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Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM).

Del Maschio A, De Luigi A, Martin-Padura I, Brockhaus M, Bartfai T, Fruscella P, Adorini L, Martino G, Furlan R, De Simoni MG, Dejana E - J. Exp. Med. (1999)

Bottom Line: The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma.Blood-brain barrier permeability was also reduced by the mAb.We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

View Article: PubMed Central - PubMed

Affiliation: Istituto di Ricerche Farmacologiche "Mario Negri, " 20157 Milan, Italy.

ABSTRACT
The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood-brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

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(A) Time course of leukocyte accumulation in the CSF (a) or brain parenchyma (b) after ICV injection of IL-1β and TNF-α. (a) The inflammatory cytokines caused a marked increase of CSF neutrophils (•) and monocytes (○). Data are expressed as percentage of total cell number in CSF counted after cytokine administration. The number of cells in sham-treated animals was essentially undetectable (see also B, panel a). Data are means ± SD of not less than five animals for each point from a typical experiment out of six performed. (b) MPO accumulation in the brain, as a parameter of leukocyte infiltration, was enhanced in a time-dependent manner. Data are means ± SD of at least five animals for each point from a typical experiment out of five performed. (B) Representative CSF samples collected at time 0 (a) and 6 h after ICV injection of cytokines (b, c). BV11 administration (c) strongly reduced leukocyte accumulation. (C) Administration of BV11 inhibited neutrophil and monocyte accumulation in the CSF after ICV cytokine injection. (a) BV11 and BV11 Fab significantly reduced neutrophil number in the CSF at 6 h after IL-1β and TNF-α administration. mAbs BV12, directed to JAM, and HB-151, as an isotype-matched control, were ineffective. (b) Monocyte accumulation after IL-1β and TNF-α was significantly reduced by BV11 and BV11 Fab but not by HB-151. Data are means ± SD of at least five animals from a typical experiment out of six performed. *P < 0.05; **P < 0.01 by analysis of variance and Dunnet test compared with saline treatment.
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Figure 2: (A) Time course of leukocyte accumulation in the CSF (a) or brain parenchyma (b) after ICV injection of IL-1β and TNF-α. (a) The inflammatory cytokines caused a marked increase of CSF neutrophils (•) and monocytes (○). Data are expressed as percentage of total cell number in CSF counted after cytokine administration. The number of cells in sham-treated animals was essentially undetectable (see also B, panel a). Data are means ± SD of not less than five animals for each point from a typical experiment out of six performed. (b) MPO accumulation in the brain, as a parameter of leukocyte infiltration, was enhanced in a time-dependent manner. Data are means ± SD of at least five animals for each point from a typical experiment out of five performed. (B) Representative CSF samples collected at time 0 (a) and 6 h after ICV injection of cytokines (b, c). BV11 administration (c) strongly reduced leukocyte accumulation. (C) Administration of BV11 inhibited neutrophil and monocyte accumulation in the CSF after ICV cytokine injection. (a) BV11 and BV11 Fab significantly reduced neutrophil number in the CSF at 6 h after IL-1β and TNF-α administration. mAbs BV12, directed to JAM, and HB-151, as an isotype-matched control, were ineffective. (b) Monocyte accumulation after IL-1β and TNF-α was significantly reduced by BV11 and BV11 Fab but not by HB-151. Data are means ± SD of at least five animals from a typical experiment out of six performed. *P < 0.05; **P < 0.01 by analysis of variance and Dunnet test compared with saline treatment.

Mentions: Mice ICV-treated with TNF-α (3 U/g body wt) and IL-1β (1.25 U/g body wt) showed a time-dependent CSF recruitment of both neutrophils and monocytes (Fig. 2 A, panel a). Maximal neutrophil recruitment at 6 h was almost 90% of the total leukocytes. Monocyte infiltration did not exceed 14% of the total recruited leukocytes. A comparable time course of leukocyte recruitment, measured as MPO activity, was observed in brain extracts of cytokine-treated mice (Fig. 2 A, panel b). After 6 h of treatment, cytokines induced a 3.7-fold increase of MPO activity compared with sham-treated animals. As reported in Fig. 2 B, panel a, the CSF of sham-treated animals was virtually devoid of circulating cells. In contrast, CSF of cytokine-treated mice contained a large number of recruited leukocytes (Fig. 2 B, panel b). This response was markedly reduced by intravenous administration of BV11 mAb (100 μg/mouse; Fig. 2 B, panel c).


Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM).

