Immunoregulation by B7 and IL-12 gene transfer.
Our recent studies using various costimulatory molecules have demonstrated that antitumor effect could be induced by B7- or B70-transduced mouse tumors. To augment antitumor effect in vivo, the combination therapy with a costimulatory gene and a cytokine, interkeukin 12 (IL-12), gene to treat metastatic mouse lung tumor was investigated. We transfected with mouse B7 and/or IL-12 into mouse lung carcinoma 3LL, and three transfectants (IL-12/3LL, B7/3LL and IL-12/B7/3LL) were generated. CTL activity induced by the inoculation of IL-12/B7/3LL was increased about 10-fold compared with parental 3LL inoculation. We then examined the therapeutic efficacy of combination with B7 and IL-12-transduced tumors. Four weeks after 3LL inoculation, lung metastasis was significantly reduced by IL-12/B7/3LL post-inoculation, indicating that potent therapeutic antitumor immunity can be induced by combination with costimulators B7 and IL-12. Recently, it was reported that p40 subunit of IL-12 appeared to be a specific inhibitor for IL-12 heterodimer in vitro. To clarify the biological functions of p40 in vivo, we generated the myoblast transfectants which produced IL-12 p40 alone. Local production of IL-12 p40 from transfectant could suppress allogenic CTL induction and Th1-type antibodies (IgG2a/2b/3) production in vivo. Furthermore, IL-12 p40 producing myoblast are less susceptible to rejection compared with parental myoblast, indicating that IL-12 p40 gene transfer may be useful therapeutically in Th1-mediated transplantation and autoimmune disorders.
Kato
K
K
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Okumura
K
K
Yagita
H
H
D000818:Animals; D000917:Antibody Formation; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D019281:Dimerization; D015316:Genetic Therapy; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification; D007167:Immunotherapy; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D046911:Macromolecular Substances; D051379:Mice; D009362:Neoplasm Metastasis; D018417:Th1 Cells / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D007074:Immunoglobulin G; D046911:Macromolecular Substances; D018664:Interleukin-12