Bone marrow transplantation in newborn rats with mucopolysaccharidosis type VI - Biochemical, pathological, and clinical findings
Bone marrow transplantation in newborn rats with mucopolysaccharidosis type VI - Biochemical, pathological, and clinical findings
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DOI：
10.1097/00007890-199705270-00003
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发表时间：
1997-05-27
期刊：
影响因子：
6.2
通讯作者：
Schuchman, EH
中科院分区：
文献类型：
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作者：
Simonardo, CM;Haskins, ME;Schuchman, EH
背景粘多糖样沉积症VI型（MPS VI）是由芳基硫酸酯酶B（AS B）活性缺陷引起的溶酶体贮积症。在这项研究中，我们评估了骨髓移植（BRIT）治疗RIBS VI和辐射对骨髓移植新生大鼠的生存和植入的影响。1 - 2日龄MPS VI大鼠在接受200、400或800 cGy照射后注射正常骨髓。接受200 cGy（n=30）单次剂量的动物中有90%在手术中存活，而400 cGy（n=23）或800 cGy（n=12）照射导致显著死亡率（分别为78%和100%）。通过测定外周白色血细胞中ASB活性和Y染色体原位杂交分析来监测植入。200-cGy组中52%的动物在BMT后移植长达8个月;在400-cGy剂量下存活的5只动物中，全部移植。相比之下，只有20%的非辐照动物在低水平下移植。在BMT后监测8个月的24只移植动物中，仅在1只（BMT动物3）中观察到临床和/或影像学改善。酶分析显示，该动物以及另外两只移植但临床未改善的动物（BMT动物1和2）网状内皮器官中的ASB活性正常或接近正常;相应地，这些器官中的糖胺聚糖水平显著降低。与临床和生化观察结果一致，与BMT动物1和2相比，BMT动物3的光镜和电镜结果更好，尽管在这些移植受体中，特别是在气管和主动脉中，储存减少是明显的，这两种组织是人类患者病理学的特征部位。这些结果表明，新生儿MPS VI患者的EMT可能会阻止这种疾病的许多病理和临床表现，但可能对骨骼异常产生非常有限和不可预测的影响。
Background. Mucopolysaccharidosis type VI (MPS VI) is the lysosomal storage disorder caused by the deficient activity of arylsulfatase B (ASB). In this study, we evaluated bone marrow transplantation (BRIT) for the treatment of RIBS VI and the effects of irradiation on the survival and engraftment of bone marrow-transplanted neonatal rats.Methods. One- to 2-day-old MPS VI rats were injected with normal bone marrow after irradiation with 200, 400, or 800 cGy. Ninety percent of the animals receiving a single dose of 200 CGy (n=30 survived the procedure, whereas irradiation with 400 cGy (n=23) or 800 cGy (n=12) resulted in significant mortality (78% and 100%, respectively). Engraftment was monitored by determining ASB activities in peripheral white blood cells and by Y chromosome in situ hybridization analysis. Fifty-two percent of the animals from the 200-cGy group engrafted for up to 8 months after BMT; among the five animals that survived the 400-cGy dose, all engrafted. In comparison, only 20% of nonirradiated animals engrafted at low levels. Of the 24 engrafted animals that were monitored for 8 months after BMT, clinical and/or radiographic improvements were noted in only one (BMT animal 3). Enzymatic analysis revealed that the ASB activities in the reticuloendothelial organs of this animal, as well as two other engrafted but clinically unimproved animals (BMT animals 1 and 2), were normal or near normal; correspondingly, the glycosaminoglycan levels in these organs were significantly reduced. Consistent with the clinical and biochemical observations, light and electron microscopic findings were more im-proved in BMT animal 3 as compared with BMT animals 1 and 2, although a reduction of storage was evident in each of these transplant recipients, particularly in the trachea and aorta, two tissues that are characteristic sites of pathology in human patients.Conclusions. These results indicate that EMT in newborn MPS VI patients may prevent many of the pathological and clinical findings in this disorder, but is likely to have very limited and unpredictable effects on the skeletal abnormalities.