Del Maschio A, De Luigi A, Martin-Padura I, Brockhaus M, Bartfai T, Fruscella P, Adorini L, Martino G, Furlan R, De Simoni MG, Dejana E - J. Exp. Med. (1999)

(A) Time course of leukocyte accumulation in the CSF (a) or brain parenchyma (b) after ICV injection of IL-1β and TNF-α. (a) The inflammatory cytokines caused a marked increase of CSF neutrophils (•) and monocytes (○). Data are expressed as percentage of total cell number in CSF counted after cytokine administration. The number of cells in sham-treated animals was essentially undetectable (see also B, panel a). Data are means ± SD of not less than five animals for each point from a typical experiment out of six performed. (b) MPO accumulation in the brain, as a parameter of leukocyte infiltration, was enhanced in a time-dependent manner. Data are means ± SD of at least five animals for each point from a typical experiment out of five performed. (B) Representative CSF samples collected at time 0 (a) and 6 h after ICV injection of cytokines (b, c). BV11 administration (c) strongly reduced leukocyte accumulation. (C) Administration of BV11 inhibited neutrophil and monocyte accumulation in the CSF after ICV cytokine injection. (a) BV11 and BV11 Fab significantly reduced neutrophil number in the CSF at 6 h after IL-1β and TNF-α administration. mAbs BV12, directed to JAM, and HB-151, as an isotype-matched control, were ineffective. (b) Monocyte accumulation after IL-1β and TNF-α was significantly reduced by BV11 and BV11 Fab but not by HB-151. Data are means ± SD of at least five animals from a typical experiment out of six performed. *P < 0.05; **P < 0.01 by analysis of variance and Dunnet test compared with saline treatment.
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Figure 2: (A) Time course of leukocyte accumulation in the CSF (a) or brain parenchyma (b) after ICV injection of IL-1β and TNF-α. (a) The inflammatory cytokines caused a marked increase of CSF neutrophils (•) and monocytes (○). Data are expressed as percentage of total cell number in CSF counted after cytokine administration. The number of cells in sham-treated animals was essentially undetectable (see also B, panel a). Data are means ± SD of not less than five animals for each point from a typical experiment out of six performed. (b) MPO accumulation in the brain, as a parameter of leukocyte infiltration, was enhanced in a time-dependent manner. Data are means ± SD of at least five animals for each point from a typical experiment out of five performed. (B) Representative CSF samples collected at time 0 (a) and 6 h after ICV injection of cytokines (b, c). BV11 administration (c) strongly reduced leukocyte accumulation. (C) Administration of BV11 inhibited neutrophil and monocyte accumulation in the CSF after ICV cytokine injection. (a) BV11 and BV11 Fab significantly reduced neutrophil number in the CSF at 6 h after IL-1β and TNF-α administration. mAbs BV12, directed to JAM, and HB-151, as an isotype-matched control, were ineffective. (b) Monocyte accumulation after IL-1β and TNF-α was significantly reduced by BV11 and BV11 Fab but not by HB-151. Data are means ± SD of at least five animals from a typical experiment out of six performed. *P < 0.05; **P < 0.01 by analysis of variance and Dunnet test compared with saline treatment.
Mentions: Mice ICV-treated with TNF-α (3 U/g body wt) and IL-1β (1.25 U/g body wt) showed a time-dependent CSF recruitment of both neutrophils and monocytes (Fig. 2 A, panel a). Maximal neutrophil recruitment at 6 h was almost 90% of the total leukocytes. Monocyte infiltration did not exceed 14% of the total recruited leukocytes. A comparable time course of leukocyte recruitment, measured as MPO activity, was observed in brain extracts of cytokine-treated mice (Fig. 2 A, panel b). After 6 h of treatment, cytokines induced a 3.7-fold increase of MPO activity compared with sham-treated animals. As reported in Fig. 2 B, panel a, the CSF of sham-treated animals was virtually devoid of circulating cells. In contrast, CSF of cytokine-treated mice contained a large number of recruited leukocytes (Fig. 2 B, panel b). This response was markedly reduced by intravenous administration of BV11 mAb (100 μg/mouse; Fig. 2 B, panel c).

Bottom Line: The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma.Blood-brain barrier permeability was also reduced by the mAb.We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

View Article: PubMed Central - PubMed

Affiliation: Istituto di Ricerche Farmacologiche "Mario Negri, " 20157 Milan, Italy.

ABSTRACT
The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood-brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

Show MeSH
Related in: MedlinePlus