Parvathaneni Kalpana, Abdeladhim Maha, Pratt Kathleen P, Scott David W
Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, Md.
Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, Md.
Transl Res. 2017 Sep;187:44-52. doi: 10.1016/j.trsl.2017.06.002. Epub 2017 Jun 9.
Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat this antidrug antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and could potentially cause general immunosuppression. Novel approaches to induce tolerance to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize, or kill FVIII-specific lymphocytes. In this review, we discuss the current state of engineered T-cell therapies, and we describe the recent progress in applying these therapies to induce FVIII-specific tolerance.
甲型血友病是一种出血性疾病，由编码凝血因子VIII（FVIII）的基因突变引起，FVIII是一种对正常血液凝固至关重要的辅助蛋白。大约三分之一的重度甲型血友病患者会产生中和抗体（抑制剂），这些抗体在凝血级联反应中会阻断其生物学功能。目前消除抑制剂的方法包括在所谓的“免疫耐受诱导”（ITI）方案下反复注射FVIII。然而，这种方法极其昂贵，并且接受ITI治疗的患者中约有30%未实现外周耐受。人类调节性T细胞（Tregs）已被提议作为治疗这种抗药物抗体反应以及其他疾病的一种新策略。多克隆Tregs是非特异性的，可能会导致全身免疫抑制。诱导对FVIII耐受的新方法包括使用工程化的人和小鼠抗原特异性Tregs，或者使用抗原特异性细胞毒性细胞来清除、使失能或杀死FVIII特异性淋巴细胞。在这篇综述中，我们讨论了工程化T细胞疗法的现状，并描述了将这些疗法应用于诱导FVIII特异性耐受的最新进展。
