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 effect of IL-12p40 in vivo. A murine myoblast cell line, C2C12, was transduced with retro-virus 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 splenocytes 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 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 beta-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.
Kato
K
K
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Shimozato
O
O
Hoshi
K
K
Wakimoto
H
H
Hamada
H
H
Yagita
H
H
Okumura
K
K
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006968:Hypersensitivity, Delayed; D007132:Immunoglobulin Isotypes; D007165:Immunosuppression Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic; D018417:Th1 Cells / Q000276:immunology*; D014162:Transfection; D014184:Transplantation, Homologous
D016207:Cytokines; D007132:Immunoglobulin Isotypes; D011994:Recombinant Proteins; D018664:Interleukin-12