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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.


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4-1BB mAb exerted beneficial effects on mice with Con A-induced liver injury. (A) representative images of H&E-stained liver tissue from mice treated with the various treatments. (B) Administration of 4-1BB mAb 2 h after or 2 h before Con A injection significantly reduced the serum levels of ALT and AST. (C) 4-1BB combined with MEP further reduced the ALT and AST levels. Data are presented as the mean ± standard deviation. *P<0.05 vs. the Con A + control IgG or Con A + preventive (4-!BB administered 2 h prior to injection with Con A) IgG groups. Con A, concanavalin A; IgG, immunoglobulin G; H&E, hematoxylin & eosin; ALT, alanine transaminase; AST, aspartate transaminase; mAb, monoclonal antibody; MEP, methylprednisolone.
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f2-etm-0-0-3503: 4-1BB mAb exerted beneficial effects on mice with Con A-induced liver injury. (A) representative images of H&E-stained liver tissue from mice treated with the various treatments. (B) Administration of 4-1BB mAb 2 h after or 2 h before Con A injection significantly reduced the serum levels of ALT and AST. (C) 4-1BB combined with MEP further reduced the ALT and AST levels. Data are presented as the mean ± standard deviation. *P<0.05 vs. the Con A + control IgG or Con A + preventive (4-!BB administered 2 h prior to injection with Con A) IgG groups. Con A, concanavalin A; IgG, immunoglobulin G; H&E, hematoxylin & eosin; ALT, alanine transaminase; AST, aspartate transaminase; mAb, monoclonal antibody; MEP, methylprednisolone.

Mentions: Compared with the control mice, the mice injected with 4-1BB mAb at 2 h post-Con A injection became increasingly active and exhibited an improved appetite at 3–4 h post-injection. H&E staining detected a marked reduction in hepatocyte necrosis and decreased lymphocyte and neutrophil infiltration into the hepatic portal area in mice treated with 4-1BB, compared with the control group mice (Fig. 2A). Furthermore, the serum levels of ALT and AST were significantly reduced by 4-1BB mAb injection post-ConA-induced (P<0.01; Fig. 2B), which indicated that treatment with 4-1BB mAb was able to preserve liver function in Con A-injected mice. Consistent with these results, injection with 4-1BB mAb at 2 h prior to the induction of liver injury by Con A markedly attenuated Con A-induced liver damage. In addition, preventive treatment of the mice with 4-1BB mAb maintained physical activity, reduced liver tissue damage (Fig. 2A) and preserved liver function in the mice (P<0.05; Fig. 2B) compared with the preventive control IgG.


Anti-4-1BB monoclonal antibodies attenuate concanavalin A-induced immune-mediated liver injury in mice
4-1BB mAb exerted beneficial effects on mice with Con A-induced liver injury. (A) representative images of H&E-stained liver tissue from mice treated with the various treatments. (B) Administration of 4-1BB mAb 2 h after or 2 h before Con A injection significantly reduced the serum levels of ALT and AST. (C) 4-1BB combined with MEP further reduced the ALT and AST levels. Data are presented as the mean ± standard deviation. *P<0.05 vs. the Con A + control IgG or Con A + preventive (4-!BB administered 2 h prior to injection with Con A) IgG groups. Con A, concanavalin A; IgG, immunoglobulin G; H&E, hematoxylin & eosin; ALT, alanine transaminase; AST, aspartate transaminase; mAb, monoclonal antibody; MEP, methylprednisolone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-etm-0-0-3503: 4-1BB mAb exerted beneficial effects on mice with Con A-induced liver injury. (A) representative images of H&E-stained liver tissue from mice treated with the various treatments. (B) Administration of 4-1BB mAb 2 h after or 2 h before Con A injection significantly reduced the serum levels of ALT and AST. (C) 4-1BB combined with MEP further reduced the ALT and AST levels. Data are presented as the mean ± standard deviation. *P<0.05 vs. the Con A + control IgG or Con A + preventive (4-!BB administered 2 h prior to injection with Con A) IgG groups. Con A, concanavalin A; IgG, immunoglobulin G; H&E, hematoxylin & eosin; ALT, alanine transaminase; AST, aspartate transaminase; mAb, monoclonal antibody; MEP, methylprednisolone.
Mentions: Compared with the control mice, the mice injected with 4-1BB mAb at 2 h post-Con A injection became increasingly active and exhibited an improved appetite at 3–4 h post-injection. H&E staining detected a marked reduction in hepatocyte necrosis and decreased lymphocyte and neutrophil infiltration into the hepatic portal area in mice treated with 4-1BB, compared with the control group mice (Fig. 2A). Furthermore, the serum levels of ALT and AST were significantly reduced by 4-1BB mAb injection post-ConA-induced (P<0.01; Fig. 2B), which indicated that treatment with 4-1BB mAb was able to preserve liver function in Con A-injected mice. Consistent with these results, injection with 4-1BB mAb at 2 h prior to the induction of liver injury by Con A markedly attenuated Con A-induced liver damage. In addition, preventive treatment of the mice with 4-1BB mAb maintained physical activity, reduced liver tissue damage (Fig. 2A) and preserved liver function in the mice (P<0.05; Fig. 2B) compared with the preventive control IgG.

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