IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice

Noboru Harada, Mitsuo Shimada, Shinji Okano, Taketoshi Suehiro, Yuji Soejima, Yukihiro Tomita, Yoshihiko Maehara

Research output: Contribution to journalArticle

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Abstract

Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2k), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 × 106 MH134 cells (H-2k) and we treated the established HCC with electroporation- mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-γ, and IFN-γ-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2d) and tumors, B7-p815 (H-2d) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.

Original languageEnglish
Pages (from-to)6635-6644
Number of pages10
JournalJournal of Immunology
Volume173
Issue number11
DOIs
Publication statusPublished - Dec 1 2004

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Interleukin-12
Genetic Therapy
Hepatocellular Carcinoma
Tacrolimus
Neoplasms
Therapeutics
Liver Transplantation
Plasmids
Growth
Transplants
Electroporation
Inbred C3H Mouse
Organ Transplantation
Immunosuppressive Agents
Microvessels
Natural Killer Cells
Immunosuppression
Neoplasm Metastasis
T-Lymphocytes
Recurrence

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice. / Harada, Noboru; Shimada, Mitsuo; Okano, Shinji; Suehiro, Taketoshi; Soejima, Yuji; Tomita, Yukihiro; Maehara, Yoshihiko.

In: Journal of Immunology, Vol. 173, No. 11, 01.12.2004, p. 6635-6644.

Research output: Contribution to journalArticle

Harada, Noboru ; Shimada, Mitsuo ; Okano, Shinji ; Suehiro, Taketoshi ; Soejima, Yuji ; Tomita, Yukihiro ; Maehara, Yoshihiko. / IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice. In: Journal of Immunology. 2004 ; Vol. 173, No. 11. pp. 6635-6644.
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