Effects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity.
Effects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity.
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杜氏肌营养不良症是一种致命的遗传性疾病，其中肌营养不良蛋白缺陷的肌肉逐渐退化，肌营养不良蛋白基因转移可以提供有效的治疗。然而，宿主对抗肌萎缩蛋白的免疫应答是治疗性基因表达的障碍。了解肌营养不良蛋白诱导的宿主免疫应答将有助于发现延长重组肌营养不良蛋白在营养不良肌肉中表达的策略。在基因转移之前，我们对营养不良的mdx小鼠进行全身照射，暂时去除免疫系统; 600拉德剂量去除外周免疫细胞，通过自我重建恢复，900拉德剂量去除中央和外周免疫细胞，通过从同基因的，肌营养不良蛋白正常的供体中过继转移骨髓恢复。抗抗肌营养不良蛋白的体液反应被延迟，肌营养不良蛋白的表达被部分保存在照射，载体治疗的小鼠。未经辐照的载体处理的对照小鼠完全失去了肌营养不良蛋白的表达，具有较早的抗肌营养不良蛋白体液应答，并表现出肌纤维局部被T细胞包围。我们的结论是，抗肌萎缩蛋白基因转移诱导抗肌萎缩蛋白体液免疫和细胞介导的反应，显着减少和延迟的主机中央或外周免疫细胞的时间去除。此外，操纵中枢免疫改变了肌肉中调节性T细胞的模式。
Duchenne muscular dystrophy is a fatal, genetic disorder in which dystrophin-deficient muscle progressively degenerates, for which dystrophin gene transfer could provide effective treatment. The host immune response to dystrophin, however, is an obstacle to therapeutic gene expression. Understanding the dystrophin-induced host immune response will facilitate the discovery of strategies to prolong expression of recombinant dystrophin in dystrophic muscle. Using whole-body irradiation of the dystrophic mdx mouse before gene transfer, we temporally removed the immune system; a 600 rad dose removed peripheral immune cells, which were restored by self-reconstitution, and a 900 rad dose removed central and peripheral immune cells, which were restored by adoptive transfer of bone marrow from a syngeneic, dystrophin-normal donor. The anti-dystrophin humoral response was delayed and dystrophin expression was partially preserved in irradiated, vector-treated mice. Nonirradiated, vector-treated control mice lost muscle dystrophin expression completely, had an earlier anti-dystrophin humoral response and demonstrated muscle fibers focally surrounded with T cells. We conclude that dystrophin gene transfer induced anti-dystrophin humoral immunity and cell-mediated responses that were significantly diminished and delayed by temporal removal of the host central or peripheral immune cells. Furthermore, manipulation of central immunity altered the pattern of regulatory T cells in muscle.
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