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A critical role for lymphotoxin in experimental allergic encephalomyelitis.

Suen WE, Bergman CM, Hjelmström P, Ruddle NH - J. Exp. Med. (1997)

Bottom Line: LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody.WT T cells transferred EAE to LT-alpha-/- recipients.These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520-8034, USA.

ABSTRACT
The lymphotoxin (LT)/tumor necrosis factor (TNF) family has been implicated in the neurologic inflammatory diseases multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). To determine the role of individual family members in EAE, C57BL/6 mice, LT-alpha-deficient (LT-alpha-/- mice), or LT-beta-deficient (LT-beta-/- mice), and their wild-type (WT) littermates were immunized with rat myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. C57BL/6 and WT mice developed chronic, sustained paralytic disease with average maximum clinical scores of 3.5 and disease indices (a measure of day of onset and sustained disease scores) ranging from 367 to 663 with central nervous system (CNS) inflammation and demyelination. LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody. However, LT-alpha-/- mice were quite resistant to EAE with low average clinical scores (<1), an average disease index of 61, and the negligible CNS inflammation and demyelination. WT T cells transferred EAE to LT-alpha-/- recipients. LT-beta-/- mice were susceptible to EAE, though less than WT, with an average maximum clinical score of 1.9 and disease index of 312. These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.

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LT-α−/− show minimal CNS inflammation and demyelination after active immunization with MOG peptide. (A and B) Paraffin sections of  spinal cord at day 30 of C57BL/6 (score 2.5) and (C) LT-α−/− (score 0.5) mice stained with hematoxylin and eosin (A and C) and Luxol fast blue with  neutral red (B). Note extensive infiltration of mononuclear cells and demyelination in sections of the control mice and minimal infiltration and no demyelination in sections from LT-α−/− mice. (Original magnification of A–C × 125). (D) Epon toluidine blue section of infiltrating mononuclear cells in  spinal cord of C57BL/6 mouse 35 d after immunization with MOG (Original magnification: × 312.5). Some demyelination is apparent.
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Figure 3: LT-α−/− show minimal CNS inflammation and demyelination after active immunization with MOG peptide. (A and B) Paraffin sections of spinal cord at day 30 of C57BL/6 (score 2.5) and (C) LT-α−/− (score 0.5) mice stained with hematoxylin and eosin (A and C) and Luxol fast blue with neutral red (B). Note extensive infiltration of mononuclear cells and demyelination in sections of the control mice and minimal infiltration and no demyelination in sections from LT-α−/− mice. (Original magnification of A–C × 125). (D) Epon toluidine blue section of infiltrating mononuclear cells in spinal cord of C57BL/6 mouse 35 d after immunization with MOG (Original magnification: × 312.5). Some demyelination is apparent.

Mentions: The brain and cervical, thoracic and lumbar spinal cord of individual C57BL/6, LT-α+/+, LT-α+/−, and LT-α−/− mice were evaluated histologically at various times after MOG immunization. All positive control mice exhibited extensive mononuclear infiltration in all areas examined, including the choroid plexus and all levels of the spinal cord. The mononuclear infiltrate, consisting of T cells, B cells, and macrophages (Suen, W.E., C.M. Bergman, and N.H. Ruddle, manuscript in preparation) was diffuse and not restricted to cuffing around the vessels but extended into the parenchyma, predominantly in the white but also in the gray matter. Demyelination was apparent (Fig. 3). In contrast, there was very little inflammation in any sections obtained from LT-α−/− mice. The minimal inflammation was limited almost exclusively to the meninges. The most extensive inflammation detected is shown in Fig. 3 C. There was no evidence of demyelination. Thus, the minimal clinical signs of LT-α−/− mice were mirrored in the very minor histological involvement.


A critical role for lymphotoxin in experimental allergic encephalomyelitis.

Suen WE, Bergman CM, Hjelmström P, Ruddle NH - J. Exp. Med. (1997)

LT-α−/− show minimal CNS inflammation and demyelination after active immunization with MOG peptide. (A and B) Paraffin sections of  spinal cord at day 30 of C57BL/6 (score 2.5) and (C) LT-α−/− (score 0.5) mice stained with hematoxylin and eosin (A and C) and Luxol fast blue with  neutral red (B). Note extensive infiltration of mononuclear cells and demyelination in sections of the control mice and minimal infiltration and no demyelination in sections from LT-α−/− mice. (Original magnification of A–C × 125). (D) Epon toluidine blue section of infiltrating mononuclear cells in  spinal cord of C57BL/6 mouse 35 d after immunization with MOG (Original magnification: × 312.5). Some demyelination is apparent.
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Related In: Results  -  Collection

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Figure 3: LT-α−/− show minimal CNS inflammation and demyelination after active immunization with MOG peptide. (A and B) Paraffin sections of spinal cord at day 30 of C57BL/6 (score 2.5) and (C) LT-α−/− (score 0.5) mice stained with hematoxylin and eosin (A and C) and Luxol fast blue with neutral red (B). Note extensive infiltration of mononuclear cells and demyelination in sections of the control mice and minimal infiltration and no demyelination in sections from LT-α−/− mice. (Original magnification of A–C × 125). (D) Epon toluidine blue section of infiltrating mononuclear cells in spinal cord of C57BL/6 mouse 35 d after immunization with MOG (Original magnification: × 312.5). Some demyelination is apparent.
Mentions: The brain and cervical, thoracic and lumbar spinal cord of individual C57BL/6, LT-α+/+, LT-α+/−, and LT-α−/− mice were evaluated histologically at various times after MOG immunization. All positive control mice exhibited extensive mononuclear infiltration in all areas examined, including the choroid plexus and all levels of the spinal cord. The mononuclear infiltrate, consisting of T cells, B cells, and macrophages (Suen, W.E., C.M. Bergman, and N.H. Ruddle, manuscript in preparation) was diffuse and not restricted to cuffing around the vessels but extended into the parenchyma, predominantly in the white but also in the gray matter. Demyelination was apparent (Fig. 3). In contrast, there was very little inflammation in any sections obtained from LT-α−/− mice. The minimal inflammation was limited almost exclusively to the meninges. The most extensive inflammation detected is shown in Fig. 3 C. There was no evidence of demyelination. Thus, the minimal clinical signs of LT-α−/− mice were mirrored in the very minor histological involvement.

Bottom Line: LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody.WT T cells transferred EAE to LT-alpha-/- recipients.These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520-8034, USA.

ABSTRACT
The lymphotoxin (LT)/tumor necrosis factor (TNF) family has been implicated in the neurologic inflammatory diseases multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). To determine the role of individual family members in EAE, C57BL/6 mice, LT-alpha-deficient (LT-alpha-/- mice), or LT-beta-deficient (LT-beta-/- mice), and their wild-type (WT) littermates were immunized with rat myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. C57BL/6 and WT mice developed chronic, sustained paralytic disease with average maximum clinical scores of 3.5 and disease indices (a measure of day of onset and sustained disease scores) ranging from 367 to 663 with central nervous system (CNS) inflammation and demyelination. LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody. However, LT-alpha-/- mice were quite resistant to EAE with low average clinical scores (<1), an average disease index of 61, and the negligible CNS inflammation and demyelination. WT T cells transferred EAE to LT-alpha-/- recipients. LT-beta-/- mice were susceptible to EAE, though less than WT, with an average maximum clinical score of 1.9 and disease index of 312. These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.

Show MeSH
Related in: MedlinePlus