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. 1995 Jul;85(3):408–418.

Dynamics of the intracerebral and splenic cytokine mRNA production in Toxoplasma gondii-resistant and -susceptible congenic strains of mice.

M Deckert-Schlüter 1, S Albrecht 1, H Hof 1, O D Wiestler 1, D Schlüter 1
PMCID: PMC1383914  PMID: 7558129

Abstract

Oral infection with a low-virulence strain of Toxoplasma gondii (Tg) induced a persisting encephalitis in resistant strains of mice. In the present study we have examined transcripts of various cytokines during acute and chronic stages of murine Tg encephalitis. In the brain of infected animals, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-6, IL-10 and IL-12 mRNA were induced to a significant extent, but only low levels of IL-4 mRNA were detectable. A similar cytokine profile was observed in the spleen. However, in contrast to the brain, the increase of IL-2 mRNA was particularly pronounced in the spleen, whereas the opposite was found for IFN-gamma and TNF-alpha mRNA. Thus, cytokines involved in T-cell proliferation were more prevalent in the spleen, but in the brain, where Tg actively multiplies, the effector molecules IFN-gamma and TNF-alpha were preferentially up-regulated. In addition, a detailed analysis of cytokine mRNA levels in major histocompatibility complex (MHC)-congenic strains of BALB and B10 mice revealed that the genetically regulated susceptibility to Tg was correlated with the amount of intracerebrally produced cytokine mRNA for IFN-gamma, TNF-alpha and IL-6. Mice with a strong increase of these cytokine mRNA were significantly better protected against Tg. This indicates that the outcome of toxoplasmosis may be critically dependent on an adequately regulated intracerebral immune response.

