Kokkola R, Li J, Sundberg E, Aveberger A-C, Palmblad K, Yang H, Tracey K J, Andersson U, Harris H Erlandsson
Rheumatology Research Unit, CMM L8:04, Karolinska Hospital, Stockholm 171 76, Sweden.
Arthritis Rheum. 2003 Jul;48(7):2052-8. doi: 10.1002/art.11161.
Extracellular high mobility group box chromosomal protein 1 (HMGB-1) is a recently identified, endogenous, potent tumor necrosis factor- and interleukin-1 (IL-1)-inducing protein detectable in inflamed synovia in both human and experimental disease. In the present study, we examined clinical effects in collagen-induced arthritis (CIA) using therapeutic administration of neutralizing HMGB-1 antibodies or truncated HMGB-1-derived A-box protein, a specific, competitive antagonist of HMGB-1.
CIA was induced in DBA/1j mice or dark agouti rats, and animals were examined daily for signs of arthritis. Treatment with polyclonal anti-HMGB-1 antibodies or the A-box protein was initiated at the onset of disease and was administered intraperitoneally twice daily for 7 days. Animals were killed 8 days after initiation of therapy, and immunohistochemical analysis of synovial tissue specimens was performed.
Systemic administration of anti-HMGB-1 antibodies or A-box protein significantly reduced the mean arthritis score, the disease-induced weight loss, and the histologic severity of arthritis. Beneficial effects were observed in both mice and rats. Immunohistochemical analysis revealed pronounced synovial IL-1beta expression and articular cartilage destruction in vehicle-treated mice. Both these features were significantly less manifested in animals treated with anti-HMGB-1 antibodies or A-box protein.
Counteracting extracellular HMGB-1 with either neutralizing antibodies or a specific HMGB-1 antagonist may offer a new method for the successful treatment of arthritis. Inflammation and tissue destruction were suppressed in CIA after HMGB-1 blockade.
细胞外高迁移率族蛋白盒1（HMGB-1）是一种最近发现的内源性强效肿瘤坏死因子和白细胞介素-1（IL-1）诱导蛋白，在人类和实验性疾病的炎症滑膜中均可检测到。在本研究中，我们使用中和HMGB-1抗体或截短的HMGB-1衍生A盒蛋白（一种HMGB-1的特异性竞争性拮抗剂）进行治疗给药，研究其对胶原诱导性关节炎（CIA）的临床效果。
在DBA/1j小鼠或深色刺豚鼠中诱导CIA，每天检查动物的关节炎体征。在疾病发作时开始用多克隆抗HMGB-1抗体或A盒蛋白治疗，每天腹腔注射两次，共7天。在治疗开始8天后处死动物，对滑膜组织标本进行免疫组织化学分析。
全身给予抗HMGB-1抗体或A盒蛋白可显著降低平均关节炎评分、疾病引起的体重减轻以及关节炎的组织学严重程度。在小鼠和大鼠中均观察到有益效果。免疫组织化学分析显示，在载体处理的小鼠中滑膜IL-1β表达明显且关节软骨破坏。在用抗HMGB-1抗体或A盒蛋白处理的动物中，这两个特征均明显减轻。
用中和抗体或特异性HMGB-1拮抗剂对抗细胞外HMGB-1可能为成功治疗关节炎提供一种新方法。HMGB-1阻断后，CIA中的炎症和组织破坏得到抑制。
