van Helden Pauline M W, van den Berg H Marijke, Gouw Samantha C, Kaijen Paul H P, Zuurveld Marleen G, Mauser-Bunschoten Evelien P, Aalberse Rob C, Vidarsson Gestur, Voorberg Jan
Department of Plasma Proteins, Van Creveld Laboratorium and Landsteiner Laboratorium of the AMC at Sanquin Research, Amsterdam, The Netherlands.
Br J Haematol. 2008 Aug;142(4):644-52. doi: 10.1111/j.1365-2141.2008.07232.x. Epub 2008 May 28.
The eradication of inhibitory antibodies in patients with haemophilia A can be accomplished by frequent administration of high or intermediate doses of factor VIII (FVIII), so-called immune tolerance induction (ITI). This study monitored the distribution of IgG subclasses of anti-FVIII antibodies during ITI. FVIII-specific antibodies of subclass IgG1 were detected in all inhibitor patients tested, anti-FVIII IgG4 in 16, IgG2 in 10 and IgG3 in one of 20 patients analysed. Levels of anti-FVIII IgG1 and IgG4 correlated well with inhibitor titres as measured by Bethesda assay. In low-titre inhibitor patients, anti-FVIII antibodies consisted primarily of subclass IgG1 whereas, anti-FVIII antibodies of subclass IgG4 were more prominent in patients with high titre inhibitors who needed prolonged treatment or who failed ITI. Longitudinal analysis of 14 patients undergoing ITI revealed that the relative contribution of IgG subclasses was constant for most of the patients analysed. In two patients, the relative contribution of IgG4 increased during ITI. Overall, our findings document the distribution and dynamics of anti-FVIII IgG subclasses during ITI. Future studies will need to address whether monitoring the relative contribution of anti-FVIII subclasses IgG1 and IgG4 may be useful for the identification of patients who are at risk of failing ITI.
通过频繁给予高剂量或中等剂量的凝血因子VIII（FVIII），即所谓的免疫耐受诱导（ITI），可以消除A型血友病患者体内的抑制性抗体。本研究监测了ITI过程中抗FVIII抗体的IgG亚类分布。在所有接受检测的抑制物患者中均检测到了IgG1亚类的FVIII特异性抗体，在20例接受分析的患者中，有16例检测到抗FVIII IgG4，10例检测到IgG2，1例检测到IgG3。抗FVIII IgG1和IgG4的水平与通过贝塞斯达检测法测得的抑制物滴度密切相关。在低滴度抑制物患者中，抗FVIII抗体主要由IgG1亚类组成，而在需要长期治疗或ITI失败的高滴度抑制物患者中，IgG4亚类的抗FVIII抗体更为突出。对14例接受ITI的患者进行的纵向分析显示，对于大多数接受分析的患者而言，IgG亚类的相对贡献是恒定的。在2例患者中，IgG4的相对贡献在ITI期间有所增加。总体而言，我们的研究结果记录了ITI过程中抗FVIII IgG亚类的分布和动态变化。未来的研究需要探讨监测抗FVIII亚类IgG1和IgG4的相对贡献是否有助于识别有ITI失败风险的患者。
