A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys
A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys
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DOI：
10.2353/ajpath.2006.050600
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发表时间：
2006-02-01
影响因子：
6
通讯作者：
Danilenko, DM
中科院分区：
文献类型：
--
作者：
Vugmeyster, Y;Seshasayee, D;Danilenko, DM
BAFF（也称为BLyS）是肿瘤坏死因子超家族的成员，在B细胞的成熟和发育中起关键作用。BAFF在B细胞上有三种受体，其中最关键的是BR 3。在这项研究中，我们证明了BAFF阻断食蟹猴使用可溶性融合蛋白组成的人BR 3和人IgG 1 Fc的生物学结果。在体外，BR 3-Fc阻断BAFF介导的食蟹猴B细胞存活和增殖。食蟹猴每周接受BR 3-Fc治疗13 - 18周，导致外周血和淋巴器官中的B细胞显著减少。淋巴组织中的CD 21（高）B细胞（类似于人边缘区B细胞的亚群）表达的BR 3水平几乎是CD 21（中）B细胞的两倍。类肉瘤组织流式细胞术分析显示，BR 3-Fc减少该CD 21 high B细胞亚群的程度大于其减少CD 21（med）B细胞的程度。双标记免疫组织化学和形态测量图像分析通过证明BR 3-Fc减少了脾内边缘区和外边缘区中B细胞的显著比例来支持这些结果。这些发现应该证明在指导BR 3-Fc在临床上用于自身免疫性疾病的期望治疗用途方面非常有用。
BAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21(high) B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21(med) B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21high B-cell subset to a greater extent than it reduced CD21(med) B cells. Dual-label inummohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic.