Intrathymic implants of genetically modified fibroblasts

Area of Science:

• Somatic gene therapy
• Immunology
• Biotechnology

Background:

• Genetically modified fibroblasts can deliver new gene products.
• Novel gene products often elicit intense antibody responses, limiting therapy effectiveness.
• The thymus is considered an immunologically privileged site that can induce tolerance.

Purpose of the Study:

• To explore inducing tolerance to a foreign gene product (human growth hormone) using genetically modified fibroblasts.
• To investigate the thymus's potential to induce donor-specific tolerance to transplanted tissues and gene products.

Main Methods:

• Implantation of allogeneic fibroblasts transfected with the human growth hormone gene into rat thymus and intraperitoneally.
• Detection of human growth hormone levels in serum.
• Measurement of anti-human growth hormone antibody titers.
• Challenge with purified human growth hormone.
• Treatment with cyclosporine A in some groups.

Main Results:

• Human growth hormone was detected in serum regardless of implantation site.
• High antibody titers against human growth hormone developed within 2-3 weeks in all groups.
• Thymic implantation did not prevent antibody response upon subsequent challenge.
• Cyclosporine A treatment prevented significant antibody responses, even after challenge.

Conclusions:

• Implantation of genetically modified fibroblasts into the thymus does not induce tolerance to soluble novel gene products.
• The thymus did not provide immune protection against the foreign antigen in this context.
• Cyclosporine A offers a potential strategy to mitigate immune responses in gene therapy.