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Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype.

Körner H, Cretney E, Wilhelm P, Kelly JM, Röllinghoff M, Sedgwick JD, Smyth MJ - J. Exp. Med. (2000)

Bottom Line: By contrast, TNF deficiency alone does not result in a striking phenotype.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.

View Article: PubMed Central - PubMed

Affiliation: Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany. heinrich.koerner@mikrobio.med.unierlangen.de

ABSTRACT
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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Mice doubly mutant for FasL and TNF have significantly reduced lymphoaccumulation. Organs were excised from individual B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice, and wet weight (in milligrams) was determined for (A) mLNs, (B) pLNs, and (C) spleen. At each time point, organ weights of six B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice were determined. Total body weights ranged from 16 to 36 g over the 4–28-wk period, regardless of the genotype. Combined kidney weights ranged from 250 to 550 mg over the 4–28-wk period, regardless of the genotype. Results were recorded as the mean ± SE of six mice. Asterisks indicate the groups of B6.gld mice that are significantly different from B6.gld.TNF−/− mice (*P < 0.04).
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Figure 1: Mice doubly mutant for FasL and TNF have significantly reduced lymphoaccumulation. Organs were excised from individual B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice, and wet weight (in milligrams) was determined for (A) mLNs, (B) pLNs, and (C) spleen. At each time point, organ weights of six B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice were determined. Total body weights ranged from 16 to 36 g over the 4–28-wk period, regardless of the genotype. Combined kidney weights ranged from 250 to 550 mg over the 4–28-wk period, regardless of the genotype. Results were recorded as the mean ± SE of six mice. Asterisks indicate the groups of B6.gld mice that are significantly different from B6.gld.TNF−/− mice (*P < 0.04).

Mentions: All B6.WT and B6 gene-deficient mice were observed for at least 420 d to assess the relative level of mortality of each strain. B6.TNF−/− mice (2.8% dead, n = 36) did not exhibit mortality over and above that observed in B6.WT mice (2.2% dead, n = 45). B6.gld mice developed symptoms of lymphoaccumulation in secondary lymphoid organs within 16–20 wk of age, and mortality was 31.9% (n = 47) within the first 60 wk of age.This is in agreement with the 33% mortality within the first 12 mo described for B6.lpr mice 11. By contrast, B6.gld.TNF−/− mice did not show obvious signs of generalized lymphoproliferation, and mortality levels were similar to B6.WT mice (4.1%, n = 49). To further analyze this observation, body weights and organ weights of mutant mice were monitored over the first 28 wk of life. The weight of the secondary lymphoid organs (mLNs, pLNs, and spleen) of B6.gld mice increased dramatically after 16 wk of age ( Fig. 1A–C). The lymphoid organs of B6.gld.TNF−/− mice did increase to a minor extent after 16 wk of age. However, they were never dramatically enlarged like the lymphoid organs in B6.gld mice ( Fig. 1A–C). Even in much older B6.gld.TNF−/− mice (>40 wk), the increase in secondary lymphoid organ weights never reached that observed in B6.gld mice (data not shown). Total body weights and the weights of the kidneys increased slightly over the 28 wk of observation, irrespective of the mouse genotype (data not shown).


Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype.

Körner H, Cretney E, Wilhelm P, Kelly JM, Röllinghoff M, Sedgwick JD, Smyth MJ - J. Exp. Med. (2000)

Mice doubly mutant for FasL and TNF have significantly reduced lymphoaccumulation. Organs were excised from individual B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice, and wet weight (in milligrams) was determined for (A) mLNs, (B) pLNs, and (C) spleen. At each time point, organ weights of six B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice were determined. Total body weights ranged from 16 to 36 g over the 4–28-wk period, regardless of the genotype. Combined kidney weights ranged from 250 to 550 mg over the 4–28-wk period, regardless of the genotype. Results were recorded as the mean ± SE of six mice. Asterisks indicate the groups of B6.gld mice that are significantly different from B6.gld.TNF−/− mice (*P < 0.04).
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Related In: Results  -  Collection

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Figure 1: Mice doubly mutant for FasL and TNF have significantly reduced lymphoaccumulation. Organs were excised from individual B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice, and wet weight (in milligrams) was determined for (A) mLNs, (B) pLNs, and (C) spleen. At each time point, organ weights of six B6.WT, B6.TNF−/−, B6.gld, and B6.gld.TNF−/− mice were determined. Total body weights ranged from 16 to 36 g over the 4–28-wk period, regardless of the genotype. Combined kidney weights ranged from 250 to 550 mg over the 4–28-wk period, regardless of the genotype. Results were recorded as the mean ± SE of six mice. Asterisks indicate the groups of B6.gld mice that are significantly different from B6.gld.TNF−/− mice (*P < 0.04).
Mentions: All B6.WT and B6 gene-deficient mice were observed for at least 420 d to assess the relative level of mortality of each strain. B6.TNF−/− mice (2.8% dead, n = 36) did not exhibit mortality over and above that observed in B6.WT mice (2.2% dead, n = 45). B6.gld mice developed symptoms of lymphoaccumulation in secondary lymphoid organs within 16–20 wk of age, and mortality was 31.9% (n = 47) within the first 60 wk of age.This is in agreement with the 33% mortality within the first 12 mo described for B6.lpr mice 11. By contrast, B6.gld.TNF−/− mice did not show obvious signs of generalized lymphoproliferation, and mortality levels were similar to B6.WT mice (4.1%, n = 49). To further analyze this observation, body weights and organ weights of mutant mice were monitored over the first 28 wk of life. The weight of the secondary lymphoid organs (mLNs, pLNs, and spleen) of B6.gld mice increased dramatically after 16 wk of age ( Fig. 1A–C). The lymphoid organs of B6.gld.TNF−/− mice did increase to a minor extent after 16 wk of age. However, they were never dramatically enlarged like the lymphoid organs in B6.gld mice ( Fig. 1A–C). Even in much older B6.gld.TNF−/− mice (>40 wk), the increase in secondary lymphoid organ weights never reached that observed in B6.gld mice (data not shown). Total body weights and the weights of the kidneys increased slightly over the 28 wk of observation, irrespective of the mouse genotype (data not shown).

Bottom Line: By contrast, TNF deficiency alone does not result in a striking phenotype.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.

View Article: PubMed Central - PubMed

Affiliation: Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany. heinrich.koerner@mikrobio.med.unierlangen.de

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus