Adenovirus-mediated gene transfer in the ovine pituitary gland is associated with hypophysitis.
Adenovirus-mediated gene transfer in the ovine pituitary gland is associated with hypophysitis.
复制标题
绵羊垂体中腺病毒介导的基因转移与垂体炎有关。
作者：
Julian R. E. Davis;R. McMahon;P. Lowenstein;M. G. Castro;G. Lincoln;A. McNeilly
垂体疾病的基因治疗需要评估安全性和有效性。我们已经报道了使用绵羊作为大型动物模型的腺病毒介导的基因转移的结果，该动物模型允许对激素分泌进行纵向评价，并且已经证实了直接立体定位注射到脑垂体中后长达7天的高水平转基因表达。在这里，我们报告的结果，详细的组织学检查的垂体从动物注射两种重组腺病毒表达β-半乳糖苷酶标记基因，或与生理盐水的车辆，以控制潜在的组织破坏作用的注射量本身。注射生理盐水的脑垂体除了偶尔出现轻微的细胞凋亡灶外，没有显示出炎症反应的证据。在所有其他方面，它们与正常的未注射对照垂体腺没有区别。另一方面，用含有hCMV-β-gal或hPRL-β-gal转基因的重组腺病毒注射的腺体显示出不同程度的炎症反应，几乎所有病例都有腺周纤维化、淋巴细胞浸润和小静脉炎。在9例病例中的6例中观察到局灶性坏死和/或凋亡。总之，我们发现在腺病毒注射的前七天内有严重炎症反应的证据，相当于显著的垂体炎。这种反应的组织学程度以前没有被啮齿类动物中基因转移的功效研究所认识，并且被激素和转基因表达的免疫细胞化学研究低估。这些发现强调需要仔细评估内分泌基因治疗的安全性，并谨慎使用载体的剂量。
Gene therapy for pituitary disease requires evaluation for safety as well as efficacy. We have reported results of adenovirus-mediated gene transfer using the sheep as a large animal model that allows longitudinal evaluation of hormone secretion and have confirmed high levels of transgene expression up to 7 days after direct stereotaxic injection into the pituitary gland. Here we report the results of detailed histological examination of the pituitary glands from animals injected with two recombinant adenoviruses expressing the beta-galactosidase marker gene, or with saline vehicle to control for the potential tissue-disruptive effect of the injection volume itself. Pituitaries injected with saline showed no evidence of inflammatory response apart from occasional minor foci of apoptosis. In all other respects they were indistinguishable from normal uninjected control pituitary glands. Glands injected with recombinant adenoviruses containing either the hCMV-beta-gal or the hPRL-beta-gal transgene, on the other hand, displayed variable degrees of inflammatory response, with periglandular fibrosis, lymphocytic infiltrate and venulitis in almost all cases. Focal necrosis and/or apoptosis was noted in six of nine cases. In summary, we have found evidence of severe inflammatory reaction within the first seven days of adenovirus injection, amounting to significant hypophysitis. The histological extent of this reaction has not previously been recognised by studies of the efficacy of gene transfer in rodents, and was underestimated by immunocytochemical studies of hormone and transgene expression. The findings emphasise the need for careful evaluation of the safety of endocrine gene therapy, and for caution with the dose of vector used.
DOI：
10.1073/pnas.91.10.4407
发表时间：
1994-05-10
影响因子：
11.1
作者：
YANG, YP;NUNES, FA;WILSON, JM
通讯作者：
WILSON, JM
正常垂体促性腺激素基因转移的高效方法：腺病毒介导的 G 蛋白偶联受体激酶 2 表达抑制黄体生成素分泌。
影响因子：
4.8
作者：
Neill,JD;Musgrove,LC;Duck,LW;Sellers,JC
通讯作者：
Sellers,JC