Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1989 Nov;57(11):3472–3478. doi: 10.1128/iai.57.11.3472-3478.1989

Comparison of immunosuppressive effects of cyclosporine A in a murine model of systemic candidiasis and of localized thrushlike lesions.

M W Krause 1, A Schaffner 1
PMCID: PMC259855  PMID: 2807532

Abstract

Candida albicans is an opportunistic human pathogen preferentially causing invasive and disseminated infection in patients with defective phagocytic defenses and serious mucocutaneous infection in patients with deficient T-cell function. Phagocytes appear to protect the host from fungal invasion even in the absence of adaptive immune mechanisms, while as-yet-undefined T-cell-dependent factors seem necessary for control of C. albicans on body surfaces. To study host defense mechanisms on body surfaces, we developed a new model of thrush in artificial pneumatized cysts in mice. Cyclosporine A, a relative selective suppressor of T-cell-mediated immunity and natural killer cell activity, promoted the formation of thrushlike lesions on cyst surfaces and impeded elimination of C. albicans from such lesions. As expected from the absence of an impairment of antimicrobial phagocytic activity, cyclosporine A had no effect on systemic candidiasis induced by intravenous inoculation. Surprisingly, athymic nude mice were not more susceptible to superficial candidiasis than control mice and were comparably affected by cyclosporine A. In contrast, beige mice, which in addition to phagocytic dysfunction have reduced natural killer cell activity, were more susceptible to thrushlike lesions, and cyclosporine A was correspondingly less active in this mouse strain. Immunosuppression with cyclosporine A affects host defense mechanisms which are operative against superficial candidiasis but appear superfluous in resistance to the invasive form of this mycosis, an indication for the divergent nature of host defense against the two forms of candidiasis.

