Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Haemophilia. 2021 Feb;27 Suppl 3:28-36. doi: 10.1111/hae.14077. Epub 2020 Jun 30.
The development of inhibitory antibodies to therapeutic factor VIII (FVIII) in haemophilia A (HA) patients is the major complication in treatment/prevention of haemorrhages. The reasons some HA patients develop inhibitors while others do not remain unclear. This review briefly summarizes our understanding of anti-FVIII immune responses, the roles of T cells, both effector and regulatory, and generally discusses the interplay between FVIII and the immune system, both in factor replacement therapy and gene therapy, with some comparisons to factor IX and haemophilia B therapies. Notably, we propose that the prevailing observed active tolerance to FVIII in both HA and non-HA individuals rests to greater or lesser extents on peripherally induced immune tolerance. We also propose that the immune systems of inhibitor-negative HA patients do not merely ignore therapeutic FVIII, but rather have immunologically assessed and actively tolerized the patients to exogenous FVIII. Induction of such peripheral immune tolerance may further be triggered in HA patients who failed to tolerize upon initial FVIII exposure by 'appropriate' stimulation of their immune system, eg by immune tolerance induction therapy via intensive FVIII therapy, by oral administration of FVIII, by cellular therapies or by gene therapy directed to immuno-tolerogenic sites such as the liver.
抑制性抗体的发展治疗因子 VIII (FVIII) 在血友病 A (HA) 患者是治疗/预防出血的主要并发症。一些 HA 患者产生抑制剂而另一些则没有的原因尚不清楚。这篇综述简要总结了我们对 FVIII 免疫反应、T 细胞的作用（包括效应和调节）的理解，并通常讨论了 FVIII 和免疫系统之间的相互作用，包括在因子替代治疗和基因治疗中的相互作用，并与因子 IX 和血友病 B 治疗进行了一些比较。值得注意的是，我们提出，在 HA 和非 HA 个体中，对 FVIII 的普遍观察到的主动耐受在不同程度上依赖于外周诱导的免疫耐受。我们还提出，抑制剂阴性 HA 患者的免疫系统并非仅仅忽视治疗性 FVIII，而是对其进行了免疫评估，并积极耐受了外源性 FVIII。在 HA 患者中，通过“适当”刺激其免疫系统，如通过密集的 FVIII 治疗、口服 FVIII、细胞治疗或基因治疗到免疫耐受部位（如肝脏），可能进一步触发这种外周免疫耐受的诱导，这些患者在初次接触 FVIII 时未能耐受。
