Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the control of leishmania donovani infection

Engwerda, CR; Ato, M; Stager, S; Alexander, CE; Stanley, AC; Kaye, PM; (2004) Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the control of leishmania donovani infection. The American journal of pathology, 165 (6). pp. 2123-33. ISSN 0002-9440 DOI: https://doi.org/10.1016/S0002-9440(10)63262-2

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Tumor necrosis factor (TNF) is critical for the control of visceral leishmaniasis caused by Leishmania donovani. However, the role of the related cytokine lymphotoxin (LT) alpha in this infection is unknown. Here we report that C57BL/6 mice deficient in TNF (B6.TNF(-/-)) or LT alpha (B6.LT alpha(-/-)) have increased susceptibility to hepatic L. donovani infection. Furthermore, the outcome of infection in bone marrow chimeric mice is dependent on donor hematopoietic cells, indicating that developmental defects in lymphoid organs were not responsible for increased susceptibility to L. donovani. Although both LT alpha and TNF regulated the migration of leukocytes into the sinusoidal area of the infected liver, their roles were distinct. LT alpha was essential for migration of leukocytes from periportal areas, an event consistent with LT alpha-dependent up-regulation of VCAM-1 on liver sinusoid lining cells, whereas TNF was essential for leukocyte recruitment to the liver. During visceral leishmaniasis, both cytokines were produced by radio-resistant cells and by CD4(+) T cells. LT alpha and TNF production by the former was required for granuloma assembly, while production of these cytokines by CD4(+) T cells was necessary to control parasite growth. The production of inducible nitric oxide synthase was also found to be deficient in TNF- and LT alpha-deficient infected mice. These results demonstrate that both LT alpha and TNF are required for control of L. donovani infection in noncompensatory ways.

Item Type: Article
Keywords: Experimental visceral leishmaniasis, beta-deficient mice, tnf-, alpha, in-vivo, t-cell, abnormal-development, granuloma-, formation, gene polymorphisms, reactive nitrogen, lymphoid-, tissues, Animals, Bone Marrow, CD4-Positive T-Lymphocytes, immunology, metabolism, Cell Movement, Comparative Study, Disease Susceptibility, Female, Genes, RAG-1, genetics, physiology, Granuloma, immunology, parasitology, Homeodomain Proteins, genetics, physiology, Leishmania donovani, growth & development, physiology, Leishmaniasis, Visceral, immunology, parasitology, Leukocytes, parasitology, pathology, Liver, immunology, parasitology, pathology, Lymphotoxin, genetics, physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric-Oxide Synthase, metabolism, Research Support, Non-U.S. Gov't, Tumor Necrosis Factor-alpha, genetics, physiology, Vascular Cell Adhesion Molecule-1, metabolism
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Leishmaniasis Group
PubMed ID: 15579454
Web of Science ID: 225381100026
URI: http://researchonline.lshtm.ac.uk/id/eprint/13979


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