Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1983 Sep;41(3):1226–1233. doi: 10.1128/iai.41.3.1226-1233.1983

Effect of cyclosporine on the response of normal human lymphocytes to cytomegalovirus in vitro.

P J Converse, A D Hess, P J Tutschka, G W Santos
PMCID: PMC264630  PMID: 6309665

Abstract

Lymphocytes from healthy volunteers seropositive for cytomegalovirus (CMV) demonstrated strong lymphoproliferative responses to CMV-infected and glutaraldehyde-fixed foreskin fibroblasts (CMVFFx) when cocultured for 6 days. Addition of the immunosuppressive drug cyclosporine (CsA) to the cultures resulted in a 10-fold reduction (P less than 0.001) in counts per minute of [3H]thymidine uptake. The proliferative response to noninfected fixed fibroblasts was also reduced 10-fold. Kinetic studies showed an inhibition of the lymphoproliferative response and not an alteration in the time course kinetics in CsA-treated cultures. Cytotoxicity to CMV-infected and unfixed fibroblasts by lymphocytes primed by CMVFFx in the presence of 0.5 micrograms of CsA per ml was significantly reduced (P less than 0.01) as compared with untreated cultures but remained significantly above background level (P less than 0.01). The cytotoxic response was still present but reduced at concentrations of greater than or equal to 1.0 micrograms/ml. Cytotoxicity to noninfected fibroblasts by CMVFFx-primed lymphocytes could be eliminated by as little as 0.5 micrograms of CsA per ml. Stimulation of lymphocytes by CMVFFx but not by noninfected fixed fibroblasts resulted in the in vitro generation of suppressor cells. CsA at a final concentration of 1.0 or 2.5 micrograms/ml did not significantly impair the induction of cells capable of suppressing the lymphoproliferative response of fresh autologous mononuclear cells to CMVFFx. The findings described above may have important clinical implications in that a degree of protective immunity to CMV-infected cells is maintained even in the presence of CsA.

