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Administration of an IL-12-Encoding DNA Plasmid Prevents the Development of Chronic Graft-Versus-Host Disease (GVHD)

Tadanobu Okubo^1,*, Eri Hagiwara^*, Shigeru Ohno^*, Takashi Tsuji^*, Atsushi Ihata^*, Atsuhisa Ueda^*, Akira Shirai^*, Ichiro Aoki, Kenji Okuda, Jun-ichi Miyazaki^§ and Yoshiaki Ishigatsubo^*

Departments of ^* First Internal Medicine, Second Pathology, and Bacteriology, Yokohama City University School of Medicine, Yokohama, Japan; and ^§ Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka, Japan

The transfer of DBA/2 spleen cells into (C57BL/10 x DBA/2)F₁ mice induces chronic graft-vs-host disease (GVHD), which is characterized by the production of Th2 cytokines, hypergammaglobulinemia, and immune complex-mediated glomerulonephritis like systemic lupus erythematosus. IL-12 strongly induces the production of Th1 cytokines and reduces Th2 activity in vivo. In this study, the effect of gene therapy on the development of murine chronic GVHD was examined using an IL-12-encoding plasmid (pCAGGSIL-12), with the expectation that it might regulate Th1/Th2 activity and have a beneficial impact on the clinical manifestations of disease. pCAGGSIL-12 or its p40 antagonist plasmid (pCAGGSp40) were injected i.m. every 3 wk in GVHD-induced (C57BL/10 x DBA/2)F₁ mice. A total of 100 µg of pCAGGSIL-12 improved the Th1/Th2 balance in vivo, suppressed the production of IgG, and significantly reduced the development of glomerulonephritis. GVHD was exacerbated by injection of the pCAGGSp40 antagonist. Our results demonstrate that GVHD can be treated successfully by the administration of an IL-12-encoding plasmid, and that such therapy does not induce acute GVHD.

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