Abstract
The granulomatous response to schistosome eggs is a CD4 T-cell-dependent, Th2-cytokine-dominated immunopathologic response. As infection proceeds to chronicity, both granuloma formation and egg-induced cytokine production become downregulated, and previous experiments have implicated CD8 T cells in this process. One mechanism by which CD8 T cells could suppress immunopathology is through the production of the counterregulatory cytokine gamma interferon (IFN-gamma), but no in vivo evidence exists to directly support this hypothesis. In this study, we analyzed hepatic granuloma formation and egg-induced cytokine production in Schistosoma mansoni-infected gene knockout mice deficient in either CD8 lymphocytes or IFN-gamma. Surprisingly, we found that neither immunologic component plays an essential function in the control of granuloma and cytokine responses during either the acute or chronic stage of infection. Thus, other mechanisms may be more important in the regulation of immunopathology in schistosomiasis.
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- Amiri P., Haak-Frendscho M., Robbins K., McKerrow J. H., Stewart T., Jardieu P. Anti-immunoglobulin E treatment decreases worm burden and egg production in Schistosoma mansoni-infected normal and interferon gamma knockout mice. J Exp Med. 1994 Jul 1;180(1):43–51. doi: 10.1084/jem.180.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bloom B. R., Salgame P., Diamond B. Revisiting and revising suppressor T cells. Immunol Today. 1992 Apr;13(4):131–136. doi: 10.1016/0167-5699(92)90110-S. [DOI] [PubMed] [Google Scholar]
- Borojevic R. Experimental murine schistosomiasis mansoni: establishment of the chronic phase of the disease. Mem Inst Oswaldo Cruz. 1992;87 (Suppl 4):171–174. doi: 10.1590/s0074-02761992000800026. [DOI] [PubMed] [Google Scholar]
- Boros D. L., Pelley R. P., Warren K. S. Spontaneous modulation of granulomatous hypersensitivity in schistosomiasis mansoni. J Immunol. 1975 May;114(5):1437–1441. [PubMed] [Google Scholar]
- Boros D. L., Warren K. S. Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J Exp Med. 1970 Sep 1;132(3):488–507. doi: 10.1084/jem.132.3.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cheever A. W. The intensity of experimental schistosome infections modulates hepatic pathology. Am J Trop Med Hyg. 1986 Jan;35(1):124–133. doi: 10.4269/ajtmh.1986.35.124. [DOI] [PubMed] [Google Scholar]
- Chensue S. W., Warmington K. S., Hershey S. D., Terebuh P. D., Othman M., Kunkel S. L. Evolving T cell responses in murine schistosomiasis. Th2 cells mediate secondary granulomatous hypersensitivity and are regulated by CD8+ T cells in vivo. J Immunol. 1993 Aug 1;151(3):1391–1400. [PubMed] [Google Scholar]
- Chensue S. W., Wellhausen S. R., Boros D. L. Modulation of granulomatous hypersensitivity. II. Participation of Ly 1+ and Ly 2+ T lymphocytes in the suppression of granuloma formation and lymphokine production in Schistosoma mansoni-infected mice. J Immunol. 1981 Jul;127(1):363–367. [PubMed] [Google Scholar]
- Colley D. G. Adoptive suppression of granuloma formation. J Exp Med. 1976 Mar 1;143(3):696–700. doi: 10.1084/jem.143.3.696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Czaja M. J., Weiner F. R., Takahashi S., Giambrone M. A., van der Meide P. H., Schellekens H., Biempica L., Zern M. A. Gamma-interferon treatment inhibits collagen deposition in murine schistosomiasis. Hepatology. 1989 Nov;10(5):795–800. doi: 10.1002/hep.1840100508. [DOI] [PubMed] [Google Scholar]
- Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
- Domingo E. O., Warren K. S. Endogenous desensitization: changing host granulomatou response to schistosome eggs at different stages of infection with schistosoma mansoni. Am J Pathol. 1968 Feb;52(2):369–379. [PMC free article] [PubMed] [Google Scholar]
- Fung-Leung W. P., Schilham M. W., Rahemtulla A., Kündig T. M., Vollenweider M., Potter J., van Ewijk W., Mak T. W. CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell. 1991 May 3;65(3):443–449. doi: 10.1016/0092-8674(91)90462-8. [DOI] [PubMed] [Google Scholar]
- Gajewski T. F., Fitch F. W. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245–4252. [PubMed] [Google Scholar]
