Bennett V J, Chang P L
Department of Pediatrics, McMaster University, Ontario, Canada.
Mol Biol Med. 1990 Dec;7(6):471-7.
We have recently demonstrated the feasibility of genetically modifying autologous primary rat fibroblasts to deliver in vivo a foreign gene product, human growth hormone. However, in this model for gene replacement therapy, all recipient animals developed extremely high titres of antibodies against human growth hormone within two weeks of grafting. We now report on two approaches to suppress this immune-response. First, rats implanted with human growth hormone-secreting rat fibroblasts were treated with an immunosuppressant, cyclosporine A, at 20 mg/kg body weight per day. The production of anti-human growth hormone antibodies in the treated animals was completely blocked during the 12-week course of treatment. Secondly, by using immunologically immature neonatal rats as recipients, the rapid antibody response to the human growth hormone was also avoided. However, after a delay of one month, these rats also developed an extremely high titre of antibodies against the human growth hormone. In comparison, rats in the adolescent, mature and aged groups developed and maintained high titres of antibodies soon after implantation. Therefore, antigenic response against novel gene products can be suppressed either totally by cyclosporine A or temporarily in neonatal animals. The combination of early implantation and subsequent immuno-suppression should be considered in somatic gene therapy for those patients who are negative for cross-reacting-material and may be expected to mount an antigenic response to the replacement gene product.
我们最近已经证明了对自体原代大鼠成纤维细胞进行基因改造以在体内递送外源基因产物——人生长激素的可行性。然而，在这个基因替代治疗模型中，所有受体动物在移植后两周内都产生了极高滴度的抗人生长激素抗体。我们现在报告两种抑制这种免疫反应的方法。首先，给植入分泌人生长激素的大鼠成纤维细胞的大鼠每天按20毫克/千克体重的剂量用免疫抑制剂环孢素A进行治疗。在12周的治疗过程中，治疗动物体内抗人生长激素抗体的产生被完全阻断。其次，通过使用免疫未成熟的新生大鼠作为受体，也避免了对人生长激素的快速抗体反应。然而，延迟一个月后，这些大鼠也产生了极高滴度的抗人生长激素抗体。相比之下，青春期、成年和老年组的大鼠在植入后很快就产生并维持了高滴度的抗体。因此，针对新基因产物的抗原反应可以通过环孢素A完全抑制，或者在新生动物中暂时抑制。对于那些交叉反应物质呈阴性且可能对替代基因产物产生抗原反应的患者，在体细胞基因治疗中应考虑早期植入和随后的免疫抑制相结合的方法。
