IMMUNOSUPPRESSION IN PROLONGING TRANSGENE EXPRESSION: CYSTIC FIBROSIS

延长转基因表达的免疫抑制：囊性纤维化

• 批准号: 6116207
• 负责人: GARY B BASKIN
• 金额: $ 16.14万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116207
• 关键词: Mammalia; gene therapy; model design /development; respiratory system

We tested the hypothesis that a humanized non-depleting anti-CD4 antibody (OKT4acdr3) would prolong adenoviral-mediated gene expression in rhesus lungs. We treated rhesus macaques with 12 mg/kg OKT4a IV daily on days -1 to day +11. On day 0, animals were given 5 x 1010 pfu of AdCMVLacZ into the lung. A subgroup was continued on a secondary gene transfer protocol by administering AdCMVLacZ into the other lung. There was less inflammation and greater gene transfer in anti-CD4 treated animals. Secondary gene transfer was not efficiently accomplished in either group. OKT4acdr3 blocked T-cell activation to adenovirus and lacZ and prolonged gene expression. OKT4cdr3 did not attenuate B-cell responses. Possibly OKT4a specifically blocked the generation of a TH1 response. Studies using anti-CD4 antibodies in rodents have been performed in naive animals. All our monkeys had baseline non-neutralizing anti-adenoviral antibodies. Thus, another hypothesis is that low numbers of memory B-cells can proliferate in the absence of CD4 dependent help. Since most patients have anti-adenoviral antibodies, we must discern the correct hypothesis for repetitive gene transfer to be developed. FUNDING Cystic Fibrosis Foundation, J. Kolls, PI, $150,000 PUBLICATIONS None

我们测试了一个假设，即人源化的非消耗性抗CD 4 抗体（OKT 4acdr 3）可延长腺病毒介导的基因表达 在恒河猴的肺里 我们用12 mg/kg OKT 4a IV处理恒河猴 第-1天至第+11天每天给药。 在第0天，给予动物5 x 1010 pfu的AdCMVLacZ进入肺。 一个亚组继续在 通过将AdCMVLacZ施用到细胞中的第二基因转移方案， 其他肺 有较少的炎症和更多的基因转移， 抗CD 4处理的动物。 二次基因转移效率不高， 在任何一组中完成。 OKT 4acdr 3阻断T细胞活化， 腺病毒和lacZ和延长的基因表达。 OKT 4cdr 3没有 减弱B细胞反应。 OKT 4a可能特异性地阻断了 产生TH 1反应。 使用抗-CD 4抗体的研究 啮齿类动物已经在幼稚动物中进行。 我们所有的猴子 基线非中和抗腺病毒抗体。 因此，另 一种假设是，在大脑中，少量的记忆B细胞可以增殖， 缺乏CD 4依赖的帮助。 由于大多数患者 抗腺病毒抗体，我们必须辨别正确的假设， 重复性基因转移有待开发。 囊性纤维化 基金会，J. Kolls，PI，$150，000 Publications无