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Selected References

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  1. Austyn J. M., Gordon S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur J Immunol. 1981 Oct;11(10):805–815. doi: 10.1002/eji.1830111013. [DOI] [PubMed] [Google Scholar]
  2. Chao C. C., Anderson W. R., Hu S., Gekker G., Martella A., Peterson P. K. Activated microglia inhibit multiplication of Toxoplasma gondii via a nitric oxide mechanism. Clin Immunol Immunopathol. 1993 May;67(2):178–183. doi: 10.1006/clin.1993.1062. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
  5. Deckert-Schlüter M., Schlüter D., Hof H., Wiestler O. D., Lassmann H. Differential expression of ICAM-1, VCAM-1 and their ligands LFA-1, Mac-1, CD43, VLA-4, and MHC class II antigens in murine Toxoplasma encephalitis: a light microscopic and ultrastructural immunohistochemical study. J Neuropathol Exp Neurol. 1994 Sep;53(5):457–468. doi: 10.1097/00005072-199409000-00005. [DOI] [PubMed] [Google Scholar]
  6. Deckert-Schlüter M., Schlüter D., Schmidt D., Schwendemann G., Wiestler O. D., Hof H. Toxoplasma encephalitis in congenic B10 and BALB mice: impact of genetic factors on the immune response. Infect Immun. 1994 Jan;62(1):221–228. doi: 10.1128/iai.62.1.221-228.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Denkers E. Y., Caspar P., Sher A. Toxoplasma gondii possesses a superantigen activity that selectively expands murine T cell receptor V beta 5-bearing CD8+ lymphocytes. J Exp Med. 1994 Sep 1;180(3):985–994. doi: 10.1084/jem.180.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  9. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  10. Frei K., Lins H., Schwerdel C., Fontana A. Antigen presentation in the central nervous system. The inhibitory effect of IL-10 on MHC class II expression and production of cytokines depends on the inducing signals and the type of cell analyzed. J Immunol. 1994 Mar 15;152(6):2720–2728. [PubMed] [Google Scholar]
  11. Gazzinelli R. T., Eltoum I., Wynn T. A., Sher A. Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation. J Immunol. 1993 Oct 1;151(7):3672–3681. [PubMed] [Google Scholar]
  12. Gazzinelli R. T., Hakim F. T., Hieny S., Shearer G. M., Sher A. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol. 1991 Jan 1;146(1):286–292. [PubMed] [Google Scholar]
  13. Gazzinelli R. T., Hieny S., Wynn T. A., Wolf S., Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. doi: 10.1073/pnas.90.13.6115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gazzinelli R. T., Wysocka M., Hayashi S., Denkers E. Y., Hieny S., Caspar P., Trinchieri G., Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed] [Google Scholar]
  15. Gazzinelli R., Xu Y., Hieny S., Cheever A., Sher A. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol. 1992 Jul 1;149(1):175–180. [PubMed] [Google Scholar]
  16. Graham R. C., Jr, Karnovsky M. J. The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: ultrastructural cytochemistry by a new technique. J Histochem Cytochem. 1966 Apr;14(4):291–302. doi: 10.1177/14.4.291. [DOI] [PubMed] [Google Scholar]
  17. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  18. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  19. Hunter C. A., Roberts C. W., Alexander J. Kinetics of cytokine mRNA production in the brains of mice with progressive toxoplasmic encephalitis. Eur J Immunol. 1992 Sep;22(9):2317–2322. doi: 10.1002/eji.1830220921. [DOI] [PubMed] [Google Scholar]
  20. Imrich H., Schwender S., Hein A., Dörries R. Cervical lymphoid tissue but not the central nervous system supports proliferation of virus-specific T lymphocytes during coronavirus-induced encephalitis in rats. J Neuroimmunol. 1994 Aug;53(1):73–81. doi: 10.1016/0165-5728(94)90066-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kasper L. H., Khan I. A., Ely K. H., Buelow R., Boothroyd J. C. Antigen-specific (p30) mouse CD8+ T cells are cytotoxic against Toxoplasma gondii-infected peritoneal macrophages. J Immunol. 1992 Mar 1;148(5):1493–1498. [PubMed] [Google Scholar]
  22. Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  23. Langermans J. A., Van der Hulst M. E., Nibbering P. H., Hiemstra P. S., Fransen L., Van Furth R. IFN-gamma-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-alpha. J Immunol. 1992 Jan 15;148(2):568–574. [PubMed] [Google Scholar]
  24. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  25. Lowenthal J. W., Corthésy P., Tougne C., Lees R., MacDonald H. R., Nabholz M. High and low affinity IL 2 receptors: analysis by IL 2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J Immunol. 1985 Dec;135(6):3988–3994. [PubMed] [Google Scholar]
  26. McLeod R., Eisenhauer P., Mack D., Brown C., Filice G., Spitalny G. Immune responses associated with early survival after peroral infection with Toxoplasma gondii. J Immunol. 1989 May 1;142(9):3247–3255. [PubMed] [Google Scholar]
  27. Moore K. W., O'Garra A., de Waal Malefyt R., Vieira P., Mosmann T. R. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
  28. Ohmori K., Hong Y., Fujiwara M., Matsumoto Y. In situ demonstration of proliferating cells in the rat central nervous system during experimental autoimmune encephalomyelitis. Evidence suggesting that most infiltrating T cells do not proliferate in the target organ. Lab Invest. 1992 Jan;66(1):54–62. [PubMed] [Google Scholar]
  29. Oswald I. P., Wynn T. A., Sher A., James S. L. Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8676–8680. doi: 10.1073/pnas.89.18.8676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  31. Schlüter D., Deckert-Schlüter M., Schwendemann G., Brunner H., Hof H. Expression of major histocompatibility complex class II antigens and levels of interferon-gamma, tumour necrosis factor, and interleukin-6 in cerebrospinal fluid and serum in Toxoplasma gondii-infected SCID and immunocompetent C.B-17 mice. Immunology. 1993 Mar;78(3):430–435. [PMC free article] [PubMed] [Google Scholar]
  32. Sher A., Oswald I. P., Hieny S., Gazzinelli R. T. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha. J Immunol. 1993 May 1;150(9):3982–3989. [PubMed] [Google Scholar]
  33. Springer T., Galfrè G., Secher D. S., Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978 Aug;8(8):539–551. doi: 10.1002/eji.1830080802. [DOI] [PubMed] [Google Scholar]
  34. Suzuki Y., Orellana M. A., Schreiber R. D., Remington J. S. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988 Apr 22;240(4851):516–518. doi: 10.1126/science.3128869. [DOI] [PubMed] [Google Scholar]
  35. Suzuki Y., Remington J. S. Dual regulation of resistance against Toxoplasma gondii infection by Lyt-2+ and Lyt-1+, L3T4+ T cells in mice. J Immunol. 1988 Jun 1;140(11):3943–3946. [PubMed] [Google Scholar]
  36. Suzuki Y., Yang Q., Conley F. K., Abrams J. S., Remington J. S. Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis. Infect Immun. 1994 Jul;62(7):2773–2778. doi: 10.1128/iai.62.7.2773-2778.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Svetić A., Finkelman F. D., Jian Y. C., Dieffenbach C. W., Scott D. E., McCarthy K. F., Steinberg A. D., Gause W. C. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J Immunol. 1991 Oct 1;147(7):2391–2397. [PubMed] [Google Scholar]
  38. Vollmer T. L., Waldor M. K., Steinman L., Conley F. K. Depletion of T-4+ lymphocytes with monoclonal antibody reactivates toxoplasmosis in the central nervous system: a model of superinfection in AIDS. J Immunol. 1987 Jun 1;138(11):3737–3741. [PubMed] [Google Scholar]
  39. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]

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