Suppression of immunological response against a novel gene product delivered by implants of genetically modified fibroblasts.
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abstract
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.
