(3):467–472. doi: 10.1111/j.1365-2249.1995.tb05574.x

The effect of cyclosporin A, FK506, and rapamycin on the murine chronic graft-versus-host response--an in vivo model of Th2-like activity.

R V Bundick 1, R I Craggs 1, E Holness 1
PMCID: PMC1534195  PMID: 7533681

Abstract

We have evaluated the effects of three potent immunosuppressive agents: cyclosporin A, FK506, and rapamycin, on a murine chronic graft-versus-host response (chronic GVHR). The chronic GVHR has previously been described to be a Th2-like response, and is characterized by a marked splenomegaly and hyper-IgE production in the early stages of the response. The effects of the immunosuppressive agents on both splenomegaly and hyper-IgE were measured 3 weeks after the induction of the chronic GVHR. Rapamycin was found to inhibit both splenomegaly and the hyper-IgE response in a dose-dependent manner. Unexpectedly cyclosporin A and FK506 were found to potentiate markedly both the splenomegaly and hyper-IgE response at low doses before exhibiting an inhibitory effect at higher doses. We propose the differences of activity seen with rapamycin compared with cyclosporin A and FK506 may be explained by their different mechanisms of action, and also by the selectivity of low dose cyclosporin A and FK506 for Th1-like lymphocytes. The implications of these observations are discussed in relation to the use of these immunosuppressives for the treatment of Th2-like diseases.

