INTRATHYMIC IMPLANTS OF GENETICALLY MODIFIED FIBROBLASTS

Implantation of autologous rodent fibroblasts genetically altered to express human growth hormone has recently been shown to be a feasible approach to the delivery of new gene products in,somatic gene therapy. However, the novel gene product elicited in its recipients an intense antibody response that would have curtailed the effectiveness of such therapy. The possibility of inducing tolerance to foreign gene product was explored by implanting allogeneic fibroblasts transfected with the human growth hormone gene into rat thymus, a site recently shown to be immunologically privileged and able to induce donor-specific tolerance to transplanted tissues. In the circulation of the implanted rats, human growth hormone was detected at 4-15 ng/ml serum within the first day and subsided to 0.6-9 ng/ml within the first wk in all animals implanted either thymically or intraperitoneally. Within 2-3 wk, high titers of anti-human growth hormone were detected in all animals regardless of the site of implantation. The failure of the thymus to offer immune protection for the foreign antigen was further confirmed when the animals were subsequently challenged with purified human growth hormone. An immediate twofold increase in titer within the first week of challenge was detected in animals previously implanted thymically. In contrast, animals implanted intraperitoneally but treated with short-term daily injection of cyclosporine A (28-41 days) did not mount any significant antibody response to human growth hormone throughout the experiment or even when challenged subsequently at weeks 8-10 with purified growth hormone. In conclusion, implantation of genetically modified fibroblasts in the thymus does not lead to tolerization toward soluble novel gene product secreted by these cells. However, a limited course of cyclosporine A treatment was effective for prolonged suppression of antibody response to novel gene products.