Targeted silencing of DNA‐specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus‐prone mice
Targeted silencing of DNA‐specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus‐prone mice
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DNA 特异性 B 细胞的靶向沉默与部分浆细胞去除相结合，对延缓狼疮易感小鼠的疾病发作显示出附加效果
DOI：
10.1111/cei.12164
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发表时间：
2013
影响因子：
4.6
通讯作者：
Vassilev
中科院分区：
文献类型：
--
作者：
Nikolova-Ganeva;Gesheva;Todorov;Vassilev
针对自身反应性 B 淋巴细胞分化的任何阶段都可以产生治疗自身免疫的可行治疗策略。目前使用的所有药物，包括最近推出的生物制剂，都缺乏靶点特异性。先前已经通过给予嵌合抗体分子来选择性沉默患有自发性狼疮的动物中的双链 DNA 特异性 B 细胞，该抗体分子将 DNA 反应性 B 细胞免疫球蛋白受体与抑制性 FcγIIb (CD32) 受体交联。然而，长寿命的浆细胞对这种嵌合抗体以及所有常规治疗都有抵抗力。硼替佐米（一种蛋白酶体抑制剂）会消耗大多数浆细胞，最近已被证明可以抑制狼疮小鼠的疾病活动。我们假设，联合使用无毒剂量的硼替佐米（部分清除长寿命浆细胞）和选择性沉默 DNA 特异性 B 细胞的药物，应该对自身抗体介导的疾病产生附加作用。事实上，我们的数据表明，用次优剂量的硼替佐米加嵌合抗体同时治疗易患狼疮的MRL/l小鼠可预防或延迟疾病表现的出现，并延长生存期。联合疗法的效果明显强于各自的单一疗法，并且与环磷酰胺给药后观察到的效果相当。
Targeting autoreactive B lymphocytes at any stage of their differentiation could yield viable therapeutic strategies for treating autoimmunity. All currently used drugs, including the most recently introduced biological agents, lack target specificity. Selective silencing of double-stranded DNA-specific B cells in animals with spontaneous lupus has been achieved previously by the administration of a chimeric antibody molecule that cross-links their DNA-reactive B cell immunoglobulin receptors with inhibitory FcγIIb (CD32) receptors. However, long-lived plasmacytes are resistant to this chimeric antibody as well as to all conventional treatments. Bortezomib (a proteasome inhibitor) depletes most plasma cells and has been shown recently to suppress disease activity in lupus mice. We hypothesized that the co-administration of non-toxic doses of bortezomib, that partially purge long-lived plasma cells, together with an agent that selectively silences DNA-specific B cells, should have additive effects in an autoantibody-mediated disease. Indeed, our data show that the simultaneous treatment of lupus-prone MRL/lprmice with suboptimal doses of bortezomib plus the chimeric antibody resulted in the prevention or the delayed appearance of the disease manifestations as well as in a prolonged survival. The effect of the combination therapy was significantly stronger than that of the respective monotherapies and was comparable to that observed after cyclophosphamide administration.
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