Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for hemophilia A
Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for hemophilia A
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DOI：
10.1073/pnas.95.10.5734
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发表时间：
1998-05-12
影响因子：
11.1
通讯作者：
Morgan, RA
中科院分区：
文献类型：
--
作者：
Evans, GL;Morgan, RA
患有严重凝血因子VIII缺乏症的患者需要频繁输注人因子VIII（hFVIII）浓缩物以治疗危及生命的疾病。因为这些患者在免疫学上是hFVIII初治的，所以显著的治疗并发症是针对hFVIII的抑制剂或循环同种抗体的发展，其结合替代的糖蛋白，增加其血浆清除率，并抑制其活性，从而阻止后续治疗具有治疗效果。诱导对hFVIII的免疫无应答的遗传方法具有长期稳定消除针对hFVIII的不期望的免疫应答的概念优势。在这里，我们报告说，在因子VIII（FVIII）缺陷的小鼠模型严重血友病Al基因修饰的供体骨髓细胞与逆转录病毒载体编码hFVIII，并移植到血友病小鼠受体，导致在50%的治疗动物免疫后，hFVIII的免疫耐受诱导，尽管事实上，hFVIII蛋白或活性是不可检测的。在耐受动物中，抗hFVIII结合抗体和hFVIII抑制剂抗体的滴度显著降低，并且有证据表明CD4（+）T细胞中hFVIII无反应性。重要的是，hFVIII的血浆清除率在耐受化动物中显著降低，并且与在FVIII未处理的血友病小鼠中观察到的没有显著差异。该模型系统将被证明可用于评估hFVIII免疫调节的遗传疗法，并使hFVIII耐受性的遗传疗法更接近血友病A患者的临床应用。
Patients with severe coagulation factor VIII deficiency require frequent infusions of human factor VIII (hFVIII) concentrates to treat life-threatening hemorrhages. Because these patients are immunologically hFVIII-naive, a significant treatment complication is the development of inhibitors or circulating alloantibodies against hFVIII, which bind the replaced glycoprotein, increase its plasma clearance, and inhibit its activity, preventing subsequent treatments from having a therapeutic effect. A genetic approach toward the induction of immunologic unresponsiveness to hFVIII has the conceptual advantage of a long-term, stable elimination of undesired immune responses against hFVIII. Here, we report that in a factor VIII (FVIII)-deficient mouse model for severe hemophilia Al genetic modification of donor bone marrow cells with a retroviral vector encoding hFVIII, and transplant to hemophiliac mouse recipients, results in the induction of immune tolerance to FVIII in 50% of treated animals after immunization with hFVIII, despite the fact that hFVIII protein or activity is undetectable. In tolerized animals, the titers of anti-hFVIII binding antibodies and of hFVIII inhibitor antibodies were significantly reduced, and there was evidence for hFVIII unresponsiveness in CD4(+) T cells. Importantly, the plasma clearance of hFVIII was significantly decreased in tolerized animals and was not significantly different from that seen in a FVIII-naive hemophiliac mouse. This model system will prove useful for the evaluation of genetic therapies for hFVIII immunomodulation and bring genetic therapies for hFVIII tolerance closer to clinical application for patients with hemophilia A.