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Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the control of Leishmania donovani infection.
- Source :
-
The American journal of pathology [Am J Pathol] 2004 Dec; Vol. 165 (6), pp. 2123-33. - Publication Year :
- 2004
-
Abstract
- 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.
- Subjects :
- Animals
Bone Marrow
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
Cell Movement
Disease Susceptibility
Female
Genes, RAG-1 genetics
Genes, RAG-1 physiology
Granuloma immunology
Granuloma parasitology
Homeodomain Proteins genetics
Homeodomain Proteins physiology
Leishmania donovani physiology
Leishmaniasis, Visceral parasitology
Leukocytes parasitology
Leukocytes pathology
Liver immunology
Liver parasitology
Liver pathology
Lymphotoxin-alpha genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type II
Tumor Necrosis Factor-alpha genetics
Vascular Cell Adhesion Molecule-1 metabolism
Leishmania donovani growth & development
Leishmaniasis, Visceral immunology
Lymphotoxin-alpha physiology
Tumor Necrosis Factor-alpha physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9440
- Volume :
- 165
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 15579454
- Full Text :
- https://doi.org/10.1016/s0002-9440(10)63262-2