Transgenic mice expressing high levels of soluble TNF‐R1 fusion protein are protected from lethal septic shock and cerebral malaria, and are highly sensitive to Listeria monocytogenes and Leishmania major infections

Iréne Garcia, Yoshitaka Miyazaki, Kimi Araki, Masatake Araki, Rudolf Lucas, Georges E. Grau, Geneviéve Milon, Yasmine Belkaid, Christine Montixi, Werner Lesslauer, Pierre Vassalli

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Mice bearing a transgene coding for a soluble tumor necrosis factor receptor type 1 (TNFR1)‐FeIgG3 fusion protein and placed under the control of the alpha‐1‐antitrypsin gene promoter were generated. Depending on the mouse line, blood levels of the protein ranged from 25 ng/ml to over 100 μg/ml; this level of expression was most often transmitted to the transgene‐bearing progeny as a relatively stable feature. High‐expressor mice were completely resistant to lipopolysaccharide‐induced shock and lethality, including after D‐galactosamine sensitization, and mice expressing about 1 μg of the fusion protein/ml were partially (60%) protected. In contrast, mice expressing less than 0.1 μg of the protein/ml were more sensitive than controls with respect to incidence and time of death, even though the biological activity of serum tumor necrosis factor (TNF) was partially neutralized. High‐expressor mice of the adequate genetic background were markedly, although not completely, protected from death by cerebral malaria after injection with Plasmodium berghei. They were highly susceptible to Listeria monocytogenes, dying from bacterial dissemination after sublethal infection, and to Leishmania major, displaying severe, non‐healing lesions after local infection. Under the same conditions, mice expressing about 1 μg protein/ml were only partially sensitive to these last agents, compared to nontransgenic littermate mice which were fully resistant. These transgenic mice represent a model of permanent, complete or partial, impairment of TNF use, which compares favorably, for ease of breeding and for the range of effects, to mice bearing gene disruptions.

Original languageEnglish (US)
Pages (from-to)2401-2407
Number of pages7
JournalEuropean Journal of Immunology
Volume25
Issue number8
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Receptors, Tumor Necrosis Factor, Type I
Cerebral Malaria
Leishmania major
Listeria monocytogenes
Septic Shock
Transgenic Mice
Infection
Proteins
Tumor Necrosis Factor-alpha
Plasmodium berghei
Transgenes
Genes
Breeding
Blood Proteins
Shock

Keywords

  • Leishmania major
  • Listeria monocytogenes
  • Septic shock
  • Transgenic mice
  • Tumor necrosis factor receptor 1 fusion protein

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Transgenic mice expressing high levels of soluble TNF‐R1 fusion protein are protected from lethal septic shock and cerebral malaria, and are highly sensitive to Listeria monocytogenes and Leishmania major infections. / Garcia, Iréne; Miyazaki, Yoshitaka; Araki, Kimi; Araki, Masatake; Lucas, Rudolf; Grau, Georges E.; Milon, Geneviéve; Belkaid, Yasmine; Montixi, Christine; Lesslauer, Werner; Vassalli, Pierre.

In: European Journal of Immunology, Vol. 25, No. 8, 01.01.1995, p. 2401-2407.

Research output: Contribution to journalArticle

Garcia, Iréne ; Miyazaki, Yoshitaka ; Araki, Kimi ; Araki, Masatake ; Lucas, Rudolf ; Grau, Georges E. ; Milon, Geneviéve ; Belkaid, Yasmine ; Montixi, Christine ; Lesslauer, Werner ; Vassalli, Pierre. / Transgenic mice expressing high levels of soluble TNF‐R1 fusion protein are protected from lethal septic shock and cerebral malaria, and are highly sensitive to Listeria monocytogenes and Leishmania major infections. In: European Journal of Immunology. 1995 ; Vol. 25, No. 8. pp. 2401-2407.
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abstract = "Mice bearing a transgene coding for a soluble tumor necrosis factor receptor type 1 (TNFR1)‐FeIgG3 fusion protein and placed under the control of the alpha‐1‐antitrypsin gene promoter were generated. Depending on the mouse line, blood levels of the protein ranged from 25 ng/ml to over 100 μg/ml; this level of expression was most often transmitted to the transgene‐bearing progeny as a relatively stable feature. High‐expressor mice were completely resistant to lipopolysaccharide‐induced shock and lethality, including after D‐galactosamine sensitization, and mice expressing about 1 μg of the fusion protein/ml were partially (60{\%}) protected. In contrast, mice expressing less than 0.1 μg of the protein/ml were more sensitive than controls with respect to incidence and time of death, even though the biological activity of serum tumor necrosis factor (TNF) was partially neutralized. High‐expressor mice of the adequate genetic background were markedly, although not completely, protected from death by cerebral malaria after injection with Plasmodium berghei. They were highly susceptible to Listeria monocytogenes, dying from bacterial dissemination after sublethal infection, and to Leishmania major, displaying severe, non‐healing lesions after local infection. Under the same conditions, mice expressing about 1 μg protein/ml were only partially sensitive to these last agents, compared to nontransgenic littermate mice which were fully resistant. These transgenic mice represent a model of permanent, complete or partial, impairment of TNF use, which compares favorably, for ease of breeding and for the range of effects, to mice bearing gene disruptions.",
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T1 - Transgenic mice expressing high levels of soluble TNF‐R1 fusion protein are protected from lethal septic shock and cerebral malaria, and are highly sensitive to Listeria monocytogenes and Leishmania major infections