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Selected References

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  1. Alexander A. G., Barnes N. C., Kay A. B. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet. 1992 Feb 8;339(8789):324–328. doi: 10.1016/0140-6736(92)91646-p. [DOI] [PubMed] [Google Scholar]
  2. Allen R. D., Staley T. A., Sidman C. L. Differential cytokine expression in acute and chronic murine graft-versus-host-disease. Eur J Immunol. 1993 Feb;23(2):333–337. doi: 10.1002/eji.1830230205. [DOI] [PubMed] [Google Scholar]
  3. Andersson J., Nagy S., Groth C. G., Andersson U. Effects of FK506 and cyclosporin A on cytokine production studied in vitro at a single-cell level. Immunology. 1992 Jan;75(1):136–142. [PMC free article] [PubMed] [Google Scholar]
  4. Andrews B. S., Eisenberg R. A., Theofilopoulos A. N., Izui S., Wilson C. B., McConahey P. J., Murphy E. D., Roths J. B., Dixon F. J. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978 Nov 1;148(5):1198–1215. doi: 10.1084/jem.148.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Appleby P., Webber D. G., Bowen J. G. Murine chronic graft-versus-host disease as a model of systemic lupus erythematosus: effect of immunosuppressive drugs on disease development. Clin Exp Immunol. 1989 Dec;78(3):449–453. [PMC free article] [PubMed] [Google Scholar]
  6. Bach J. F. Cyclosporine in autoimmune diseases. Transplant Proc. 1989 Jun;21(3 Suppl 1):97–113. [PubMed] [Google Scholar]
  7. Bierer B. E., Mattila P. S., Standaert R. F., Herzenberg L. A., Burakoff S. J., Crabtree G., Schreiber S. L. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9231–9235. doi: 10.1073/pnas.87.23.9231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bruijn J. A., van Elven E. H., Hogendoorn P. C., Corver W. E., Hoedemaeker P. J., Fleuren G. J. Murine chronic graft-versus-host disease as a model for lupus nephritis. Am J Pathol. 1988 Mar;130(3):639–641. [PMC free article] [PubMed] [Google Scholar]
  9. Chen S. S., Li Q., Pearlman E., Chen W. H. Dual mechanisms of potentiation of murine antigen-specific IgE production by cyclosporin A in vitro. J Immunol. 1992 Aug 1;149(3):762–767. [PubMed] [Google Scholar]
  10. Chen S. S., Stanescu G., Magalski A. E., Qian Y. Y. Cyclosporin A is an adjuvant in murine IgE antibody responses. J Immunol. 1989 Jun 15;142(12):4225–4232. [PubMed] [Google Scholar]
  11. Chung J., Kuo C. J., Crabtree G. R., Blenis J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell. 1992 Jun 26;69(7):1227–1236. doi: 10.1016/0092-8674(92)90643-q. [DOI] [PubMed] [Google Scholar]
  12. Claman H. N., Spiegelberg H. L. Immunoglobulin dysregulation in murine graft-vs-host disease: a hyper-IgE syndrome. Clin Immunol Immunopathol. 1990 Jul;56(1):46–53. doi: 10.1016/0090-1229(90)90168-p. [DOI] [PubMed] [Google Scholar]
  13. De Wit D., Van Mechelen M., Zanin C., Doutrelepont J. M., Velu T., Gérard C., Abramowicz D., Scheerlinck J. P., De Baetselier P., Urbain J. Preferential activation of Th2 cells in chronic graft-versus-host reaction. J Immunol. 1993 Jan 15;150(2):361–366. [PubMed] [Google Scholar]
  14. Doutrelepont J. M., Moser M., Leo O., Abramowicz D., Vanderhaegen M. L., Urbain J., Goldman M. Hyper IgE in stimulatory graft-versus-host disease: role of interleukin-4. Clin Exp Immunol. 1991 Jan;83(1):133–136. doi: 10.1111/j.1365-2249.1991.tb05602.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dumont F. J., Staruch M. J., Koprak S. L., Melino M. R., Sigal N. H. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol. 1990 Jan 1;144(1):251–258. [PubMed] [Google Scholar]
  16. Feutren G. Clinical experience with sandimmune (cyclosporine) in autoimmune diseases. Transplant Proc. 1992 Aug;24(4 Suppl 2):55–60. [PubMed] [Google Scholar]
  17. Gajewski T. F., Schell S. R., Fitch F. W. Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J Immunol. 1990 Jun 1;144(11):4110–4120. [PubMed] [Google Scholar]
  18. Gleichmann E., Van Elven E. H., Van der Veen J. P. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol. 1982 Feb;12(2):152–159. doi: 10.1002/eji.1830120210. [DOI] [PubMed] [Google Scholar]
  19. Granelli-Piperno A., Nolan P., Inaba K., Steinman R. M. The effect of immunosuppressive agents on the induction of nuclear factors that bind to sites on the interleukin 2 promoter. J Exp Med. 1990 Dec 1;172(6):1869–1872. doi: 10.1084/jem.172.6.1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hauser C., Snapper C. M., Ohara J., Paul W. E., Katz S. I. T helper cells grown with hapten-modified cultured Langerhans' cells produce interleukin 4 and stimulate IgE production by B cells. Eur J Immunol. 1989 Feb;19(2):245–251. doi: 10.1002/eji.1830190205. [DOI] [PubMed] [Google Scholar]
  21. Henderson D. J., Naya I., Bundick R. V., Smith G. M., Schmidt J. A. Comparison of the effects of FK-506, cyclosporin A and rapamycin on IL-2 production. Immunology. 1991 Jul;73(3):316–321. [PMC free article] [PubMed] [Google Scholar]
  22. Herman J. G., Beschorner W. E., Baughman K. L., Boitnott J. K., Vogelsang G. B., Baumgartner W. A. Pseudo-graft-versus-host disease in heart and heart-lung recipients. Transplantation. 1988 Jul;46(1):93–98. doi: 10.1097/00007890-198807000-00017. [DOI] [PubMed] [Google Scholar]
  23. Kay J. E., Kromwel L., Doe S. E., Denyer M. Inhibition of T and B lymphocyte proliferation by rapamycin. Immunology. 1991 Apr;72(4):544–549. [PMC free article] [PubMed] [Google Scholar]
