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.
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DOI：
10.1016/j.omtm.2017.05.006
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发表时间：
2017-09-15
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影响因子：
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通讯作者：
Wada J
中科院分区：
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作者：
Watanabe H;Watanabe KS;Liu K;Hiramatsu S;Zeggar S;Katsuyama E;Tatebe N;Akahoshi A;Takenaka F;Hanada T;Akehi M;Sasaki T;Sada KE;Matsuura E;Nishibori M;Wada J
我们评估了中和抗高迁移率族蛋白1（HMGB 1）单克隆抗体在MRL/lpr狼疮易感小鼠中的疗效。抗HMGB 1单克隆抗体（5 mg/kg体重）或类别匹配的对照免疫球蛋白G2 a（IgG 2a）每周静脉给药2次，持续4-15周。监测尿白蛋白，并在16周时进行肾脏组织学评价。在12周时通过1-（2′-脱氧-2 ′-[18 F]氟-β-D-阿拉伯呋喃糖基）胞嘧啶（[18 F]FAC）正电子发射断层扫描/计算机断层扫描（PET/CT）评价淋巴结病。治疗4周后，[18 F]FAC-PET/CT显示12周龄时颈部和腋窝淋巴结中的蓄积相似。然而，与同种型对照相比，抗HMGB 1单克隆抗体治疗15周后可充分抑制白蛋白尿的增加。补体沉积也有所改善;然而，两组之间的IgG沉积和肾脏病理评分无显著差异。抗双链DNA（dsDNA）抗体滴度和细胞因子和趋化因子水平也没有改变。虽然肾小球巨噬细胞浸润无显著差异，但抗HMGB 1单克隆抗体可显著降低中性粒细胞浸润。拮抗HMGB 1治疗抑制HMGB 1从肾细胞核的易位，并抑制中性粒细胞胞外陷阱。抗HMGB 1单克隆抗体通过抑制中性粒细胞募集和中性粒细胞胞外陷阱，对狼疮性肾炎中的蛋白尿表现出治疗潜力。
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.