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Treatment with anti-HMGB1 monoclonal antibody does not affect lupus nephritis in MRL/lpr mice.

ABSTRACT: High Mobility Group Box 1 (HMGB1) is a nuclear DNA binding protein which acts as an alarmin when secreted. HMGB1 is increased in SLE and might represent a potential therapeutic target. We investigated whether treatment with a anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice.Seven week old MRL/lpr mice were injected intraperitoneally twice weekly for 10 weeks with 50 ?g monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n=12) or control antibody (n=11). Control MRL/MPJ mice (n=10) were left untreated. Every two weeks blood was drawn and urine was collected at week 7, 11 and 17. Mice were sacrificed at 17 weeks for complete disease evaluation.Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared to control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and pro-inflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 mAb was classified as class III (n=3) and class IV (n=9), while mice treated with control mAb were classified as class II (n=4), class III (n=2) and class IV (n=5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb.Treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or pro-inflammatory cytokines levels in MRL/lpr mice. This indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

SUBMITTER: Schaper F

PROVIDER: S-EPMC5004709 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice.

Schaper Fleur F van Timmeren Mirjan M MM Petersen Arjen A Horst Gerda G Bijl Marc M Limburg Pieter C PC Westra Johanna J Heeringa Peter P

Molecular medicine (Cambridge, Mass.) 20160113

High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 μg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = ...[more]

PMID: 26837069

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Project description:BackgroundLupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus (SLE). However, the aetiology and pathogenesis of LN remain unknown. 1,25-dihydroxyvitamin D3 [1,25-(OH)2-VitD3] is the active form of vitamin D, and it has been shown to perform important functions in inflammatory and immune-related diseases. In this study, we investigated the time-dependent effects of 1,25-dihydroxyvitamin D3 and explored the underlying mechanism in MRL/lpr mice, a well-studied animal model of LN.MethodsBeginning at 8 weeks of age, 24-h urine samples were collected weekly to measure the levels of protein in the urine. We treated female MRL/lpr mice with 1,25-dihydroxyvitamin D3 (4 μg/kg) or 1% DMSO by intraperitoneal injection twice weekly for 3 weeks beginning at the age of 11 weeks. The mice were separately sacrificed, and serum and kidney samples were collected at the ages of 14, 16, 18, and 20 weeks to measure creatinine (Cr) levels, blood urea nitrogen (BUN) levels, histological damage, immunological marker (A-ds DNA, C1q, C3, IgG, IgM) levels, and inflammatory factor (TNF-α, IL-17, MCP-1) levels. Furthermore, the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signalling pathways were also assessed to elucidate the underlying mechanism.ResultsWe found that MRL/lpr mice treated with 1,25-dihydroxyvitamin D3 displayed significantly attenuated LN. VitD3-treated mice exhibited significantly improved renal pathological damage and reduced proteinuria, BUN, SCr, A-ds DNA antibody and immune complex deposition levels (P < 0.05) compared with untreated MRL/lpr mice. Moreover, 1,25-dihydroxyvitamin D3 inhibited the complement cascade, inhibited the release of proinflammatory cytokines, such as TNF-α, IL-17, and MCP-1, and inhibited NF-κB and MAPK activation (P < 0.05).Conclusion1,25-dihydroxyvitamin D3 exerts a protective effect against LN by inhibiting the NF-κB and MAPK signalling pathways, providing a potential treatment strategy for LN. Interestingly, the NF-κB and MAPK signalling pathways are time-dependent mediators of LN and may be associated with lupus activity.

Dataset Information

Treatment with anti-HMGB1 monoclonal antibody does not affect lupus nephritis in MRL/lpr mice.

Publications

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice.

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