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. 1999 Nov 1;190(9):1351-6.
doi: 10.1084/jem.190.9.1351.

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

A Del Maschio  1 , A De Luigi, I Martin-Padura, M Brockhaus, T Bartfai, P Fruscella, L Adorini, G Martino, R Furlan, M G De Simoni, E Dejana
Affiliations

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

A Del Maschio et al. J Exp Med. .

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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Figures

Figure 1
Figure 1
Binding of anti-JAM antibodies to brain vessels. Mice were treated intravenously with BV11 mAb. mAb binding was evidenced by TRIC-conjugated anti–rat IgG. BV11 was able to bind vessels in the brain parenchyma (a) and in the choroid plexus (b).
Figure 2
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.
Figure 3
Figure 3
Administration of BV11 inhibited neutrophil and monocyte accumulation in the CSF after ICV injection of MCP-3. BV11 significantly reduced monocyte (a) and neutrophil (b) number in the CSF at 6 h after MCP-3 administration, whereas mAbs HB-151 and BV12 were ineffective. Data are means ± SD of at least five animals from a typical experiment out of three performed. *P < 0.01 by analysis of variance and Dunnet test compared with saline treatment.
Figure 4
Figure 4
(A) Neutrophil infiltration in the brain detected by immunofluorescence analysis of areas surrounding blood vessels (a–c) or submeningeal space (d–f). Sham-treated animals showed essentially no staining with an anti-CD15 mAb (a and d). When mice were treated with IL-1β and TNF-α for 6 h, a marked increase in neutrophil infiltration was observed (b and e). This phenomenon was inhibited by BV11 administration (c and f). (B) MPO activity in brain extracts. ICV administration of IL-1β and TNF-α increased MPO activity in the brain (compare sham with saline). BV11 significantly reduced MPO accumulation, whereas HB-151 and BV12 were ineffective. Data are means ± SD of five animals per group of a typical experiment out of four performed. *P < 0.01 versus saline treatment by analysis of variance and Dunnet test.
Figure 4
Figure 4
(A) Neutrophil infiltration in the brain detected by immunofluorescence analysis of areas surrounding blood vessels (a–c) or submeningeal space (d–f). Sham-treated animals showed essentially no staining with an anti-CD15 mAb (a and d). When mice were treated with IL-1β and TNF-α for 6 h, a marked increase in neutrophil infiltration was observed (b and e). This phenomenon was inhibited by BV11 administration (c and f). (B) MPO activity in brain extracts. ICV administration of IL-1β and TNF-α increased MPO activity in the brain (compare sham with saline). BV11 significantly reduced MPO accumulation, whereas HB-151 and BV12 were ineffective. Data are means ± SD of five animals per group of a typical experiment out of four performed. *P < 0.01 versus saline treatment by analysis of variance and Dunnet test.
Figure 5
Figure 5
Cytokine (IL-1β and TNF-α) treatment increased FITC-albumin accumulation in the CSF (compare sham with saline). BV11 administration significantly reduced this parameter, whereas HB-151 was ineffective. Data are means ± SD of seven animals of a typical experiment out of three performed. *P < 0.01 by analysis of variance and Dunnet test compared with saline treatment.
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