Adair Patrick, Su Yan, Scott David W
Molecular Medicine Program, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Discov Med. 2013 May;15(84):275-82.
Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes).
甲型血友病是一种X连锁隐性出血性疾病，由于F8基因突变，导致血液凝固蛋白因子VIII（FVIII）缺乏或活性大幅降低。这给FVIII替代疗法带来了重大挑战，因为血友病患者对该蛋白没有免疫耐受性。因此，一部分接受血浆源性或重组FVIII替代疗法的患者会产生抗FVIII中和抗体，即“抑制剂”。这些患者需要长期高剂量FVIII给药方案，但其成功率各异且成本高昂。因此，需要针对此类有抑制剂的患者诱导耐受性的治疗方法。在本综述中，我们阐述了在甲型血友病动物模型中诱导FVIII特异性耐受性的免疫疗法的当前进展。具体而言，我们讨论了B细胞清除对免疫耐受性诱导（ITI）的有益作用、B细胞介导的基因治疗、抗原偶联淋巴细胞治疗以及调节性T细胞表位（Tregitopes）。
