Division of Blood Diseases and Resources, National Heart Lung and Blood Institute, Bethesda, MD 20892, USA.
J Thromb Haemost. 2011 Jul;9 Suppl 1:216-25. doi: 10.1111/j.1538-7836.2011.04349.x.
Given the inhibitor-associated morbidity resulting from limited effective treatment options, antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). First reported over 30 years ago, much of our current knowledge about ITI in haemophilia A and B was derived from small cohort studies and retrospective national and international ITI registries. More recently, prospective randomised ITI trials have been designed and initiated to answer outstanding questions related to the optimisation of current therapeutic strategy in haemophilia A. However, due to the low incidence of inhibitor development in haemophilia B compared to haemophilia A, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of FIX inhibitors. The lack of an effective strategy is particularly problematic given the even greater morbidity associated with the almost unique occurrence of allergic and anaphylactic reactions that often herald FIX antibody development, and further complicates attempts to eradicate FIX inhibitors. Ultimately, successful inhibitor prevention and eradication strategies for both diseases will emerge from the clinical translation of our evolving knowledge of immune stimulation and tolerance. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; it will also review the current consensus recommendations for ITI, as well as the emerging scientific body of immunological knowledge that may significantly impact the therapeutic and preventative strategies of the future.
鉴于抑制物相关疾病的发生，且有效治疗选择有限，抗体清除是抑制物管理的最终目标。实现因子 VIII 抗原特异性耐受的唯一临床验证策略是免疫耐受诱导（ITI）。ITI 最初于 30 多年前报道，目前我们关于血友病 A 和 B 中 ITI 的大部分知识都源自小队列研究和回顾性国家和国际 ITI 登记处。最近，为回答与血友病 A 中当前治疗策略优化相关的未决问题，专门设计并启动了前瞻性随机 ITI 试验。然而，由于与血友病 A 相比，血友病 B 中抑制物的发生率较低，因此很少有可比数据可用于制定预防和消除 FIX 抑制剂的有用循证方法。由于与 FIX 抗体发展相关的独特过敏和过敏反应的发生率更高，缺乏有效策略的问题尤其严重，这进一步使消除 FIX 抑制剂的尝试复杂化。最终，这两种疾病的成功抑制物预防和消除策略将从我们对免疫刺激和耐受的不断发展的知识的临床转化中产生。本文将讨论我们目前对血友病 A 和 B 的免疫耐受结果和结果预测因子的理解；它还将回顾 ITI 的当前共识建议，以及可能对未来治疗和预防策略产生重大影响的新兴免疫学知识体系。
