Role of the endogenous production of interleukin 12 in immunotherapy.
Previous studies demonstrated that injecting mice with the cytokine interleukin 12 (IL-12) could significantly suppress the growth of a number of tumors, including murine B16 melanoma. In this report, the persistence of the antitumor effects of IL-12 is investigated. The i.p. injection of IL-12 (0.1 microg) on days 14, 16, 18, 20, and 22 was found to significantly suppress the growth of s.c. inoculated B16 melanoma for up to 2 weeks after the last injection of IL-12. Interestingly, the IL-12 serum level 4 days after the last injection of IL-12 was significantly elevated in tumor-bearing mice compared with that of IL-12-treated normal mice. The in vivo depletion of either CD4+ or CD8+ T cells abrogated the antitumor activity of IL-12 and diminished the apparent autocrine stimulation of IL-12 release seen after IL-12 treatment. Resection of the tumor-draining lymph nodes (LNs) but not of the spleen abrogated the antitumor effect of IL-12 treatment as well as the elevation of serum IL-12. Expression of mRNA encoding IL-12 as well as CD40 ligand (CD40L) was detected in the tumor-draining LNs but not in the spleen of tumor-bearing mice after IL-12 treatment. Furthermore, the antitumor activity observed after IL-12 treatment was diminished by the in vivo administration of either anti-IL-12 or anti-CD40L monoclonal antibodies. Collectively, these results suggest that the endogenous production of IL-12 resulting from the CD40-CD40L interaction between antigen-presenting cells and CD4+ T cells in the tumor-draining LNs may play a role in the persistence of the antitumor effects seen after IL-12 treatment.
Department of Virology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. haradam@pop.nci.nih.gov
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M
Harada
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Tamada
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K
Abe
K
K
Yasumoto
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G
Kimura
K
K
Nomoto
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D008546:Melanoma, Experimental / Q000097:blood / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D018664:Interleukin-12