Ohtsuka Y, Udaka K, Yamashiro Y, Yagita H, Okumura K
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
J Immunol. 1998 May 1;160(9):4635-40.
Duchenne muscular dystrophy is a lethal and common X-linked recessive disease caused by a defect in dystrophin. Normal myoblast transplantation and dystrophin gene transfer have been expected to correct the deficiency in the muscles, but their clinical application has been hampered by the limited preservation of dystrophin-positive myofibers. In this study we investigated the mechanism for immunologic rejection of normal C57BL/10 (B10) myoblasts transplanted into dystrophin-deficient mdx mice, an animal model of Duchenne muscular dystrophy. We found that mdx mice develop CTL specific for dystrophin itself, which were CD8 dominant and restricted by H-2Kb. We identified several antigenic peptides derived from dystrophin that bind to H-2Kb and are recognized by the mdx anti-B10 CTL. Immunologic tolerance against dystrophin was successfully induced by i.v. injection of these peptides before B10 myoblast transplantation, which resulted in sustained preservation of dystrophin-expressing myofibers in mdx mice. These results demonstrate that dystrophin is antigenic in dystrophin-deficient mice and that immunologic regimen would be necessary to achieve the persistent expression of introduced dystrophin in the muscles of dystrophin-deficient individuals.
杜兴氏肌营养不良症是一种由肌营养不良蛋白缺陷引起的常见致死性X连锁隐性疾病。正常成肌细胞移植和肌营养不良蛋白基因转移有望纠正肌肉中的缺陷，但它们的临床应用因肌营养不良蛋白阳性肌纤维的保存有限而受到阻碍。在本研究中，我们调查了将正常C57BL/10（B10）成肌细胞移植到杜兴氏肌营养不良症动物模型——肌营养不良蛋白缺陷的mdx小鼠体内时免疫排斥的机制。我们发现mdx小鼠产生了针对肌营养不良蛋白本身的细胞毒性T淋巴细胞（CTL），这些CTL以CD8为主且受H-2Kb限制。我们鉴定了几种源自肌营养不良蛋白的抗原肽，它们与H-2Kb结合并被mdx抗B10 CTL识别。在B10成肌细胞移植前通过静脉注射这些肽成功诱导了对肌营养不良蛋白的免疫耐受，这导致mdx小鼠中持续保存表达肌营养不良蛋白的肌纤维。这些结果表明，肌营养不良蛋白在肌营养不良蛋白缺陷小鼠中具有抗原性，并且免疫方案对于在肌营养不良蛋白缺陷个体的肌肉中实现导入的肌营养不良蛋白的持续表达是必要的。
