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Anti-4-1BB monoclonal antibodies attenuate concanavalin A-induced immune-mediated liver injury in mice

View Article: PubMed Central - PubMed

ABSTRACT

Effective therapies for the treatment of immune-mediated liver disease are currently lacking. As a member of the tumor necrosis factor receptor superfamily, 4-1BB has a key role in T-cell activation and has been implicated in the development of autoimmune disorders. The purpose of the present study was to evaluate the potential therapeutic or preventive function of an anti-4-1BB monoclonal antibody (mAb) in a mouse model of concanavalin (Con) A-induced immune-mediated liver injury. A mouse model of immune-mediated liver injury was established by tail vein injection of Con A (20 mg/kg). 4-1BB mAb (100 µg), with or without methylprednisolone (MEP; 3 mg/kg), was intraperitoneally injected into the tail vein 2 h prior to or 2 h following Con A injection. Con A induced marked hepatocyte necrosis, significantly reduced CD 4+/CD25+ T-cell levels, and increased the serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), in addition to the percentage of 4-1BB+ T-cells, compared with the control (all P<0.05). The administration of 4-1BB mAb prior to or following Con A injection was able to attenuate Con A-induced liver tissue damage and significantly reduce serum AST and ALT levels (P<0.05). A combination of MEP and 4-1BB mAb further reduced serum AST and ALT levels, compared with either treatment alone. In addition, administration of 4-1BB mAb and MEP alone or in combination significantly increased CD4+/CD25+ T-cell levels, compared with the control (P<0.05). These results suggested that 4-1BB mAb was able to attenuate liver injury and preserve liver function in a mouse model of Con A-induced immune-mediated liver injury by promoting the expansion of CD4+/CD25+ T-cells. Furthermore, a combination of 4-1BB mAb with MEP was associated with greater beneficial effects than either treatment alone. The clinical significance of 4-1BB mAb in immune-mediated liver disease remains to be elucidated in future studies.

No MeSH data available.


Related in: MedlinePlus

Establishment of the mouse model of Con A-induced immune-mediated liver injury. Representative images of H&E-stained (A) healthy liver tissue and (B) liver tissue from mice injected with Con A. Mice were sacrificed at 8 h following Con A injection, after which liver tissue was harvested, fixed and sectioned. Images of H&E-stained sections were obtained using an Olympus BH2 microscope (magnification, ×20). (C) Levels of ALT and AST were significantly increased following Con A injection. Blood samples were collected 8 h following Con A injection and the ALT and AST levels were measured. (D) Proportion of CD3+ 4-1BB+ T-cells was significantly increased following Con A injection. Blood samples were incubated with CD3-fluorescein isothiocyanate and 4-1BB-phycoerythrin antibodies and analyzed by flow cytometry. Data are presented as the mean ± standard deviation (n=10). *P<0.05 vs. control. Con A, concanavalin A; H&E, hematoxylin and eosin; ALT, alanine transaminase; AST, aspartate transaminase; CD3, cluster of differentiation 3.
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f1-etm-0-0-3503: Establishment of the mouse model of Con A-induced immune-mediated liver injury. Representative images of H&E-stained (A) healthy liver tissue and (B) liver tissue from mice injected with Con A. Mice were sacrificed at 8 h following Con A injection, after which liver tissue was harvested, fixed and sectioned. Images of H&E-stained sections were obtained using an Olympus BH2 microscope (magnification, ×20). (C) Levels of ALT and AST were significantly increased following Con A injection. Blood samples were collected 8 h following Con A injection and the ALT and AST levels were measured. (D) Proportion of CD3+ 4-1BB+ T-cells was significantly increased following Con A injection. Blood samples were incubated with CD3-fluorescein isothiocyanate and 4-1BB-phycoerythrin antibodies and analyzed by flow cytometry. Data are presented as the mean ± standard deviation (n=10). *P<0.05 vs. control. Con A, concanavalin A; H&E, hematoxylin and eosin; ALT, alanine transaminase; AST, aspartate transaminase; CD3, cluster of differentiation 3.

Mentions: Compared with the control group, the mice that were injected with Con A appeared less active and had a poor appetite. A histopathological examination detected a large number of necrotic hepatocytes in the liver tissue from the Con A group, and these necrotic hepatocytes were smaller, than normal hepatocytes, containing condensed chromatin and exhibiting reticular degeneration and steatosis. In addition, the liver tissue from the Con A group exhibited marked lymphocyte and neutrophil infiltration, in particular within the hepatic portal area. Furthermore, severe erythrocyte sedimentation was observed in the hepatic sinusoid (Fig. 1A and B). The Con A-injected mice exhibited significantly increased serum levels of ALT and AST, compared with the control mice (P<0.01; Fig. 1C); thus suggesting that the liver function was impaired following Con A injection. In addition, the percentage of 4-1BB-positive T-cells was significantly increased in the Con A-injected mice compared with the control mice (P=0.0018; Fig. 1D). These results suggest that Con A injection may cause liver damage in mice and stimulate 4-1BB expression in T-cells.


