Abstract
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.
Highlights
Lupus nephritis (LN) is a refractory complication of systemic lupus erythematosus (SLE), which causes end-stage renal disease, resulting in lower survival rates and quality of life.[1]
We examined the efficacy of anti-HMGB1 monoclonal antibody (mAb) to determine whether it ameliorates lupus activities, including nephritis and serological abnormalities, in MRL/ lpr lupus-prone mice
Serological Abnormalities and the Effects of the Anti-HMGB1 mAb As shown in Figure 2A, anti-HMGB1 mAb treatment did not result in any significant reduction in anti-double-stranded DNA antibody titers at 16 weeks
Summary
Lupus nephritis (LN) is a refractory complication of systemic lupus erythematosus (SLE), which causes end-stage renal disease, resulting in lower survival rates and quality of life.[1] The pathogenesis of LN has yet to be fully elucidated; it is assumed that innate and adaptive immunity abnormalities are associated with chronic systemic inflammation.[2] novel biologics targeting B or T cells have. 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. Our mAb recognizes the C-terminal sequence of the HMGB1 molecule and can neutralize the intercellular adhesion molecule 1 (ICAM1)-inducing activity of HMGB1 in vitro;[19] therapeutic effects against brain stroke, atherosclerosis, and viral infections have been reported.[19,20,21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Molecular Therapy - Methods & Clinical Development
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
