Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2003-4-22
pubmed:abstractText
The etiology of autoimmune liver disease is poorly understood. BALB/c mice deficient in the immunoregulatory cytokine TGF-beta1 spontaneously develop necroinflammatory liver disease, but the immune basis for the development of this pathology has not been demonstrated. Here, we show that BALB/c-TGF-beta1(-/-) mice exhibit abnormal expansion in hepatic mononuclear cells (MNCs) compared with wild-type littermate control mice, particularly in the T cell and macrophage lineages. To test whether lymphocytes of the adaptive immune system are required for the spontaneous development of necroinflammatory liver disease, BALB/c-TGF-beta1(-/-) mice were rendered deficient in B and T cells by crossing them with BALB/c-recombinase-activating gene 1(-/-) mice. BALB/c-TGF-beta1(-/-)/recombinase-activating gene 1(-/-) double-knockout mice showed extended survival and did not develop necroinflammatory liver disease. The cytolytic activity of BALB/c-TGF-beta1(-/-) hepatic lymphocytes was assessed using an in vitro CTL assay. CTL activity was much higher in BALB/c-TGF-beta1(-/-) hepatic MNCs compared with littermate control hepatic MNCs and was particularly pronounced in the CD4(+) T cell subset. Experimental depletion of CD4(+) T cells in young BALB/c-TGF-beta1(-/-) mice prevented the subsequent development of necroinflammatory liver disease, indicating that CD4(+) T cells are essential for disease pathogenesis in vivo. These data definitively establish an immune-mediated etiology for necroinflammatory liver disease in BALB/c-TGF-beta1(-/-) mice and demonstrate the importance of CD4(+) T cells in disease pathogenesis in vivo. Furthermore, TGF-beta1 has a critical role in homeostatic regulation of the hepatic immune system, inhibiting the development or expansion of hepatic cytolytic CD4(+) T cells.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
170
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4785-92
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12707360-Animals, pubmed-meshheading:12707360-Autoimmune Diseases, pubmed-meshheading:12707360-CD4-Positive T-Lymphocytes, pubmed-meshheading:12707360-Crosses, Genetic, pubmed-meshheading:12707360-Cytotoxicity, Immunologic, pubmed-meshheading:12707360-Female, pubmed-meshheading:12707360-Genetic Predisposition to Disease, pubmed-meshheading:12707360-Hepatitis, Animal, pubmed-meshheading:12707360-Immunity, Cellular, pubmed-meshheading:12707360-Lymphocyte Depletion, pubmed-meshheading:12707360-Male, pubmed-meshheading:12707360-Mice, pubmed-meshheading:12707360-Mice, Inbred BALB C, pubmed-meshheading:12707360-Mice, Knockout, pubmed-meshheading:12707360-Necrosis, pubmed-meshheading:12707360-T-Lymphocyte Subsets, pubmed-meshheading:12707360-Transforming Growth Factor beta, pubmed-meshheading:12707360-Transforming Growth Factor beta1
pubmed:year
2003
pubmed:articleTitle
Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells.
pubmed:affiliation
Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't