AU - Garcia, Iréne

AU - Miyazaki, Yoshitaka

AU - Araki, Kimi

AU - Araki, Masatake

AU - Lucas, Rudolf

AU - Grau, Georges E.

AU - Milon, Geneviéve

AU - Belkaid, Yasmine

AU - Montixi, Christine

AU - Lesslauer, Werner

AU - Vassalli, Pierre

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N2 - Mice bearing a transgene coding for a soluble tumor necrosis factor receptor type 1 (TNFR1)‐FeIgG3 fusion protein and placed under the control of the alpha‐1‐antitrypsin gene promoter were generated. Depending on the mouse line, blood levels of the protein ranged from 25 ng/ml to over 100 μg/ml; this level of expression was most often transmitted to the transgene‐bearing progeny as a relatively stable feature. High‐expressor mice were completely resistant to lipopolysaccharide‐induced shock and lethality, including after D‐galactosamine sensitization, and mice expressing about 1 μg of the fusion protein/ml were partially (60%) protected. In contrast, mice expressing less than 0.1 μg of the protein/ml were more sensitive than controls with respect to incidence and time of death, even though the biological activity of serum tumor necrosis factor (TNF) was partially neutralized. High‐expressor mice of the adequate genetic background were markedly, although not completely, protected from death by cerebral malaria after injection with Plasmodium berghei. They were highly susceptible to Listeria monocytogenes, dying from bacterial dissemination after sublethal infection, and to Leishmania major, displaying severe, non‐healing lesions after local infection. Under the same conditions, mice expressing about 1 μg protein/ml were only partially sensitive to these last agents, compared to nontransgenic littermate mice which were fully resistant. These transgenic mice represent a model of permanent, complete or partial, impairment of TNF use, which compares favorably, for ease of breeding and for the range of effects, to mice bearing gene disruptions.

AB - Mice bearing a transgene coding for a soluble tumor necrosis factor receptor type 1 (TNFR1)‐FeIgG3 fusion protein and placed under the control of the alpha‐1‐antitrypsin gene promoter were generated. Depending on the mouse line, blood levels of the protein ranged from 25 ng/ml to over 100 μg/ml; this level of expression was most often transmitted to the transgene‐bearing progeny as a relatively stable feature. High‐expressor mice were completely resistant to lipopolysaccharide‐induced shock and lethality, including after D‐galactosamine sensitization, and mice expressing about 1 μg of the fusion protein/ml were partially (60%) protected. In contrast, mice expressing less than 0.1 μg of the protein/ml were more sensitive than controls with respect to incidence and time of death, even though the biological activity of serum tumor necrosis factor (TNF) was partially neutralized. High‐expressor mice of the adequate genetic background were markedly, although not completely, protected from death by cerebral malaria after injection with Plasmodium berghei. They were highly susceptible to Listeria monocytogenes, dying from bacterial dissemination after sublethal infection, and to Leishmania major, displaying severe, non‐healing lesions after local infection. Under the same conditions, mice expressing about 1 μg protein/ml were only partially sensitive to these last agents, compared to nontransgenic littermate mice which were fully resistant. These transgenic mice represent a model of permanent, complete or partial, impairment of TNF use, which compares favorably, for ease of breeding and for the range of effects, to mice bearing gene disruptions.

KW - Leishmania major

KW - Listeria monocytogenes

KW - Septic shock

KW - Transgenic mice

KW - Tumor necrosis factor receptor 1 fusion protein

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