IMMUNOSUPPRESSION IN PROLONGING TRANSGENE EXPRESSION: CYSTIC FIBROSIS

我们测试了一种人源化的非耗竭的抗CD4抗体的假设 抗体(OKT4acdr3)可延长腺病毒介导的基因表达 在恒河猴的肺里。我们用12毫克/公斤的OKT4A静脉注射给恒河猴 每天-1天到+11天。在第0天，动物被给予5x1010 肺内注射AdCMVLacZ的PFU。一个小组继续在一个 AdCMVLacZ介导的二次基因转移方案 另一个肺。更少的炎症和更多的基因转移 抗CD4治疗的动物。二次基因转移效率不高 在任何一组都能完成。OKT4acdr3阻断T细胞活化 腺病毒和LacZ及延长的基因表达。OKT4cdr3没有 减弱B细胞的反应。可能是OKT4a专门阻止了 生成TH1响应。使用抗CD4抗体的研究 啮齿动物在幼稚的动物身上进行了实验。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 假说是低数量的记忆B细胞可以在 缺乏对CD4的依赖帮助。因为大多数患者都有 抗腺病毒抗体，我们必须辨别正确的假说 重复性基因转移有待开发。资助囊性纤维化 基金会，J.Kolls，PI，15万美元出版物无

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