Skip to main content
PMC home page
Immunology logoLink to Immunology
. 1990 Jul;70(3):398–404.

The influence of FK-506 on the thymus: an immunophenotypic and structural analysis.

R G Pugh-Humphreys 1, C S Ross 1, A W Thomson 1
PMCID: PMC1384172  PMID: 1696242

Abstract

The influence of the powerful new immunosuppressant FK-506 on the thymus was investigated in Sprague-Dawley rats that were immunized with sheep erythrocytes and treated with FK-506 (1 mg/kg/day i.m.) for 7 days. Suppression of humoral immunity in drug-treated animals was accompanied by reductions in circulating lymphocytes bearing activation markers (interleukin-2 receptor beta-chain and OX40, activated CD4+ cells) and by striking thymic medullary atrophy. There were, however, no significant differences in thymic weights or in thymocyte numbers between experimental and control groups during the period of FK-506 administration. Reduction of the medullary compartment was visualized immunohistochemically, by decreases in major histocompatibility complex (MHC) class I- and MHC class II-positive cells and in CD37+ (mature medullary) thymocytes. Flow cytometric analysis of thymocytes showed that FK-506 induced increases in bright, Thy-1.1+ cells and in numbers of CD4+ and CD8+ thymocytes, whilst CD37+ cells were less numerous than in controls. Percentages of MHC class I- and MHC class II-positive cells varied little throughout the course of FK-506 administration. Evidence of selective damage to medullary epithelial cells, attributable to FK-506, was found at both the light and electron microscopic levels, whilst thymic macrophages in drug-treated rats displayed features of enhanced phagocytic activity, including ingestion of damaged epithelial cells. These FK-506-induced abnormalities were reversed within 14 days of drug withdrawal. These findings suggest that, like cyclosporin A, FK-506 reversibly disrupts the thymic microenvironment and may interfere with the function/maturation of T lymphocytes.

