Development of immune supression against gene product in gene therapy

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Gene therapy to treat recessive genodermatoses may provoke unwanted immune response against the introduced gene product because tolerance against this novel protein is absent in patients. In this study, using desmoglein 3 knockout (Dsg3-/-) mice as a disease model for genetic defect of DSG3, we investigated whether immune response against Dsg3 is provoked by nonviral gene therapy and whether such reaction could be prevented. When mouse Dsg3 CDNA was introduced in the skin of Dsg3-/- mice by naked DNA injection, some Dsg3-/- mice developed anti-Dsg3 IgG which bound to Dsg3 expressed by the therapy in vivo. To overcome this problem, we used anti-CD40L monoclonal antibody (MR1) to block co-stimulatory interaction between CD40-CD40L, which is important in the triggering and maintenance of immune responses. For this assay, we employed the Dsg3+/+ skin graft on Dsg3-/- mice to represent stable gene transfer of Dsg3. After skin grafting, all recipient Dsg3-/- mice were treated either with MR1 or with hamster IgG regularly. All of hamster IgG treated mice developed circulating anti-Dsg3 IgG 2-3 weeks after the skin graft. This IgG production lasted: more than 4 weeks and IgG deposition was observed on the surfaces of the keratinocytes in grafts.; However, this anti-Dsg3 IgG production was efficiently suppressed when the recipient mice were treated with MR1. These findings indicate that effective prevention of such undesirable immune response is required for a successful gene therapy for recessive genodermatoses and that the blockade of CD40-CD40L interaction may be a valuable way to achieve this prevention.