Teaching tolerance New approaches to enzyme replacement therapy for Pompe disease
Teaching tolerance New approaches to enzyme replacement therapy for Pompe disease
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DOI：
10.4161/hv.21405
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发表时间：
2012-10-01
影响因子：
4.8
通讯作者：
De Groot, Anne S.
中科院分区：
文献类型：
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作者：
Cousens, Leslie P.;Mingozzi, Federico;De Groot, Anne S.
出生时患有庞贝病的婴儿需要用酶替代疗法(ERT)进行终身治疗。尽管这种疗法源于人类，但重组人溶酶体酸a葡萄糖苷酶(GAA，rhGAA)，ERT不幸地导致了高滴度的抗rhGAA抗体的产生，降低了ERT的有效性，并对大量患有庞贝病的儿童造成了致命的后果。疾病的严重程度、抗药抗体(ADA)的产生及其后果与酶缺乏的程度直接相关。出生时GAA完全缺乏的婴儿被认为患有交叉反应免疫物质(CRIM)阴性的庞贝病，并极有可能患上GAA ADA。少见的是，GAA ADA发生在CRIM阳性的个体中。目前，GAA-ADA血清阳性的婴儿接受联合免疫抑制药物的治疗，以诱导对ERT的免疫耐受，但这些方案的长期效果尚不清楚。需要替代的方法，可以将免疫反应重定向到抗原特异性耐受，而不需要免疫抑制剂。诱导抗原特异性调节性T细胞(Tregs)的方法，使用Tregitope(T调节细胞表位)等多肽，正在考虑用于未来Crim阴性Pompe病的治疗。T表位是源于免疫球蛋白G(Ig G)的天然T细胞表位，可导致调节性T细胞(Treg)的扩张和激活。通过与Tregitope多肽共同传递GAA来教导免疫系统耐受GAA，可能会极大地改善CRIM阴性婴儿的生命，并可应用于已诱导ADA的其他酶替代疗法。
Babies born with Pompe disease require life-long treatment with enzyme-replacement therapy (ERT). Despite the human origin of the therapy, recombinant human lysosomal acid a glucosidase (GAA, rhGAA), ERT unfortunately leads to the development of high titers of anti-rhGAA antibody, decreased effectiveness of ERT, and a fatal outcome for a significant number of children who have Pompe disease. The severity of disease, anti-drug antibody (ADA) development, and the consequences thereof are directly related to the degree of the enzyme deficiency. Babies born with a complete deficiency GAA are said to have cross-reactive immunologic material (CRIM)-negative Pompe disease and are highly likely to develop GAA ADA. Less frequently, GAA ADA develop in CRIM-positive individuals. Currently, GAA-ADA sero-positive babies are treated with a combination of immunosuppressive drugs to induce immunological tolerance to ERT, but the long-term effect of these regimens is unknown. Alternative approaches that might redirect the immune response toward antigen-specific tolerance without immunosuppressive agents are needed. Methods leading to the induction of antigen-specific regulatory T cells (Tregs), using peptides such as Tregitopes (T regulatory cell epitopes) are under consideration for the future treatment of CRIM-negative Pompe disease. Tregitopes are natural T cell epitopes derived from immunoglobulin G (IgG) that cause the expansion and activation of regulatory T cells (Treg). Teaching the immune system to tolerate GAA by co-delivering GAA with Tregitope peptides might dramatically improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced.