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. 1996 Jan;64(1):161–166. doi: 10.1128/iai.64.1.161-166.1996

Multiple host defense defects in failure of C57BL/6 ep/ep (pale ear) mice to resolve visceral Leishmania donovani infection.

H W Murray 1, J Hariprashad 1, D F McDermott 1, M Y Stoeckle 1
PMCID: PMC173741  PMID: 8557335

Abstract

Euthymic C57BL/L ep/ep (pale ear [PE]) mice halt the visceral replication of intracellular Leishmania donovani but fail to properly resolve infection. A previous study identified an isolated defect in tissue granuloma formation in these mice; CD4+ and CD8+ cell number, gamma interferon (IFN-gamma) production, and macrophage antimicrobial activity in vitro were all intact. New in vivo results reported here suggest a considerably more complex immune defect, with evidence indicating (i) enhanced control over L. donovani after transfer of normal C57BL/6 spleen cells, (ii) a partially suppressive Th2 cell-associated response mediated by interleukin-4 (IL-4) but not reversed by CD4+ cell depletion, (iii) absent responses to endogenous Th1 cell lymphokines (IFN-gamma and IL-2) but preserved responsiveness to endogenous tumor necrosis factor alpha, (iv) absent responses to exogenous treatment with recognized antileishmanial cytokines (IFN-gamma, IL-2, IL-12, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) not corrected by transfer of C57BL/6 spleen cells, and (v) a deficient response to antimony chemotherapy. Defective hepatic granuloma formation was not corrected by transfer of C57BL/6 spleen cells or by anti-IL-4 administration. While treatment with IL-2 and GM-CSF modified the tissue reaction and induced selected effector cells to encase tissue macrophages, no antileishmanial activity resulted. Together, these observations suggest that the failure of PE mice to resolve visceral L. donovani infection likely represents expression of multiple suboptimal immune responses and/or partial defects, probably involving a combination of T-cell dysfunction, a Th2 cell response, and target cell (macrophage) hyporesponsiveness.