Full text

PDF
1226

Selected References

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

  1. Borel J. F. Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology. 1976 Oct;31(4):631–641. [PMC free article] [PubMed] [Google Scholar]
  2. Borel J. F., Feurer C., Magnée C., Stähelin H. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977 Jun;32(6):1017–1025. [PMC free article] [PubMed] [Google Scholar]
  3. Bunjes D., Hardt C., Röllinghoff M., Wagner H. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol. 1981 Aug;11(8):657–661. doi: 10.1002/eji.1830110812. [DOI] [PubMed] [Google Scholar]
  4. Calne R. Y., White D. J., Rolles K., Smith D. P., Herbertson B. M. Prolonged survival of pig orthotopic heart grafts treated with cyclosporin A. Lancet. 1978 Jun 3;1(8075):1183–1185. doi: 10.1016/s0140-6736(78)90971-6. [DOI] [PubMed] [Google Scholar]
  5. Carney W. P., Rubin R. H., Hoffman R. A., Hansen W. P., Healey K., Hirsch M. S. Analysis of T lymphocyte subsets in cytomegalovirus mononucleosis. J Immunol. 1981 Jun;126(6):2114–2116. [PubMed] [Google Scholar]
  6. Dowling J. N., Saslow A. R., Armstrong J. A., Ho M. Cytomegalovirus infection in patients receiving immunosuppressive therapy for rheumatologic disorders. J Infect Dis. 1976 Apr;133(4):399–408. doi: 10.1093/infdis/133.4.399. [DOI] [PubMed] [Google Scholar]
  7. Flood P., Yamauchi K., Gershon R. K. Analysis of the interactions between two molecules that are required for the expression of Ly-2 suppressor cell activity. Three different types of focusing events may be needed to deliver the suppressive signal. J Exp Med. 1982 Aug 1;156(2):361–371. doi: 10.1084/jem.156.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Green C. J., Allison A. C. Extensive prolongation of rabbit kidney allograft survival after short-term cyclosporin-A treatment. Lancet. 1978 Jun 3;1(8075):1182–1183. doi: 10.1016/s0140-6736(78)90970-4. [DOI] [PubMed] [Google Scholar]
  9. Hess A. D., Tutschka P. J. Effect of cyclosporin A on human lymphocyte responses in vitro. I. CsA allows for the expression of alloantigen-activated suppressor cells while preferentially inhibiting the induction of cytolytic effector lymphocytes in MLR. J Immunol. 1980 Jun;124(6):2601–2608. [PubMed] [Google Scholar]
  10. Hess A. D., Tutschka P. J., Pu Z., Santos G. W. Effect of cyclosporin A on human lymphocyte responses in vitro. IV. Production of T cell stimulatory growth factors and development of responsiveness to these growth factors in CsA-treated primary MLR cultures. J Immunol. 1982 Jan;128(1):360–367. [PubMed] [Google Scholar]
  11. Hess A. D., Tutschka P. J., Santos G. W. Effect of cyclosporin A on human lymphocyte responses in vitro. II. Induction of specific alloantigen unresponsiveness mediated by a nylon wool adherent suppressor cell. J Immunol. 1981 Mar;126(3):961–968. [PubMed] [Google Scholar]
  12. Hess A. D., Tutschka P. J., Santos G. W. Effect of cyclosporin A on human lymphocyte responses in vitro. III. CsA inhibits the production of T lymphocyte growth factors in secondary mixed lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF. J Immunol. 1982 Jan;128(1):355–359. [PubMed] [Google Scholar]
  13. LaFemina R. L., Hayward G. S. Replicative forms of human cytomegalovirus DNA with joined termini are found in permissively infected human cells but not in non-permissive Balb/c-3T3 mouse cells. J Gen Virol. 1983 Feb;64(Pt 2):373–389. doi: 10.1099/0022-1317-64-2-373. [DOI] [PubMed] [Google Scholar]
  14. Larsson E. L. Cyclosporin A and dexamethasone suppress T cell responses by selectively acting at distinct sites of the triggering process. J Immunol. 1980 Jun;124(6):2828–2833. [PubMed] [Google Scholar]
  15. Linnemann C. C., Jr, Kauffman C. A., First M. R., Schiff G. M., Phair J. P. Cellular immune response to cytomegalovirus infection after renal transplantation. Infect Immun. 1978 Oct;22(1):176–180. doi: 10.1128/iai.22.1.176-180.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Moller-Larsen A., Andersen H. K., Heron I., Sarov I. In vitro stimulation of human lymphocytes by purified cytomegalovirus. Intervirology. 1975;6(4-5):249–257. doi: 10.1159/000149479. [DOI] [PubMed] [Google Scholar]
  17. Quinnan G. V., Jr, Kirmani N., Rook A. H., Manischewitz J. F., Jackson L., Moreschi G., Santos G. W., Saral R., Burns W. H. Cytotoxic t cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N Engl J Med. 1982 Jul 1;307(1):7–13. doi: 10.1056/NEJM198207013070102. [DOI] [PubMed] [Google Scholar]
  18. Schirm J., Roenhorst H. W., The T. H. Comparison of in vitro lymphocyte proliferations induced by cytomegalovirus-infected human fibroblasts and cell-free cytomegalovirus. Infect Immun. 1980 Dec;30(3):621–627. doi: 10.1128/iai.30.3.621-627.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Starr S. E., Dalton B., Garrabrant T., Paucker K., Plotkin S. A. Lymphocyte blastogenesis and interferon production in adult human leukocyte cultures stimulated with cytomegalovirus antigens. Infect Immun. 1980 Oct;30(1):17–22. doi: 10.1128/iai.30.1.17-22.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Thong Y. H., Hensen S. A., Vincent M. M., Fuccillo D. A., Stiles W. A., Bellanti J. A. Use of cryopreserved virus-infected target cells in a lymphocytotoxicity 51Cr release microassay for cell-mediated immunity to cytomegalovirus. Infect Immun. 1976 Feb;13(2):643–645. doi: 10.1128/iai.13.2.643-645.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Thorsby E., Lie S. Antigens on human fibroblasts demonstrated with HL-A antisera and anti-human lymphocytic sera. Vox Sang. 1968;15(1):44–53. doi: 10.1111/j.1423-0410.1968.tb04446.x. [DOI] [PubMed] [Google Scholar]
  22. Tsoi M. S., Aprile J., Dobbs S., Goehle S., Storb R. Enrichment (and depletion) of human suppressor cells with monoclonal antibodies and immunoglobulin-coated plates. J Immunol Methods. 1982 Sep 30;53(3):293–305. doi: 10.1016/0022-1759(82)90176-4. [DOI] [PubMed] [Google Scholar]
  23. Tutschka P. J., Beschorner W. E., Hess A. D. Use of cyclosporin A (CsA) in a rat model of allogeneic marrow transplantation. Haematol Blood Transfus. 1980;25:241–253. doi: 10.1007/978-3-642-67319-1_20. [DOI] [PubMed] [Google Scholar]
  24. Wang B. S., Heacock E. H., Collins K. H., Hutchinson I. F., Tilney N. L., Mannick J. A. Suppressive effects of cyclosporin A on the induction of alloreactivity in vitro and in vivo. J Immunol. 1981 Jul;127(1):89–93. [PubMed] [Google Scholar]
  25. van Oers M. H., Pinkster J., Zeijlemaker W. P. Quantification of antigen-reactive cells among human T lymphocytes. Eur J Immunol. 1978 Jul;8(7):477–484. doi: 10.1002/eji.1830080706. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES