Biomedical Engineering Center, Toin University of Yokohama, 1614 Kurogane-cho, Aoba-ku, Yokohama 225-8502, Japan.
Arthritis Res Ther. 2011;13(5):R149. doi: 10.1186/ar3463. Epub 2011 Sep 14.
Binding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies.
Rheumatoid arthritis synovial membrane (RASM) was engrafted into SCID mice. Following successful engraftment, mice were intravenously injected with BiP or human serum albumin in the presence or absence of anti-IL-10 mAb. Twelve days later the grafts were removed for analysis and human cytokines in the sera were quantified by ELISA. The extent of residual inflammatory cellular infiltrate in the synovial explants was determined by weight of the explants.
The RASM transplants from mice treated with BiP showed visual reduction in cellular infiltrate and downregulation of all quantifiable features of inflammation as assessed by the Koizumi or Rooney histological criteria. Also downregulated were HLA-DR, CD86, IL-6 and TNFα expression as assessed by immunohistology. ELISA detected significantly less human IL-6 circulating in the BiP-treated mouse serum. After removal of transplanted tissue 12 days post administration of BiP, the RASM explants from the BiP-treated SCID mice weighed significantly less, indicating a suppression of tissue inflammation. Mice given concomitant neutralising anti-IL-10 antibody and BiP showed no such suppression.
BiP has anti-inflammatory properties partially dependent on the downregulation of HLA-DR and co-stimulatory molecules and the predominant production of IL-10.
结合免疫球蛋白蛋白（BiP）在胶原诱导性关节炎（CIA）模型中表现出强大的抗炎特性，单次给予 BiP 被证明具有长期预防和治疗作用。在 CIA 和人类体外研究中，BiP 诱导调节性 T 细胞。本研究观察了 BiP 对炎性人滑膜组织移植到严重联合免疫缺陷小鼠（SCID）中的抗炎作用，SCID 是一种先前用于测试生物治疗疗效的嵌合体内模型。
将类风湿关节炎滑膜（RASM）移植到 SCID 小鼠中。成功移植后，在存在或不存在抗 IL-10 mAb 的情况下，通过静脉注射 BiP 或人血清白蛋白。12 天后，取出移植物进行分析，并通过 ELISA 定量血清中人细胞因子。通过称重滑膜外植体来确定滑膜外植体中残留炎症细胞浸润的程度。
用 BiP 处理的小鼠的 RASM 移植物显示出细胞浸润明显减少，并且根据 Koizumi 或 Rooney 组织学标准评估的所有可量化炎症特征下调。通过免疫组织化学评估，HLA-DR、CD86、IL-6 和 TNFα 的表达也下调。ELISA 检测到在 BiP 处理的小鼠血清中循环的人 IL-6 明显减少。在给予 BiP 后 12 天去除移植组织后，BiP 处理的 SCID 小鼠的 RASM 外植体重量明显减轻，表明组织炎症受到抑制。同时给予中和抗 IL-10 抗体和 BiP 的小鼠则没有观察到这种抑制作用。
BiP 具有抗炎特性，部分依赖于 HLA-DR 和共刺激分子的下调以及 IL-10 的主要产生。
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