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Selected References

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  1. Afonso L. C., Scott P. Immune responses associated with susceptibility of C57BL/10 mice to Leishmania amazonensis. Infect Immun. 1993 Jul;61(7):2952–2959. doi: 10.1128/iai.61.7.2952-2959.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown J. A., Novak E. K., Swank R. T. Effects of ammonia on processing and secretion of precursor and mature lysosomal enzyme from macrophages of normal and pale ear mice: evidence for two distinct pathways. J Cell Biol. 1985 Jun;100(6):1894–1904. doi: 10.1083/jcb.100.6.1894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cervia J. S., Rosen H., Murray H. W. Effector role of blood monocytes in experimental visceral leishmaniasis. Infect Immun. 1993 Apr;61(4):1330–1333. doi: 10.1128/iai.61.4.1330-1333.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang K. P., Dwyer D. M. Leishmania donovani. Hamster macrophage interactions in vitro: cell entry, intracellular survival, and multiplication of amastigotes. J Exp Med. 1978 Feb 1;147(2):515–530. doi: 10.1084/jem.147.2.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chatelain R., Varkila K., Coffman R. L. IL-4 induces a Th2 response in Leishmania major-infected mice. J Immunol. 1992 Feb 15;148(4):1182–1187. [PubMed] [Google Scholar]
  6. 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]
  7. Crocker P. R., Blackwell J. M., Bradley D. J. Expression of the natural resistance gene Lsh in resident liver macrophages. Infect Immun. 1984 Mar;43(3):1033–1040. doi: 10.1128/iai.43.3.1033-1040.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Howard M., O'Garra A. Biological properties of interleukin 10. Immunol Today. 1992 Jun;13(6):198–200. doi: 10.1016/0167-5699(92)90153-X. [DOI] [PubMed] [Google Scholar]
  11. Miralles G. D., Stoeckle M. Y., McDermott D. F., Finkelman F. D., Murray H. W. Th1 and Th2 cell-associated cytokines in experimental visceral leishmaniasis. Infect Immun. 1994 Mar;62(3):1058–1063. doi: 10.1128/iai.62.3.1058-1063.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Morris L., Troutt A. B., McLeod K. S., Kelso A., Handman E., Aebischer T. Interleukin-4 but not gamma interferon production correlates with the severity of murine cutaneous leishmaniasis. Infect Immun. 1993 Aug;61(8):3459–3465. doi: 10.1128/iai.61.8.3459-3465.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Murray H. W., Cervia J. S., Hariprashad J., Taylor A. P., Stoeckle M. Y., Hockman H. Effect of granulocyte-macrophage colony-stimulating factor in experimental visceral leishmaniasis. J Clin Invest. 1995 Mar;95(3):1183–1192. doi: 10.1172/JCI117767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Murray H. W. Effect of continuous administration of interferon-gamma in experimental visceral leishmaniasis. J Infect Dis. 1990 May;161(5):992–994. doi: 10.1093/infdis/161.5.992. [DOI] [PubMed] [Google Scholar]
  15. Murray H. W., Hariprashad J., Aguero B., Arakawa T., Yeganegi H. Antimicrobial response of a T cell-deficient host to cytokine therapy: effect of interferon-gamma in experimental visceral leishmaniasis in nude mice. J Infect Dis. 1995 May;171(5):1309–1316. doi: 10.1093/infdis/171.5.1309. [DOI] [PubMed] [Google Scholar]
  16. Murray H. W., Hariprashad J., Fichtl R. E. Treatment of experimental visceral leishmaniasis in a T-cell-deficient host: response to amphotericin B and pentamidine. Antimicrob Agents Chemother. 1993 Jul;37(7):1504–1505. doi: 10.1128/aac.37.7.1504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Murray H. W., Hariprashad J. Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis. J Exp Med. 1995 Jan 1;181(1):387–391. doi: 10.1084/jem.181.1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Murray H. W., Miralles G. D., Stoeckle M. Y., McDermott D. F. Role and effect of IL-2 in experimental visceral leishmaniasis. J Immunol. 1993 Jul 15;151(2):929–938. [PubMed] [Google Scholar]
  19. Murray H. W., Oca M. J., Granger A. M., Schreiber R. D. Requirement for T cells and effect of lymphokines in successful chemotherapy for an intracellular infection. Experimental visceral leishmaniasis. J Clin Invest. 1989 Apr;83(4):1253–1257. doi: 10.1172/JCI114009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Murray H. W., Stern J. J., Welte K., Rubin B. Y., Carriero S. M., Nathan C. F. Experimental visceral leishmaniasis: production of interleukin 2 and interferon-gamma, tissue immune reaction, and response to treatment with interleukin 2 and interferon-gamma. J Immunol. 1987 Apr 1;138(7):2290–2297. [PubMed] [Google Scholar]
  21. Orn A., Håkansson E. M., Gidlund M., Ramstedt U., Axberg I., Wigzell H., Lundin L. G. Pigment mutations in the mouse which also affect lysosomal functions lead to suppressed natural killer cell activity. Scand J Immunol. 1982 Mar;15(3):305–310. doi: 10.1111/j.1365-3083.1982.tb00653.x. [DOI] [PubMed] [Google Scholar]
  22. Reiner S. L., Zheng S., Wang Z. E., Stowring L., Locksley R. M. Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection. J Exp Med. 1994 Feb 1;179(2):447–456. doi: 10.1084/jem.179.2.447. [DOI] [PMC free article] [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. Squires K. E., Kirsch M., Silverstein S. C., Acosta A., McElrath M. J., Murray H. W. Defect in the tissue cellular immune response: experimental visceral leishmaniasis in euthymic C57BL/6 ep/ep mice. Infect Immun. 1990 Dec;58(12):3893–3898. doi: 10.1128/iai.58.12.3893-3898.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Squires K. E., Schreiber R. D., McElrath M. J., Rubin B. Y., Anderson S. L., Murray H. W. Experimental visceral leishmaniasis: role of endogenous IFN-gamma in host defense and tissue granulomatous response. J Immunol. 1989 Dec 15;143(12):4244–4249. [PubMed] [Google Scholar]
  26. Stern J. J., Oca M. J., Rubin B. Y., Anderson S. L., Murray H. W. Role of L3T4+ and LyT-2+ cells in experimental visceral leishmaniasis. J Immunol. 1988 Jun 1;140(11):3971–3977. [PubMed] [Google Scholar]
  27. Tumang M. C., Keogh C., Moldawer L. L., Helfgott D. C., Teitelbaum R., Hariprashad J., Murray H. W. Role and effect of TNF-alpha in experimental visceral leishmaniasis. J Immunol. 1994 Jul 15;153(2):768–775. [PubMed] [Google Scholar]

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