Local Production of the p40 Subunit of Interleukin 12 Suppresses T-Helper 1-Mediated Immune Responses and Prevents Allogeneic Myoblast Rejection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 17; pp. 9085 - 9089
• Main Authors: Kato, Kazunori, Shimozato, Osamu, Hoshi, Kenichi, Wakimoto, Hiroaki, Hamada, Hirofumi, Yagita, Hideo, Okumura, Ko
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 20.08.1996; National Acad Sciences; National Academy of Sciences
• Subjects: AIDS/HIV; Animals; Antibodies; Cell lines; Cytokines; Cytokines - biosynthesis; Graft rejection; Graft Rejection - prevention & control; Graft Survival; Hematopoietic Stem Cell Transplantation; Hypersensitivity, Delayed; Immunoglobulin Isotypes; Immunosuppression - methods; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Mice; Mice, Inbred C57BL; Myoblasts; Recombinant Proteins - biosynthesis; Splenocytes; T lymphocytes; T-Lymphocytes, Cytotoxic; Th1 Cells - immunology; Transfection; Transplantation; Transplantation, Homologous; Washing
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.17.9085

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 effect of IL-12p40 in vivo. A murine myoblast cell line, C2C12, was transduced 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 γ (IFN-γ ) production by splenocytes in vitro. Survival of C2C12 transplanted into allogeneic recipients was substantially prolonged when transduced with IL-12p40. Cytokine (IL-2 and IFN-γ ) production and cytotoxic T lymphocyte induction against allogeneic C2C12 were impaired in the recipients transplanted with the IL-12p40 transfectant. Delayed-type hypersensitivity response against C2C12 was also diminished in the IL-12p40 recipients. Furthermore, serum antibodies against β -galactosidase of the T-helper 1-dependent isotypes (IgG2 and IgG3) were decreased in the IL-12p40 recipients. These results indicate that locally produced IL-12p40 exerts a potent immunosuppressive effect on T-helper 1-mediated immune responses that lead to allograft rejection. Therefore, IL-12p40 gene transduction would be useful for preventing the rejection of allografts and genetically modified own cells that are transduced with potentially antigenic molecules in gene therapy.