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

Schaper, Fleur; Timmeren, Mirjan M. van; Petersen, Arjen H.; Horst, G.; Bijl, Marc; Limburg, Pieter C.; Westra, Johanna; Heeringa, Peter

doi:10.2119/molmed.2015.00176

Cited by 18 publications

(19 citation statements)

References 46 publications

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“…Moreover, we first tried subcutaneous injection using the same dosage (5 mg/kg) as a preliminary experiment; however, we were not able to find any beneficial effects for MRL/ lpr mice ( data not shown ). Although our results could not show absolute efficacy (organomegaly and serological abnormalities did not improve), increased dose and higher blood concentration compared to the previous study might contribute to the efficacy for nephritis 18 . However, HMGB1 was actively translocated from the nucleus in MRL/ lpr mice, as determined by immunofluorescence; therefore, the dose might be insufficient to antagonize the target in this mouse model.…”

Section: Discussioncontrasting

confidence: 79%

“…Although the antibody dose seems considerably low, they showed attenuated proteinuria, glomerulonephritis, anti-dsDNA, and serum cytokine levels. However, a recent study has reported that the anti-HMGB1 antibody did not affect lupus activities in MRL/ lpr mice 18 . Although this previous study used the same mouse model, the treatment protocol was different from our protocol, i.e., an antibody dose of 100 μg/mouse/week was used in contrast to our dose of approximately 150–400 μg/mouse/week, with peritoneal administration and a treatment period of 7–17 weeks.…”

Section: Discussionmentioning

confidence: 92%

“…Interestingly, HMGB1 inhibition by a specific antibody has been shown to alleviate lupus-like disease in BXSB mice 17 . In contrast, a different study has recently reported that treatment with an anti-HMGB1 monoclonal antibody (mAb) does not affect lupus activities in MRL/ lpr mice 18 . To elucidate this discrepancy, we examined the efficacy of anti-HMGB1 mAb to determine whether it ameliorates lupus activities, including nephritis and serological abnormalities, in MRL/ lpr lupus-prone mice.…”

Section: Introductionmentioning

confidence: 99%

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Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice

Watanabe

Liu

et al. 2017

Molecular Therapy - Methods & Clinical Development

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We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4–15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2′-deoxy-2′-[18F]fluoro-β-D-arabinofuranosyl)cytosine ([18F]FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks. Following 4-week treatment, [18F]FAC-PET/CT showed similar accumulation in cervical and axillary lymph nodes at 12 weeks of age. However, anti-HMGB1 monoclonal antibody sufficiently inhibited the increase in albuminuria compared to an isotype control following 15-week treatment. Complement deposition was also improved; however, there were no significant differences in IgG deposition and renal pathological scores between the two groups. Anti-double-stranded DNA (dsDNA) antibody titers and cytokine and chemokine levels were also unaltered. Although there were no significant differences in glomerular macrophage infiltration, neutrophil infiltration was significantly decreased by the anti-HMGB1 monoclonal antibody. Antagonizing HMGB1 treatment suppressed HMGB1 translocation from nuclei in the kidney and suppressed neutrophil extracellular traps. The anti-HMGB1 monoclonal antibody demonstrated therapeutic potential against albuminuria in lupus nephritis by inhibiting neutrophil recruitment and neutrophil extracellular traps.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice

Watanabe

Liu

et al. 2017

Molecular Therapy - Methods & Clinical Development

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“…Administration of monoclonal anti-HMGB1 antibodies have shown opposing effects in animal models of lupus [83,84]. In animal models of arthritis anti-HMGB1 treatment have attenuated the disease [85,86].…”

Section: Antibodies Against High Mobility Group Box Protein-1 (Hmgb1)mentioning

confidence: 99%

“…Studies in animal models of arthritis have shown that treatment with anti-HMGB1 antibodies can attenuate disease by blocking pro-inflammatory actions of HMGB1 [85,86]. Opposing effects of anti-HMGB1 have been demonstrated in two different murine lupus models [83,84]. HMGB1 has different…”

Section: Antibodies Against High Mobility Group Box Protein-1 (Hmgb1)mentioning

confidence: 99%

Biomarkers of disease activity and organ damage in systemic lupus erythematosus

Wirestam¹

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Jag tror att när vi går igenom tiden att allt det bästa inte hänt än Håkan Hellström ABSTRACTSystemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients.High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation.Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated.As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels.Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity.Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-sectional study, circulating OPN levels were found to be raised in SLE (Paper III). In patients with recent-onset disease, OPN reflected disease activity, while in established disease, OPN appeared to mirror damage accrual and cardiovascular damage. In Paper IV, OPN was instead analyzed in an international longitudinal multi-center study based on patients with recent-onset SLE and follow-up data. OPN turned out to be a poor predictor of organ damage, but significant associations were observed between OPN and disease activity both at disease onset, as well as over 5 years of follow-up.In conclusion, increased anti-HMGB1 antibody and decreased PTX3 levels could potentially sustain the impaired waste-disposal. Of the molecules analyzed in this thesis, OPN seems to be the best marker of disease activity. Further studies of these proteins may help to better understand SLE pathogenesis and to optimize treatment of patients.

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Nucleic acids delivered by PEGylated cationic liposomes in systemic lupus erythematosus-prone mice: A possible exacerbation of lupus nephritis in the presence of pre-existing anti-nucleic acid antibodies

Takata

Shimizu

Kawaguchi

et al. 2021

International Journal of Pharmaceutics

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

Cited by 18 publications

References 46 publications

Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice

Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice

Biomarkers of disease activity and organ damage in systemic lupus erythematosus

Nucleic acids delivered by PEGylated cationic liposomes in systemic lupus erythematosus-prone mice: A possible exacerbation of lupus nephritis in the presence of pre-existing anti-nucleic acid antibodies

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