Immune deviation by mucosal antigen administration suppresses gene-transfer-induced inhibitor formation to factor IX
Immune deviation by mucosal antigen administration suppresses gene-transfer-induced inhibitor formation to factor IX
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DOI：
10.1182/blood-2005-11-4668
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发表时间：
2006-07-15
期刊：
影响因子：
20.3
通讯作者：
Herzog, Roland W.
中科院分区：
文献类型：
--
作者：
Cao, Ou;Armstrong, Elina;Herzog, Roland W.
抑制性抗体的形成是血友病、先天性X连锁出血性疾病的蛋白质或基因替代疗法的严重并发症。在血友病B（凝血因子IX [F.IX]缺乏）中，缺乏内源性F.IX抗原表达和其他遗传因素可能会增加功能性F. IX抗体形成的风险。在此，我们开发了一种通过在血友病B小鼠中预先粘膜（鼻内）给予代表人F. IX特异性CD 4（+）T细胞表位的肽来减少基因治疗中抑制剂形成的方案。在用腺相关病毒载体进行肝基因转移后，具有F.IX基因缺失的C3 H/HeJ小鼠产生针对人F.IX的抑制性IgG。这些动物随后丧失了全身F.IX表达。相反，反复鼻内给药的特定肽导致抑制剂形成减少，持续循环F.IX水平，并持续部分纠正凝血肝基因转移后。这是通过免疫偏离T辅助细胞应答，增加IL-10和TGF-β的产生以及调节性CD 4（+）CD 25（+）T细胞的激活来实现的。
Formation of inhibitory antibodies is a serious complication of protein or gene replacement therapy for hemophilias, congenital X-linked bleeding disorders. In hemophilia B (coagulation factor IX [F.IX] deficiency), lack of endogenous F.IX antigen expression and other genetic factors may increase the risk of antibody formation to functional F.IX. Here, we developed a protocol for reducing inhibitor formation in gene therapy by prior mucosal (intranasal) administration of a peptide representing a human F.IX-specific CD4(+) T-cell epitope in hemophilia B mice. C3H/HeJ mice with a F.IX gene deletion produced inhibitory IgG to human F.IX after hepatic gene transfer with an adeno-associated viral vector. These animals subsequently lost systemic F.IX expression. In contrast, repeated intranasal administration of the specific peptide resulted in reduced inhibitor formation, sustained circulating F.IX levels, and sustained partial correction of coagulation following hepatic gene transfer. This was achieved through immune deviation to a T-helper-cell response with increased IL-10 and TGF-beta production and activation of regulatory CD4(+)CD25(+) T cells.