Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect
Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect
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DOI：
10.1089/hum.2013.092
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发表时间：
2013-09-01
影响因子：
4.2
通讯作者：
Mendell, Jerry R.
中科院分区：
文献类型：
--
作者：
Flanigan, Kevin M.;Campbell, Katie;Mendell, Jerry R.
杜氏肌营养不良症（DMD）通常是由于DMD基因中的截短突变而发生的，所述截短突变导致肌纤维中肌营养不良蛋白蛋白的表达缺乏。正在开发的各种疗法都是针对恢复肌营养不良蛋白在肌膜下的表达，包括基因转移。在肌内腺相关病毒（AAV）介导的治疗性小肌萎缩蛋白构建体的递送试验中，我们在六名受试者中的两名中鉴定了在转基因递送之前已被引发以识别肌营养不良蛋白表位的T细胞群体的存在。由于预先存在的T细胞免疫的存在可能对恢复肌营养不良蛋白的治疗方法的成功具有显著影响，我们试图确定来自我们的肌营养不良协会诊所的DMD队列中这种免疫的患病率。在接受糖皮质激素类固醇泼尼松（n = 24）或地夫可特（n = 29）或未接受类固醇（n = 17）的DMD受试者以及正常年龄匹配的对照受试者（n = 21）中评估了肌营养不良蛋白特异性T细胞免疫。我们证明，年龄的增加与抗肌营养不良蛋白T细胞免疫存在的风险增加相关，并且与不治疗相比，使用皮质类固醇治疗可降低风险，这表明类固醇治疗部分可能通过调节T细胞反应获得一些益处。酶联免疫斑点试验检测到的肌营养不良蛋白特异性T细胞的频率较低，与泼尼松治疗的受试者，尽管相似的总体皮质类固醇暴露，这表明两种皮质类固醇的效果可能是不相同的DMD患者。T细胞靶向抗肌萎缩蛋白基因突变的上游和下游表位，并涉及CD4（+）辅助细胞和/或CD8（+）细胞毒性亚群。我们的数据证实，相当大比例的DMD患者中存在针对肌营养不良蛋白的预先存在的循环T细胞免疫，并强调在临床基因治疗试验的设计和解释中需要考虑这一点。
Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene transfer. In a trial of intramuscular adeno-associated virus (AAV)-mediated delivery of a therapeutic minidystrophin construct, we identified in two of six subjects the presence of a population of T cells that had been primed to recognize dystrophin epitopes before transgene delivery. As the presence of preexisting T cell immunity may have a significant effect on the success of therapeutic approaches for restoring dystrophin, we sought to determine the prevalence of such immunity within a DMD cohort from our Muscular Dystrophy Association clinic. Dystrophin-specific T cell immunity was evaluated in subjects with DMD who were either receiving the glucocorticoid steroid prednisone (n=24) or deflazacort (n=29), or who were not receiving steroids (n=17), as well as from normal age-matched control subjects (n=21). We demonstrate that increasing age correlates with an increased risk for the presence of anti-dystrophin T cell immunity, and that treatment with either corticosteroid decreases risk compared with no treatment, suggesting that steroid therapy in part may derive some of its benefit through modulation of T cell responses. The frequency of dystrophin-specific T cells detected by enzyme-linked immunospot assay was lower in subjects treated with deflazacort versus prednisone, despite similar overall corticosteroid exposure, suggesting that the effects of the two corticosteroids may not be identical in patients with DMD. T cells targeted epitopes upstream and downstream of the dystrophin gene mutation and involved the CD4(+) helper and/or CD8(+) cytotoxic subsets. Our data confirm the presence of preexisting circulating T cell immunity to dystrophin in a sizable proportion of patients with DMD, and emphasize the need to consider this in the design and interpretation of clinical gene therapy trials.