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. 1992 Jul 1;176(1):19–25. doi: 10.1084/jem.176.1.19

Neutralizing antibody to interleukin 4 induces systemic protection and T helper type 1-associated immunity in murine candidiasis

PMCID: PMC2119284  PMID: 1535368

Abstract

An interleukin 4 (IL-4)-specific monoclonal antibody (mAb) was administered to mice infected systemically with the yeast Candida albicans, and the animals were monitored for mortality, development of delayed-type hypersensitivity, production of antibodies of different isotypes, release of IL-2, IL-4, IL-6, and interferon gamma (IFN-gamma) in vitro by splenic CD4+ lymphocytes, and levels of IL-4 and IFN-gamma mRNA in these cells. Neutralization of IL-4 by three weekly injections of mAb in several independent experiments resulted in an overall cure rate of 81% versus 0% of controls. Cure was associated with efficient clearance of the yeast from infected organs and histologic evidence of disease resolution, detection of strong T helper type 1 (Th1) responses, and establishment of long-lasting protective immunity. Soon after infection, and as a result of the first or second injection of mAb, there was a decrease in IL-4 mRNA in CD4+ cells, which was accompanied by an increase in the levels of IFN-gamma-specific transcripts. Our data thus indicate that the production of IL-4 by Th2 cells may limit Th1-associated protective immunity in murine candidiasis.

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Selected References

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  1. Ashman R. B. Murine candidiasis: cell-mediated immune responses correlate directly with susceptibility and resistance to infection. Immunol Cell Biol. 1990 Feb;68(Pt 1):15–20. doi: 10.1038/icb.1990.2. [DOI] [PubMed] [Google Scholar]
  2. Ashman R. B., Papadimitriou J. M. What's new in the mechanisms of host resistance to Candida albicans infection? Pathol Res Pract. 1990 Aug;186(4):527–534. doi: 10.1016/S0344-0338(11)80477-2. [DOI] [PubMed] [Google Scholar]
  3. Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
  4. Bistoni F., Vecchiarelli A., Cenci E., Puccetti P., Marconi P., Cassone A. Evidence for macrophage-mediated protection against lethal Candida albicans infection. Infect Immun. 1986 Feb;51(2):668–674. doi: 10.1128/iai.51.2.668-674.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bistoni F., Verducci G., Perito S., Vecchiarelli A., Puccetti P., Marconi P., Cassone A. Immunomodulation by a low-virulence, agerminative variant of Candida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection. J Med Vet Mycol. 1988;26(5):285–299. doi: 10.1080/02681218880000401. [DOI] [PubMed] [Google Scholar]
  6. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brummer E., Morrison C. J., Stevens D. A. Recombinant and natural gamma-interferon activation of macrophages in vitro: different dose requirements for induction of killing activity against phagocytizable and nonphagocytizable fungi. Infect Immun. 1985 Sep;49(3):724–730. doi: 10.1128/iai.49.3.724-730.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cantorna M. T., Balish E. Mucosal and systemic candidiasis in congenitally immunodeficient mice. Infect Immun. 1990 Apr;58(4):1093–1100. doi: 10.1128/iai.58.4.1093-1100.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cenci E., Bartocci A., Puccetti P., Mocci S., Stanley E. R., Bistoni F. Macrophage colony-stimulating factor in murine candidiasis: serum and tissue levels during infection and protective effect of exogenous administration. Infect Immun. 1991 Mar;59(3):868–872. doi: 10.1128/iai.59.3.868-872.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cenci E., Romani L., Vecchiarelli A., Puccetti P., Bistoni F. Role of L3T4+ lymphocytes in protective immunity to systemic Candida albicans infection in mice. Infect Immun. 1989 Nov;57(11):3581–3587. doi: 10.1128/iai.57.11.3581-3587.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cenci E., Romani L., Vecchiarelli A., Puccetti P., Bistoni F. T cell subsets and IFN-gamma production in resistance to systemic candidosis in immunized mice. J Immunol. 1990 Jun 1;144(11):4333–4339. [PubMed] [Google Scholar]
  12. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  13. Coffman R. L., Varkila K., Scott P., Chatelain R. Role of cytokines in the differentiation of CD4+ T-cell subsets in vivo. Immunol Rev. 1991 Oct;123:189–207. doi: 10.1111/j.1600-065x.1991.tb00611.x. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Domer J. E. Intragastric colonization of infant mice with Candida albicans induces systemic immunity demonstrable upon challenge as adults. J Infect Dis. 1988 May;157(5):950–958. doi: 10.1093/infdis/157.5.950. [DOI] [PubMed] [Google Scholar]
  16. Essner R., Rhoades K., McBride W. H., Morton D. L., Economou J. S. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol. 1989 Jun 1;142(11):3857–3861. [PubMed] [Google Scholar]
  17. Garner R. E., Childress A. M., Human L. G., Domer J. E. Characterization of Candida albicans mannan-induced, mannan-specific delayed hypersensitivity suppressor cells. Infect Immun. 1990 Aug;58(8):2613–2620. doi: 10.1128/iai.58.8.2613-2620.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mosmann T. R., Fong T. A. Specific assays for cytokine production by T cells. J Immunol Methods. 1989 Jan 17;116(2):151–158. doi: 10.1016/0022-1759(89)90198-1. [DOI] [PubMed] [Google Scholar]
  20. Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
  21. Romani L., Mocci S., Bietta C., Lanfaloni L., Puccetti P., Bistoni F. Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance. Infect Immun. 1991 Dec;59(12):4647–4654. doi: 10.1128/iai.59.12.4647-4654.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Romani L., Mocci S., Cenci E., Rossi R., Puccetti P., Bistoni F. Candida albicans-specific Ly-2+ lymphocytes with cytolytic activity. Eur J Immunol. 1991 Jun;21(6):1567–1570. doi: 10.1002/eji.1830210636. [DOI] [PubMed] [Google Scholar]
  23. Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  25. Savolainen J., Koivikko A., Kalimo K., Nieminen E., Viander M. IgE, IgA and IgG antibodies and delayed skin response towards Candida albicans antigens in atopics with and without saprophytic growth. Clin Exp Allergy. 1990 Sep;20(5):549–554. doi: 10.1111/j.1365-2222.1990.tb03148.x. [DOI] [PubMed] [Google Scholar]
  26. Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991 Nov 1;147(9):3149–3155. [PubMed] [Google Scholar]
  27. Van Snick J., Vink A., Cayphas S., Uyttenhove C. Interleukin-HP1, a T cell-derived hybridoma growth factor that supports the in vitro growth of murine plasmacytomas. J Exp Med. 1987 Mar 1;165(3):641–649. doi: 10.1084/jem.165.3.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Vecchiarelli A., Mazzolla R., Farinelli S., Cassone A., Bistoni F. Immunomodulation by Candida albicans: crucial role of organ colonization and chronic infection with an attenuated agerminative strain of C. albicans for establishment of anti-infectious protection. J Gen Microbiol. 1988 Sep;134(9):2583–2592. doi: 10.1099/00221287-134-9-2583. [DOI] [PubMed] [Google Scholar]
  29. Witkin S. S., Jeremias J., Ledger W. J. Vaginal eosinophils and IgE antibodies to Candida albicans in women with recurrent vaginitis. J Med Vet Mycol. 1989;27(1):57–58. [PubMed] [Google Scholar]

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