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

我们检验了一个人性化的非消耗抗CD4的假设 抗体（OKT4ACDR3）将延长腺病毒介导的基因表达 在恒河肺中。 我们用12 mg/kg Okt4a IV治疗了恒河猕猴 每天在天-1至一天+11。 在第0天，为动物提供了5 x 1010 ADCMVLACZ的PFU进入肺部。 一个子组继续 次级基因转移方案通过将ADCMVLACZ施加到 其他肺。 炎症较少和基因转移更大 抗CD4治疗的动物。 次级基因转移不是有效的 在任一组中完成。 OKT4ACDR3阻止了T细胞激活 腺病毒和LACZ以及延长基因表达。 OKT4CDR3没有 减弱B细胞的响应。 OKT4A可能专门阻止了 产生Th1响应。 使用抗CD4抗体的研究 啮齿动物已经在幼稚的动物中进行。 我们所有的猴子都有 基线非中和抗腺病毒抗体。 因此，另一个 假设是，少数的内存B细胞可以在 缺乏CD4依赖的帮助。 由于大多数患者有 抗腺病毒抗体，我们必须辨别正确的假设 重复基因转移要开发。 资助囊性纤维化 基金会，J。Kolls，PI，15万美元的出版物无