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Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype

Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and stra...

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Autores principales: Körner, Heinrich, Cretney, Erika, Wilhelm, Patricia, Kelly, Janice M., Röllinghoff, Martin, Sedgwick, Jonathon D., Smyth, Mark J.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2000
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195803/
https://www.ncbi.nlm.nih.gov/pubmed/10620607
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author Körner, Heinrich
Cretney, Erika
Wilhelm, Patricia
Kelly, Janice M.
Röllinghoff, Martin
Sedgwick, Jonathon D.
Smyth, Mark J.
author_facet Körner, Heinrich
Cretney, Erika
Wilhelm, Patricia
Kelly, Janice M.
Röllinghoff, Martin
Sedgwick, Jonathon D.
Smyth, Mark J.
author_sort Körner, Heinrich
collection PubMed
description Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and strain-dependent systemic autoimmune disease, and succumb to premature death. It is consequently termed generalized lymphoproliferative disorder (gld). By contrast, TNF deficiency alone does not result in a striking phenotype. Thus, we sought to determine what role TNF might play in contributing to the gld phenotype by creating C57BL/6.gld.TNF(−/−) mice. Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia. To confirm these data in a strain highly permissive for the phenotype, C3H/HeJ.gld and C3H.HeJ.lpr mice were treated with a TNF-specific monoclonal antibody. This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype. We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation. Most importantly, absence of TNF protects gld mice against premature death.
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spelling pubmed-21958032008-04-16 Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype Körner, Heinrich Cretney, Erika Wilhelm, Patricia Kelly, Janice M. Röllinghoff, Martin Sedgwick, Jonathon D. Smyth, Mark J. J Exp Med Original Article Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and strain-dependent systemic autoimmune disease, and succumb to premature death. It is consequently termed generalized lymphoproliferative disorder (gld). By contrast, TNF deficiency alone does not result in a striking phenotype. Thus, we sought to determine what role TNF might play in contributing to the gld phenotype by creating C57BL/6.gld.TNF(−/−) mice. Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia. To confirm these data in a strain highly permissive for the phenotype, C3H/HeJ.gld and C3H.HeJ.lpr mice were treated with a TNF-specific monoclonal antibody. This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype. We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation. Most importantly, absence of TNF protects gld mice against premature death. The Rockefeller University Press 2000-01-03 /pmc/articles/PMC2195803/ /pubmed/10620607 Text en © 2000 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Original Article
Körner, Heinrich
Cretney, Erika
Wilhelm, Patricia
Kelly, Janice M.
Röllinghoff, Martin
Sedgwick, Jonathon D.
Smyth, Mark J.
Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype
title Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype
title_full Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype
title_fullStr Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype
title_full_unstemmed Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype
title_short Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder ( gld ) Phenotype
title_sort tumor necrosis factor sustains the generalized lymphoproliferative disorder ( gld ) phenotype
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195803/
https://www.ncbi.nlm.nih.gov/pubmed/10620607
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