Full text

PDF
401

Images in this article

400Figure 2
on p.400
401Figure 4
on p.401
402Figure 5
on p.402

Selected References

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

  1. Beschorner W. E., Namnoum J. D., Hess A. D., Shinn C. A., Santos G. W. Cyclosporin A and the thymus. Immunopathology. Am J Pathol. 1987 Mar;126(3):487–496. [PMC free article] [PubMed] [Google Scholar]
  2. Bevan D. J., Chisholm P. M. Co-expression of CD4 and CD8 molecules and de novo expression of MHC class II antigens on activated rat T cells. Immunology. 1986 Dec;59(4):621–625. [PMC free article] [PubMed] [Google Scholar]
  3. Blair J. T., Thomson A. W., Whiting P. H., Davidson R. J., Simpson J. G. Toxicity of the immune suppressant cyclosporin A in the rat. J Pathol. 1982 Oct;138(2):163–178. doi: 10.1002/path.1711380206. [DOI] [PubMed] [Google Scholar]
  4. Cunningham A. J., Szenberg A. Further improvements in the plaque technique for detecting single antibody-forming cells. Immunology. 1968 Apr;14(4):599–600. [PMC free article] [PubMed] [Google Scholar]
  5. Fowlkes B. J., Pardoll D. M. Molecular and cellular events of T cell development. Adv Immunol. 1989;44:207–264. doi: 10.1016/s0065-2776(08)60643-4. [DOI] [PubMed] [Google Scholar]
  6. Harding M. W., Galat A., Uehling D. E., Schreiber S. L. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature. 1989 Oct 26;341(6244):758–760. doi: 10.1038/341758a0. [DOI] [PubMed] [Google Scholar]
  7. Inamura N., Nakahara K., Kino T., Goto T., Aoki H., Yamaguchi I., Kohsaka M., Ochiai T. Prolongation of skin allograft survival in rats by a novel immunosuppressive agent, FK506. Transplantation. 1988 Jan;45(1):206–209. doi: 10.1097/00007890-198801000-00042. [DOI] [PubMed] [Google Scholar]
  8. Kanariou M., Huby R., Ladyman H., Colic M., Sivolapenko G., Lampert I., Ritter M. Immunosuppression with cyclosporin A alters the thymic microenvironment. Clin Exp Immunol. 1989 Nov;78(2):263–270. [PMC free article] [PubMed] [Google Scholar]
  9. Kay J. E., Benzie C. R., Goodier M. R., Wick C. J., Doe S. E. Inhibition of T-lymphocyte activation by the immunosuppressive drug FK-506. Immunology. 1989 Aug;67(4):473–477. [PMC free article] [PubMed] [Google Scholar]
  10. Kino T., Hatanaka H., Hashimoto M., Nishiyama M., Goto T., Okuhara M., Kohsaka M., Aoki H., Imanaka H. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1987 Sep;40(9):1249–1255. doi: 10.7164/antibiotics.40.1249. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Matsuhashi N., Kawase Y., Suzuki G. Effects of cyclosporine A on thymocyte differentiation in fetal thymus organ culture. Cell Immunol. 1989 Oct 15;123(2):307–315. doi: 10.1016/0008-8749(89)90291-8. [DOI] [PubMed] [Google Scholar]
  13. McIntosh L. C., Morrice L. M., Udagawa Y., Thomson A. W. Influence of tumour carriage on the production of lymphokines affecting macrophage behaviour. Immunology. 1986 Mar;57(3):359–365. [PMC free article] [PubMed] [Google Scholar]
  14. Nalesnik M. A., Todo S., Murase N., Gryzan S., Lee P. H., Makowka L., Starzl T. E. Toxicology of FK-506 in the Lewis rat. Transplant Proc. 1987 Oct;19(5 Suppl 6):89–92. [PMC free article] [PubMed] [Google Scholar]
  15. Ochiai T., Nagata M., Nakajima K., Suzuki T., Sakamoto K., Enomoto K., Gunji Y., Uematsu T., Goto T., Hori S. Studies of the effects of FK506 on renal allografting in the beagle dog. Transplantation. 1987 Dec;44(6):729–733. doi: 10.1097/00007890-198712000-00001. [DOI] [PubMed] [Google Scholar]
  16. Ochiai T., Nakajima K., Nagata M., Hori S., Asano T., Isono K. Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats. Transplantation. 1987 Dec;44(6):734–738. doi: 10.1097/00007890-198712000-00002. [DOI] [PubMed] [Google Scholar]
  17. Savino W., Dardenne M. Thymic hormone-containing cells VI. Immunohistologic evidence for the simultaneous presence of thymulin, thymopoietin and thymosin alpha 1 in normal and pathological human thymuses. Eur J Immunol. 1984 Nov;14(11):987–991. doi: 10.1002/eji.1830141105. [DOI] [PubMed] [Google Scholar]
  18. Second International Workshop on FK 506. A potential breakthrough in immunosuppression: clinical implications. October 31, 1989, Barcelona, Spain. Proceedings. Transplant Proc. 1990 Feb;22(1):5–113. [PubMed] [Google Scholar]
  19. Starzl T. E., Todo S., Fung J., Demetris A. J., Venkataramman R., Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989 Oct 28;2(8670):1000–1004. doi: 10.1016/s0140-6736(89)91014-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Takeuchi Y., Habu S., Okumura K., Suzuki G. Cyclosporin A and anti-Ia antibody cause a maturation defect of CD4+8- cells in organ-cultured fetal thymus. Immunology. 1989 Mar;66(3):362–367. [PMC free article] [PubMed] [Google Scholar]
  21. Tanaka M., Shinohara K., Fukumoto T., Tanaka H., Kaneko T. Effect of Cyclosporin A on rat thymus: time course analysis by immunoperoxidase technique and flow cytofluorometry. Clin Exp Immunol. 1988 May;72(2):216–221. [PMC free article] [PubMed] [Google Scholar]
  22. Tocci M. J., Matkovich D. A., Collier K. A., Kwok P., Dumont F., Lin S., Degudicibus S., Siekierka J. J., Chin J., Hutchinson N. I. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol. 1989 Jul 15;143(2):718–726. [PubMed] [Google Scholar]
  23. Todo S., Ueda Y., Demetris J. A., Imventarza O., Nalesnik M., Venkataramanan R., Makowka L., Starzl T. E. Immunosuppression of canine, monkey, and baboon allografts by FK 506: with special reference to synergism with other drugs and to tolerance induction. Surgery. 1988 Aug;104(2):239–249. [PMC free article] [PubMed] [Google Scholar]
  24. Woo J., Ross C. S., Milton J. I., Thomson A. W. Immunosuppressive activity of FK-506 in rats: flow cytometric analysis of lymphocyte populations in blood, spleen and thymus during treatment and following drug withdrawal. Clin Exp Immunol. 1990 Jan;79(1):109–114. doi: 10.1111/j.1365-2249.1990.tb05136.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Woo J., Sewell H. F., Thomson A. W. The influence of FK-506 and low-concentration ciclosporin on human lymphocyte activation antigen expression and blastogenesis: a flow cytometric analysis. Scand J Immunol. 1990 Mar;31(3):297–304. doi: 10.1111/j.1365-3083.1990.tb02772.x. [DOI] [PubMed] [Google Scholar]
  26. Woo J., Stephen M., Thomson A. W. Spleen lymphocyte populations and expression of activation markers in rats treated with the potent new immunosuppressive agent FK-506. Immunology. 1988 Sep;65(1):153–155. [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 Immunology are provided here courtesy of British Society for Immunology

RESOURCES