LOCAL PRODUCTION OF THE P40 SUBUNIT OF INTERLEUKIN-12 SUPPRESSES T-HELPER 1-MEDIATED IMMUNE-RESPONSES AND PREVENTS ALLOGENEIC MYOBLAST REJECTION

The p40 subunit of interleukin 12 (IL-12p40) has been known to act as an IL-12 antagonist in vitro. We here describe the immunosuppressive e ffect of IL-12p40 in vivo. A murine myoblast cell line, C2C12, was tra nsduced with retrovirus vectors carrying the lacZ gene as a marker and the IL-12p40 gene, IL-12p40 secreted from the transfectant inhibited the IL-12-induced interferon gamma (IFN-gamma) production by splenocyt es in vitro. Survival of C2C12 transplanted into allogeneic recipients was substantially prolonged when transduced with IL-12p40, Cytokine ( IL-2 and IFN-gamma) production and cytotoxic T lymphocyte induction ag ainst allogeneic C2C12 were impaired in the recipients transplanted wi th the IL-12p40 transfectant. Delayed-type hypersensitivity response a gainst C2C12 was also diminished in the IL-12p40 recipients. Furthermo re, serum antibodies against beta-galactosidase of the T-helper 1-depe ndent isotypes (IgG2 and IgG3) were decreased in the IL-12p40 recipien ts, These results indicate that locally produced IL-12p40 exerts a pot ent immunosuppressive effect on T-helper 1-mediated immune responses t hat lead to allograft rejection. Therefore, IL-12p40 gene transduction would be useful for preventing the rejection of allografts and geneti cally modified own cells that are transduced with potentially antigeni c molecules in gene therapy.