Doshi Bhavya S, Raffini Leslie J, George Lindsey A
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
J Thromb Haemost. 2020 Apr;18(4):848-852. doi: 10.1111/jth.14740. Epub 2020 Mar 2.
Hemophilia A (HA) inhibitor patients that fail traditional immune tolerance induction (ITI) have increased morbidity and mortality. Preclinical studies support factor VIII (FVIII) tolerance induction with a combined approach of anti-CD20 mediated transient B cell depletion and rapamycin mediated regulatory T cell (Treg) induction.
Two refractory HA inhibitor patients were treated with rituximab, rapamycin, and FVIII ITI. Their clinical course, anti-FVIII immunoglobulins, cytokines, and select lymphocytes were followed.
One patient achieved complete and the other partial FVIII tolerance; both had marked annualized bleeding rate improvement. FVIII-specific immunoglobulins, but not total Treg counts, correlated with tolerance induction. IL-6 and IL-21 correlation with complete tolerance induction may support that down-regulation of T effectors and IgG4 production, respectively, contribute to the pathogenesis of tolerance induction.
This regimen may be considered to induce FVIII tolerance in HA patients with refractory inhibitors. Further characterization of the FVIII-specific immune response is necessary to clarify the mechanism of immune tolerance.
对传统免疫耐受诱导（ITI）治疗失败的甲型血友病（HA）抑制剂患者，其发病率和死亡率均有所增加。临床前研究支持采用抗CD20介导的短暂性B细胞清除与雷帕霉素介导的调节性T细胞（Treg）诱导相结合的方法来诱导因子VIII（FVIII）耐受。
两名难治性HA抑制剂患者接受了利妥昔单抗、雷帕霉素和FVIII ITI治疗。对他们的临床病程、抗FVIII免疫球蛋白、细胞因子和特定淋巴细胞进行了跟踪观察。
一名患者实现了完全FVIII耐受，另一名患者实现了部分FVIII耐受；两人的年化出血率均有显著改善。FVIII特异性免疫球蛋白而非总Treg计数与耐受诱导相关。IL-6和IL-21与完全耐受诱导的相关性可能支持T效应细胞的下调和IgG4的产生分别有助于耐受诱导的发病机制。
对于患有难治性抑制剂的HA患者，可考虑采用该方案诱导FVIII耐受。有必要进一步明确FVIII特异性免疫反应，以阐明免疫耐受的机制。