Anti-4-1BB monoclonal antibodies attenuate concanavalin A-induced immune-mediated liver injury in mice
Establishment of the mouse model of Con A-induced immune-mediated liver injury. Representative images of H&E-stained (A) healthy liver tissue and (B) liver tissue from mice injected with Con A. Mice were sacrificed at 8 h following Con A injection, after which liver tissue was harvested, fixed and sectioned. Images of H&E-stained sections were obtained using an Olympus BH2 microscope (magnification, ×20). (C) Levels of ALT and AST were significantly increased following Con A injection. Blood samples were collected 8 h following Con A injection and the ALT and AST levels were measured. (D) Proportion of CD3+ 4-1BB+ T-cells was significantly increased following Con A injection. Blood samples were incubated with CD3-fluorescein isothiocyanate and 4-1BB-phycoerythrin antibodies and analyzed by flow cytometry. Data are presented as the mean ± standard deviation (n=10). *P<0.05 vs. control. Con A, concanavalin A; H&E, hematoxylin and eosin; ALT, alanine transaminase; AST, aspartate transaminase; CD3, cluster of differentiation 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998111&req=5

f1-etm-0-0-3503: Establishment of the mouse model of Con A-induced immune-mediated liver injury. Representative images of H&E-stained (A) healthy liver tissue and (B) liver tissue from mice injected with Con A. Mice were sacrificed at 8 h following Con A injection, after which liver tissue was harvested, fixed and sectioned. Images of H&E-stained sections were obtained using an Olympus BH2 microscope (magnification, ×20). (C) Levels of ALT and AST were significantly increased following Con A injection. Blood samples were collected 8 h following Con A injection and the ALT and AST levels were measured. (D) Proportion of CD3+ 4-1BB+ T-cells was significantly increased following Con A injection. Blood samples were incubated with CD3-fluorescein isothiocyanate and 4-1BB-phycoerythrin antibodies and analyzed by flow cytometry. Data are presented as the mean ± standard deviation (n=10). *P<0.05 vs. control. Con A, concanavalin A; H&E, hematoxylin and eosin; ALT, alanine transaminase; AST, aspartate transaminase; CD3, cluster of differentiation 3.
Mentions: Compared with the control group, the mice that were injected with Con A appeared less active and had a poor appetite. A histopathological examination detected a large number of necrotic hepatocytes in the liver tissue from the Con A group, and these necrotic hepatocytes were smaller, than normal hepatocytes, containing condensed chromatin and exhibiting reticular degeneration and steatosis. In addition, the liver tissue from the Con A group exhibited marked lymphocyte and neutrophil infiltration, in particular within the hepatic portal area. Furthermore, severe erythrocyte sedimentation was observed in the hepatic sinusoid (Fig. 1A and B). The Con A-injected mice exhibited significantly increased serum levels of ALT and AST, compared with the control mice (P<0.01; Fig. 1C); thus suggesting that the liver function was impaired following Con A injection. In addition, the percentage of 4-1BB-positive T-cells was significantly increased in the Con A-injected mice compared with the control mice (P=0.0018; Fig. 1D). These results suggest that Con A injection may cause liver damage in mice and stimulate 4-1BB expression in T-cells.

View Article: PubMed Central - PubMed

ABSTRACT

Effective therapies for the treatment of immune-mediated liver disease are currently lacking. As a member of the tumor necrosis factor receptor superfamily, 4-1BB has a key role in T-cell activation and has been implicated in the development of autoimmune disorders. The purpose of the present study was to evaluate the potential therapeutic or preventive function of an anti-4-1BB monoclonal antibody (mAb) in a mouse model of concanavalin (Con) A-induced immune-mediated liver injury. A mouse model of immune-mediated liver injury was established by tail vein injection of Con A (20 mg/kg). 4-1BB mAb (100 &micro;g), with or without methylprednisolone (MEP; 3 mg/kg), was intraperitoneally injected into the tail vein 2 h prior to or 2 h following Con A injection. Con A induced marked hepatocyte necrosis, significantly reduced CD 4+/CD25+ T-cell levels, and increased the serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), in addition to the percentage of 4-1BB+ T-cells, compared with the control (all P&lt;0.05). The administration of 4-1BB mAb prior to or following Con A injection was able to attenuate Con A-induced liver tissue damage and significantly reduce serum AST and ALT levels (P&lt;0.05). A combination of MEP and 4-1BB mAb further reduced serum AST and ALT levels, compared with either treatment alone. In addition, administration of 4-1BB mAb and MEP alone or in combination significantly increased CD4+/CD25+ T-cell levels, compared with the control (P&lt;0.05). These results suggested that 4-1BB mAb was able to attenuate liver injury and preserve liver function in a mouse model of Con A-induced immune-mediated liver injury by promoting the expansion of CD4+/CD25+ T-cells. Furthermore, a combination of 4-1BB mAb with MEP was associated with greater beneficial effects than either treatment alone. The clinical significance of 4-1BB mAb in immune-mediated liver disease remains to be elucidated in future studies.

No MeSH data available.


Related in: MedlinePlus