- Henderson G. S., Lu X., McCurley T. L., Colley D. G. In vivo molecular analysis of lymphokines involved in the murine immune response during Schistosoma mansoni infection. II. Quantification of IL-4 mRNA, IFN-gamma mRNA, and IL-2 mRNA levels in the granulomatous livers, mesenteric lymph nodes, and spleens during the course of modulation. J Immunol. 1992 Apr 1;148(7):2261–2269. [PubMed] [Google Scholar]
- Inoue T., Asano Y., Matsuoka S., Furutani-Seiki M., Aizawa S., Nishimura H., Shirai T., Tada T. Distinction of mouse CD8+ suppressor effector T cell clones from cytotoxic T cell clones by cytokine production and CD45 isoforms. J Immunol. 1993 Mar 15;150(6):2121–2128. [PubMed] [Google Scholar]
- Koh D. R., Fung-Leung W. P., Ho A., Gray D., Acha-Orbea H., Mak T. W. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice. Science. 1992 May 22;256(5060):1210–1213. doi: 10.1126/science.256.5060.1210. [DOI] [PubMed] [Google Scholar]
- Koller B. H., Marrack P., Kappler J. W., Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990 Jun 8;248(4960):1227–1230. doi: 10.1126/science.2112266. [DOI] [PubMed] [Google Scholar]
- LITT M. Studies in experimental eosinophilia. V. Eosinophils in lynph nodes of guinea pigs following primary antigenic stimulation. Am J Pathol. 1963 May;42:529–549. [PMC free article] [PubMed] [Google Scholar]
- Lammie P. J., Phillips S. M., Linette G. P., Michael A. I., Bentley A. G. In vitro granuloma formation using defined antigenic nidi. Ann N Y Acad Sci. 1986;465:340–350. doi: 10.1111/j.1749-6632.1986.tb18509.x. [DOI] [PubMed] [Google Scholar]
- Ljunggren H. G., Glas R., Sandberg J. K., Kärre K. Reactivity and specificity of CD8+ T cells in mice with defects in the MHC class I antigen-presenting pathway. Immunol Rev. 1996 Jun;151:123–148. doi: 10.1111/j.1600-065x.1996.tb00706.x. [DOI] [PubMed] [Google Scholar]
- Lukacs N. W., Boros D. L. Lymphokine regulation of granuloma formation in murine schistosomiasis mansoni. Clin Immunol Immunopathol. 1993 Jul;68(1):57–63. doi: 10.1006/clin.1993.1095. [DOI] [PubMed] [Google Scholar]
- Pearce E. J., Caspar P., Grzych J. M., Lewis F. A., Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. doi: 10.1084/jem.173.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pedras-Vasconcelos J. A., Pearce E. J. Type 1 CD8+ T cell responses during infection with the helminth Schistosoma mansoni. J Immunol. 1996 Oct 1;157(7):3046–3053. [PubMed] [Google Scholar]
- Pernis A., Gupta S., Gollob K. J., Garfein E., Coffman R. L., Schindler C., Rothman P. Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells. Science. 1995 Jul 14;269(5221):245–247. doi: 10.1126/science.7618088. [DOI] [PubMed] [Google Scholar]
- Ragheb S., Boros D. L. Characterization of granuloma T lymphocyte function from Schistosoma mansoni-infected mice. J Immunol. 1989 May 1;142(9):3239–3246. [PubMed] [Google Scholar]
- Sher A., Coffman R. L., Hieny S., Scott P., Cheever A. W. Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni. Proc Natl Acad Sci U S A. 1990 Jan;87(1):61–65. doi: 10.1073/pnas.87.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Kaer L., Ashton-Rickardt P. G., Ploegh H. L., Tonegawa S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4-8+ T cells. Cell. 1992 Dec 24;71(7):1205–1214. doi: 10.1016/s0092-8674(05)80068-6. [DOI] [PubMed] [Google Scholar]
- Vella A. T., Pearce E. J. CD4+ Th2 response induced by Schistosoma mansoni eggs develops rapidly, through an early, transient, Th0-like stage. J Immunol. 1992 Apr 1;148(7):2283–2290. [PubMed] [Google Scholar]
- Warren K. S., Domingo E. O., Cowan R. B. Granuloma formation around schistosome eggs as a manifestation of delayed hypersensitivity. Am J Pathol. 1967 Nov;51(5):735–756. [PMC free article] [PubMed] [Google Scholar]
- Wynn T. A., Cheever A. W., Jankovic D., Poindexter R. W., Caspar P., Lewis F. A., Sher A. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature. 1995 Aug 17;376(6541):594–596. doi: 10.1038/376594a0. [DOI] [PubMed] [Google Scholar]
- Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]
- Wynn T. A., Eltoum I., Oswald I. P., Cheever A. W., Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. doi: 10.1084/jem.179.5.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