Full text

PDF
3472

Images in this article

3473Image
on p.3473
3473Image
on p.3473

Selected References

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

  1. Andriole G. L., Mulé J. J., Hansen C. T., Linehan W. M., Rosenberg S. A. Evidence that lymphokine-activated killer cells and natural killer cells are distinct based on an analysis of congenitally immunodeficient mice. J Immunol. 1985 Nov;135(5):2911–2913. [PubMed] [Google Scholar]
  2. Armerding D., Scriba M., Kirchner H., Hren A., Rossiter H. Modulation by cyclosporin A of murine natural resistance against herpes simplex virus infection. II. Influence on the HSV-induced natural killer cell responses, macrophage activities and interferon levels. Antiviral Res. 1982 May;2(1-2):13–26. doi: 10.1016/0166-3542(82)90023-7. [DOI] [PubMed] [Google Scholar]
  3. Baghian A., Lee K. W. Systemic candidosis in beige mice. J Med Vet Mycol. 1989;27(1):51–55. doi: 10.1080/02681218980000071. [DOI] [PubMed] [Google Scholar]
  4. Bonavida B., Katz J., Gottlieb M. Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. I. Defective trigger on NK cells for NKCF production by target cells, and partial restoration by IL 2. J Immunol. 1986 Aug 15;137(4):1157–1163. [PubMed] [Google Scholar]
  5. 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]
  6. Cohen M. S., Isturiz R. E., Malech H. L., Root R. K., Wilfert C. M., Gutman L., Buckley R. H. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med. 1981 Jul;71(1):59–66. doi: 10.1016/0002-9343(81)90259-x. [DOI] [PubMed] [Google Scholar]
  7. Cutler J. E. Acute systemic candidiasis in normal and congenitally thymic-deficient (nude) mice. J Reticuloendothel Soc. 1976 Feb;19(2):121–124. [PubMed] [Google Scholar]
  8. Djeu J. Y., Blanchard D. K., Richards A. L., Friedman H. Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J Immunol. 1988 Dec 1;141(11):4047–4052. [PubMed] [Google Scholar]
  9. Edwards J. C., Sedgwick A. D., Willoughby D. A. The formation of a structure with the features of synovial lining by subcutaneous injection of air: an in vivo tissue culture system. J Pathol. 1981 Jun;134(2):147–156. doi: 10.1002/path.1711340205. [DOI] [PubMed] [Google Scholar]
  10. Edwards J. E., Jr, Lehrer R. I., Stiehm E. R., Fischer T. J., Young L. S. Severe candidal infections: clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann Intern Med. 1978 Jul;89(1):91–106. doi: 10.7326/0003-4819-89-1-91. [DOI] [PubMed] [Google Scholar]
  11. Elin R. J., Edelin J. B., Wolff S. M. Infection and immunoglobulin concentrations in Chediak-Higashi mice. Infect Immun. 1974 Jul;10(1):88–91. doi: 10.1128/iai.10.1.88-91.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fodstad O., Hansen C. T., Cannon G. B., Statham C. N., Lichtenstein G. R., Boyd M. R. Lack of correlation between natural killer activity and tumor growth control in nude mice with different immune defects. Cancer Res. 1984 Oct;44(10):4403–4408. [PubMed] [Google Scholar]
  13. Gallin J. I., Bujak J. S., Patten E., Wolff S. M. Granulocyte function in the Chediak-Higashi syndrome of mice. Blood. 1974 Feb;43(2):201–206. [PubMed] [Google Scholar]
  14. Hess A. D., Colombani P. M., Esa A. H. Cyclosporine and the immune response: basic aspects. Crit Rev Immunol. 1986;6(2):123–149. [PubMed] [Google Scholar]
  15. Holmberg K., Meyer R. D. Fungal infections in patients with AIDS and AIDS-related complex. Scand J Infect Dis. 1986;18(3):179–192. doi: 10.3109/00365548609032326. [DOI] [PubMed] [Google Scholar]
  16. Hurtrel B., Langrange P. H., Michel J. C. Absence of correlation between delayed-type hypersensitivity and protection in experimental systemic candidiasis in immunized mice. Infect Immun. 1981 Jan;31(1):95–101. doi: 10.1128/iai.31.1.95-101.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Introna M., Allavena P., Spreafico F., Mantovani A. Inhibition of human natural killer activity by cyclosporin A. Transplantation. 1981 Feb;31(2):113–116. doi: 10.1097/00007890-198102000-00004. [DOI] [PubMed] [Google Scholar]
  18. Kirkland T. N., Fierer J. Cyclosporin A inhibits Coccidioides immitis in vitro and in vivo. Antimicrob Agents Chemother. 1983 Dec;24(6):921–924. doi: 10.1128/aac.24.6.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Klein R. S., Harris C. A., Small C. B., Moll B., Lesser M., Friedland G. H. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med. 1984 Aug 9;311(6):354–358. doi: 10.1056/NEJM198408093110602. [DOI] [PubMed] [Google Scholar]
  20. Kung J. T., Thomas C. A., 3rd Athymic nude CD4+8- T cells produce IL-2 but fail to proliferate in response to mitogenic stimuli. J Immunol. 1988 Dec 1;141(11):3691–3696. [PubMed] [Google Scholar]
  21. Mahanty S., Greenfield R. A., Joyce W. A., Kincade P. W. Inoculation candidiasis in a murine model of severe combined immunodeficiency syndrome. Infect Immun. 1988 Dec;56(12):3162–3166. doi: 10.1128/iai.56.12.3162-3166.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Marquis G., Montplaisir S., Pelletier M., Mousseau S., Auger P. Genetic resistance to murine cryptococcosis: the beige mutation (Chédiak-Higashi syndrome) in mice. Infect Immun. 1985 Jan;47(1):288–293. doi: 10.1128/iai.47.1.288-293.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mitchell W. M., Forti R. L., Vogler L. B., Lawton A. R., Gregg C. R. Spontaneous and interferon resistant natural killer cell anergy in AIDS. AIDS Res. 1983 1984;1(3):221–229. doi: 10.1089/aid.1.1983.1.221. [DOI] [PubMed] [Google Scholar]
  24. Mody C. H., Toews G. B., Lipscomb M. F. Treatment of murine cryptococcosis with cyclosporin-A in normal and athymic mice. Am Rev Respir Dis. 1989 Jan;139(1):8–13. doi: 10.1164/ajrccm/139.1.8. [DOI] [PubMed] [Google Scholar]
  25. Murphy J. W., McDaniel D. O. In vitro reactivity of natural killer (NK) cells against Cryptococcus neoformans. J Immunol. 1982 Apr;128(4):1577–1583. [PubMed] [Google Scholar]
  26. Roder J., Duwe A. The beige mutation in the mouse selectively impairs natural killer cell function. Nature. 1979 Mar 29;278(5703):451–453. doi: 10.1038/278451a0. [DOI] [PubMed] [Google Scholar]
  27. Rogers T. J., Balish E. Immunity to Candida albicans. Microbiol Rev. 1980 Dec;44(4):660–682. doi: 10.1128/mr.44.4.660-682.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Root R. K., Rosenthal A. S., Balestra D. J. Abnormal bactericidal, metabolic, and lysosomal functions of Chediak-Higashi Syndrome leukocytes. J Clin Invest. 1972 Mar;51(3):649–665. doi: 10.1172/JCI106854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schaffner A., Davis C. E., Schaffner T., Markert M., Douglas H., Braude A. I. In vitro susceptibility of fungi to killing by neutrophil granulocytes discriminates between primary pathogenicity and opportunism. J Clin Invest. 1986 Aug;78(2):511–524. doi: 10.1172/JCI112603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schaffner A., Douglas H., Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest. 1982 Mar;69(3):617–631. doi: 10.1172/JCI110489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schaffner A., Douglas H., Davis C. E. Models of T cell deficiency in listeriosis: the effects of cortisone and cyclosporin A on normal and nude BALB/c mice. J Immunol. 1983 Jul;131(1):450–453. [PubMed] [Google Scholar]
  32. Shevach E. M. The effects of cyclosporin A on the immune system. Annu Rev Immunol. 1985;3:397–423. doi: 10.1146/annurev.iy.03.040185.002145. [DOI] [PubMed] [Google Scholar]
  33. Thaler M., Pastakia B., Shawker T. H., O'Leary T., Pizzo P. A. Hepatic candidiasis in cancer patients: the evolving picture of the syndrome. Ann Intern Med. 1988 Jan;108(1):88–100. doi: 10.7326/0003-4819-108-1-88. [DOI] [PubMed] [Google Scholar]
  34. Wagner H., Hardt C., Heeg K., Röllinghoff M., Pfizenmaier K. T-cell-derived helper factor allows in vivo induction of cytotoxic T cells in nu/nu mice. Nature. 1980 Mar 20;284(5753):278–278. doi: 10.1038/284278a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES