T Cell Responses to Dystrophin in a Natural History Study of Duchenne Muscular Dystrophy.
T Cell Responses to Dystrophin in a Natural History Study of Duchenne Muscular Dystrophy.
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杜氏肌营养不良症自然史研究中 T 细胞对肌营养不良蛋白的反应。
DOI：
10.1089/hum.2022.166
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发表时间：
2023
影响因子：
4.2
通讯作者：
Anthony K
中科院分区：
文献类型：
--
作者：
Anthony K
Duchenne肌营养不良症(DMD)是由于缺乏dystrophin引起的，但许多患者都有罕见的表达dystrophin的可逆性纤维。DMD患者的骨骼肌病理包括免疫细胞浸润和炎症级联反应。有几种策略可以恢复患者骨骼肌中的肌营养不良蛋白，包括外显子跳跃和基因治疗。有一些证据表明，dystrophin的恢复会导致免疫细胞的减少，但dystrophin表位在重复性纤维中的表达，或者在腺相关病毒基因治疗后的基因组编辑、细胞治疗或微dystrophin传递之后，可能会诱导患者产生T细胞。这可能会影响治疗干预的效果，并可能导致严重的不良事件。为了证实和扩展先前的研究，我们对自然病史研究中招募的77名患有DMD的儿童进行了每年一次的酶联免疫斑点干扰素-γ检测，其中69人(89.6%)接受了皮质类固醇治疗。使用跨越整个dystrophin蛋白的总共368个肽来量化T细胞对dystrophin的反应，这些肽被组织成9个肽库。多肽图库被用来进一步定位一名阳性患者的免疫反应。6名患者(7.8%)至少在一个时间点有T细胞介导的免疫应答。所有阳性结果的患者都接受了皮质类固醇治疗，要么是强的松龙，要么是强的松。我们的结果显示，尽管接受了类固醇治疗，我们队列中8%的∼患者对Dstrophin有预先存在的T细胞介导的免疫反应。尽管这些反应水平相对较低，但在进行临床试验和未来的DMD研究之前，这些信息应该被视为有用的免疫学基线。我们进一步强调了从多个中心收集、存储和运送样品的可靠、可重复的标准操作程序的重要性，以最大限度地减少不确定数据的数量。
Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, but many patients have rare revertant fibers that express dystrophin. The skeletal muscle pathology of DMD patients includes immune cell infiltration and inflammatory cascades. There are several strategies to restore dystrophin in skeletal muscles of patients, including exon skipping and gene therapy. There is some evidence that dystrophin restoration leads to a reduction in immune cells, but dystrophin epitopes expressed in revertant fibers or following genome editing, cell therapy, or microdystrophin delivery after adeno-associated viral gene therapy may elicit T cell production in patients. This may affect the efficacy of the therapeutic intervention, and potentially lead to serious adverse events. To confirm and extend previous studies, we performed annual enzyme- linked immunospot interferon-gamma assays on peripheral blood mononuclear cells from 77 pediatric boys with DMD recruited into a natural history study, 69 of whom (89.6%) were treated with corticosteroids. T cell responses to dystrophin were quantified using a total of 368 peptides spanning the entire dystrophin protein, organized into nine peptide pools. Peptide mapping pools were used to further localize the immune response in one positive patient. Six (7.8%) patients had a T cell-mediated immune response to dystrophin at at least one time point. All patients who had a positive result had been treated with corticosteroids, either prednisolone or prednisone. Our results show that ∼8% of DMD individuals in our cohort have a pre-existing T cell-mediated immune response to dystrophin, despite steroid treatment. Although these responses are relatively low level, this information should be considered a useful immunological baseline before undertaking clinical trials and future DMD studies. We further highlight the importance for a robust, reproducible standard operating procedure for collecting, storing, and shipping samples from multiple centers to minimize the number of inconclusive data.
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影响因子：
3.7
作者：
Kourakis S;Timpani CA;Campelj DG;Hafner P;Gueven N;Fischer D;Rybalka E
通讯作者：
Rybalka E
遗传病中的自身免疫——一个警示故事。
DOI：
10.1056/nejme1009056
发表时间：
2010
期刊：
The New England journal of medicine
影响因子：
--
作者：
M. Moore;T. Flotte
通讯作者：
T. Flotte
影响因子：
10.9
作者：
Janetzki S
通讯作者：
Janetzki S
对肌营养不良蛋白的免疫反应：对杜氏肌营养不良症基因治疗的影响。
影响因子：
5.1
作者：
A. Ferrer;K. Wells;D. Wells
通讯作者：
D. Wells
DOI：
10.1056/nejmoa1000228
发表时间：
2010-10-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Mendell JR;Campbell K;Rodino-Klapac L;Sahenk Z;Shilling C;Lewis S;Bowles D;Gray S;Li C;Galloway G;Malik V;Coley B;Clark KR;Li J;Xiao X;Samulski J;McPhee SW;Samulski RJ;Walker CM
通讯作者：
Walker CM