Anti-CD11b antibody treatment suppresses the osteoclast generation, inflammatory cell infiltration, and autoantibody production in arthritis-prone FcγRIIB-deficient mice.
Anti-CD11b antibody treatment suppresses the osteoclast generation, inflammatory cell infiltration, and autoantibody production in arthritis-prone FcγRIIB-deficient mice.
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DOI：
10.1186/s13075-018-1523-1
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发表时间：
2018-02-08
影响因子：
4.9
通讯作者：
Hirose S
中科院分区：
文献类型：
--
作者：
Ohtsuji M;Lin Q;Okazaki H;Takahashi K;Amano H;Yagita H;Nishimura H;Hirose S
此前，我们建立了一种易患关节炎的FcγRIIB缺陷小鼠品系(命名为KO1)。据报道，抗鼠CD11b单抗(5C6)可抑制外周血中CD11b+粒单核细胞向炎症部位的募集。这些细胞包括中性粒细胞和单核细胞，这两种细胞在关节炎的发展过程中都扮演着重要的角色。在这里，我们用5C6单抗治疗KO1小鼠，以研究其对关节炎形成的影响。为评价5C6的防病效果，将4月龄临床前KO1小鼠随机分为3组，第1组用5C6治疗6个月，第2组用正常大鼠免疫球蛋白治疗6个月，第3组不治疗。比较了不同组别的关节炎严重程度和免疫异常，以及踝关节、脾和外周血细胞中几个重要的关节炎相关因子的转录水平。5C6治疗可改善KO1小鼠的关节炎，表现为炎症细胞浸润和破骨细胞形成减少。踝关节组织转录水平分析显示，与两对照组相比，5C6治疗组RANK、RANKL、单核细胞趋化蛋白-1、RANTES、肿瘤坏死因子α和IL-6的表达下调，同时RANKL的诱骗受体即护骨素的表达显著上调。此外，疾病的抑制与血清自身抗体水平的降低以及活化的B细胞和浆细胞频率的降低有关。经5C6处理的小鼠脾和外周血白细胞中B细胞活化/分化相关细胞因子的表达水平受到抑制。有趣的是，尽管未经处理的KO1小鼠自发地出现明显的单核细胞增多症，但经5C6处理的小鼠的单核细胞频率显著下调。5C6治疗的结果是复杂的，其中5C6介导的疾病预防作用可能一方面是由于减少了炎症细胞和破骨细胞前体单核细胞从周围到关节的募集，另一方面是通过抑制B细胞刺激细胞因子的产生而抑制了B细胞的激活/成熟和自身抗体的产生。这些细胞因子水平较低可能是单核细胞频率较低的次要影响，因为单核/巨噬细胞是这些细胞因子的主要产生细胞。
Previously we established an arthritis-prone FcγRIIB-deficient mouse strain (designated KO1). Anti-mouse CD11b mAb (5C6) has been reported to inhibit the recruitment of peripheral CD11b+ myelomonocytic cells from the blood to the inflammatory site. These cells include neutrophils and monocytes, both of which play important roles in the development of arthritis. Here we treated KO1 mice with 5C6 mAb in order to study its effect on arthritis development. To evaluate the disease-preventive effect of 5C6, 4-month-old preclinical KO1 mice were divided into three groups: the first treated with 5C6 for 6 months, the second treated with normal rat IgG for 6 months, as a control, and the third left untreated. Arthritis severity and immunological abnormalities were compared among the groups, along with transcriptional levels of several important arthritis-related factors in ankle joints, spleen, and peripheral blood cells. The 5C6 treatment ameliorated arthritis in KO1 mice, showing decreases in inflammatory cell infiltration and osteoclast formation. Analysis of transcriptional levels in ankle joints revealed that compared with the two control groups, the 5C6-treated group showed downregulated expression of RANK, RANKL, MCP-1, RANTES, TNFα, and IL-6, and at the same time showed significantly up-regulated expression of the decoy receptor for RANKL, i.e. osteoprotegerin. In addition, the disease suppression was associated with the lower serum levels of autoantibodies, and the decreased frequencies of activated B cells and plasma cells. The expression levels of B cell activation/differentiation-related cytokines were suppressed in spleen and peripheral leukocytes of the 5C6-treated mice. Intriguingly, while untreated KO1 mice spontaneously developed marked monocytosis, the 5C6-treated mice showed the significantly down-regulated frequency of monocytes. The outcome of 5C6 treatment was complex, in which the 5C6-mediated disease-preventive effect is likely due on one hand to the decrease in the recruitment of inflammatory cells and osteoclast precursor monocytes from the periphery into the joints, and on the other hand to the suppression of B cell activation/maturation and of autoantibody production via the suppression of B cell stimulating cytokine production. The lower levels of these cytokines may be the secondary effect of the lower frequency of monocytes, since monocytes/macrophages are the major producers of these cytokines.
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DOI：
10.1084/jem.20061775
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sato K;Suematsu A;Okamoto K;Yamaguchi A;Morishita Y;Kadono Y;Tanaka S;Kodama T;Akira S;Iwakura Y;Cua DJ;Takayanagi H
通讯作者：
Takayanagi H
DOI：
10.1073/pnas.1301001110
发表时间：
2013-06-25
影响因子：
11.1
作者：
Seeling, Michaela;Hillenhoff, Ulrike;Nimmerjahn, Falk
通讯作者：
Nimmerjahn, Falk
影响因子：
2.2
作者：
Abe, Yasuharu;Ohtsuji, Mareki;Hirose, Sachiko
通讯作者：
Hirose, Sachiko
影响因子：
5.5
作者：
Hashizume, M.;Hayakawa, N.;Mihara, M.
通讯作者：
Mihara, M.
影响因子：
32.4
作者：
Bolland, S;Ravetch, JV
通讯作者：
Ravetch, JV