  24. Lagodziński Z., Górski A., Stepień-Sopniewska B., Wasik M. Effect of FK 506 on B-cell responses. Transplant Proc. 1991 Feb;23(1 Pt 2):942–943. [PubMed] [Google Scholar]
  25. Lahesmaa R., Yssel H., Batsford S., Luukkainen R., Möttönen T., Steinman L., Peltz G. Yersinia enterocolitica activates a T helper type 1-like T cell subset in reactive arthritis. J Immunol. 1992 May 15;148(10):3079–3085. [PubMed] [Google Scholar]
  26. Liu J., Farmer J. D., Jr, Lane W. S., Friedman J., Weissman I., Schreiber S. L. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807–815. doi: 10.1016/0092-8674(91)90124-h. [DOI] [PubMed] [Google Scholar]
  27. Luo H. Y., Chen H. F., Daloze P., Chang J., St-Louis G., Wu J. P. In vitro IgE production by interleukin 4-stimulated human peripheral blood mononuclear cells is suppressed by rapamycin. Clin Immunol Immunopathol. 1991 Dec;61(3):410–420. doi: 10.1016/s0090-1229(05)80012-1. [DOI] [PubMed] [Google Scholar]
  28. Luo H., Chen H., Daloze P., Chang J. Y., St-Louis G., Wu J. Inhibition of in vitro immunoglobulin production by rapamycin. Transplantation. 1992 May;53(5):1071–1076. doi: 10.1097/00007890-199205000-00019. [DOI] [PubMed] [Google Scholar]
  29. Luo H., Chen H., Daloze P., Chang J., Wu J. Rapamycin suppresses in vitro immunoglobulin production by human lymphocytes. Transplant Proc. 1991 Aug;23(4):2236–2238. [PubMed] [Google Scholar]
  30. Martel R. R., Klicius J., Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol. 1977 Feb;55(1):48–51. doi: 10.1139/y77-007. [DOI] [PubMed] [Google Scholar]
  31. Mason J. Cyclosporins past, present, and future. Transplant Proc. 1992 Aug;24(4 Suppl 2):61–63. [PubMed] [Google Scholar]
  32. Morris R. E., Wu J., Shorthouse R. Comparative immunopharmacologic effects of FK 506 and CyA in in vivo models of organ transplantation. Transplant Proc. 1990 Feb;22(1):110–112. [PubMed] [Google Scholar]
  33. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  34. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  35. Popovic S., Bartlett R. R. The use of the murine chronic graft vs host (CGVH) disease, a model for systemic lupus erythematosus (SLE), for drug discovery. Agents Actions. 1987 Aug;21(3-4):284–286. doi: 10.1007/BF01966492. [DOI] [PubMed] [Google Scholar]
  36. Prud'homme G. J., Parfrey N. A., Vanier L. E. Cyclosporine-induced autoimmunity and immune hyperreactivity. Autoimmunity. 1991;9(4):345–356. doi: 10.3109/08916939108997137. [DOI] [PubMed] [Google Scholar]
  37. Schreiber S. L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991 Jan 18;251(4991):283–287. doi: 10.1126/science.1702904. [DOI] [PubMed] [Google Scholar]
  38. Sears M. R., Burrows B., Flannery E. M., Herbison G. P., Hewitt C. J., Holdaway M. D. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med. 1991 Oct 10;325(15):1067–1071. doi: 10.1056/NEJM199110103251504. [DOI] [PubMed] [Google Scholar]
  39. Sigal N. H., Dumont F. J. Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519–560. doi: 10.1146/annurev.iy.10.040192.002511. [DOI] [PubMed] [Google Scholar]
  40. Sigal N. H., Lin C. S., Siekierka J. J. Inhibition of human T-cell activation by FK 506, rapamycin, and cyclosporine A. Transplant Proc. 1991 Apr;23(2 Suppl 2):1–5. [PubMed] [Google Scholar]
  41. Simon A. K., Seipelt E., Wu P., Wenzel B., Braun J., Sieper J. Analysis of cytokine profiles in synovial T cell clones from chlamydial reactive arthritis patients: predominance of the Th1 subset. Clin Exp Immunol. 1993 Oct;94(1):122–126. doi: 10.1111/j.1365-2249.1993.tb05988.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sliman G. A., Beschorner W. E., Baughman K. L., Hutchins G. M., Borkon M. A., Baumgartner W. A. Graft-versus-host-like disease in a heart allograft recipient. A possible autoimmune phenomenon. Transplantation. 1988 Jan;45(1):253–256. doi: 10.1097/00007890-198801000-00057. [DOI] [PubMed] [Google Scholar]
  43. Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
  44. Street N. E., Mosmann T. R. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991 Feb;5(2):171–177. doi: 10.1096/fasebj.5.2.1825981. [DOI] [PubMed] [Google Scholar]
  45. Thomson A. W., Nalesnik M. A., Rilo H. R., Woo J., Carroll P. B., Van Thiel D. H. ICAM-1 and E-selectin expression in lesional biopsies of psoriasis patients responding to systemic FK 506 therapy. Autoimmunity. 1993;15(3):215–223. doi: 10.3109/08916939309019930. [DOI] [PubMed] [Google Scholar]
  46. Uyemura K., Yamamura M., Fivenson D. F., Modlin R. L., Nickoloff B. J. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993 Nov;101(5):701–705. doi: 10.1111/1523-1747.ep12371679. [DOI] [PubMed] [Google Scholar]
  47. Wang J. M., Denis M., Fournier M., Laviolette M. Cyclosporin A increases the pulmonary eosinophilia induced by inhaled Aspergillus antigen in mice. Clin Exp Immunol. 1993 Sep;93(3):323–330. doi: 10.1111/j.1365-2249.1993.tb08180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wasik M., Stepień-Sopniewska B., Lagodziński Z., Górski A. Effect of FK-506 and cyclosporine on human T and B lymphoproliferative responses. Immunopharmacology. 1990 Jul-Aug;20(1):57–61. doi: 10.1016/0162-3109(90)90007-2. [DOI] [PubMed] [Google Scholar]
  49. Zieg G., Lack G., Harbeck R. J., Gelfand E. W., Leung D. Y. In vivo effects of glucocorticoids on IgE production. J Allergy Clin Immunol. 1994 Aug;94(2 Pt 1):222–230. doi: 10.1016/0091-6749(94)90044-2. [DOI] [PubMed] [Google Scholar]

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