化学二聚化静脉注射免疫球蛋白在小鼠免疫性血小板减少性紫癜模型中具有显著的改善作用。

Chemically dimerized intravenous immunoglobulin has potent ameliorating activity in a mouse immune thrombocytopenic purpura model.

机构信息

Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan.

出版信息

Biochem Biophys Res Commun. 2012 Feb 24;418(4):748-53. doi: 10.1016/j.bbrc.2012.01.092. Epub 2012 Jan 28.

DOI:10.1016/j.bbrc.2012.01.092

Abstract

High-dose intravenous immunoglobulin (IVIG) preparations are currently used for the treatment of autoimmune diseases such as immune thrombocytopenic purpura (ITP). Although the mechanisms of IVIG efficacy remain enigmatic, some clinical and laboratory studies suggest that interaction of the Fc domain of IgG, especially the Fc domain of dimeric IgG, with its receptors (Fc gamma receptors; FcγRs) plays an essential role. In this study, IVIG was dimerized with chemical crosslinkers to augment its therapeutic efficacy. Dimerized IVIG was found to have a much higher affinity for FcγRs than monomeric IVIG. In a mouse ITP model, chemically dimerized IVIG abrogated the decrease in platelet numbers in the blood that was caused by an anti-platelet antibody at a dose that was one tenth of the required dose of IVIG. These results suggest that chemical dimerization of IVIG should greatly improve the efficacy of IVIG therapy of ITP.

摘要

高剂量静脉注射免疫球蛋白（IVIG）制剂目前被用于治疗免疫性血小板减少症（ITP）等自身免疫性疾病。虽然 IVIG 疗效的机制仍然不清楚，但一些临床和实验室研究表明，IgG 的 Fc 结构域，特别是二聚体 IgG 的 Fc 结构域与它的受体（Fcγ 受体；FcγRs）的相互作用起着至关重要的作用。在这项研究中，用化学交联剂将 IVIG 二聚化以增强其治疗效果。结果发现，二聚化的 IVIG 与 FcγRs 的亲和力比单体 IVIG 高得多。在小鼠 ITP 模型中，化学二聚化的 IVIG 在一种抗血小板抗体导致血液中血小板数量减少的情况下，其剂量仅为 IVIG 所需剂量的十分之一，就消除了血小板数量的减少。这些结果表明，IVIG 的化学二聚化应该大大提高 IVIG 治疗 ITP 的疗效。