Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells.
Int Immunol. 1995 Jul;7(7):1135-45. Unique Identifier : AIDSLINE MED/96134437 Zou JP; Yamamoto N; Fujii T; Takenaka H; Kobayashi M; Herrmann SH; Wolf SF; Fujiwara H; Hamaoka T; Biomedical Research Center, Osaka University Medical School,; Japan.
Abstract:
Unfractionated spleen cells taken from tumor-bearing mice 2 weeks after tumor implantation contained tumor-primed T cells which produced cytokines including IL-2 and IFN-gamma when cultured in vitro. With progressive tumor growth this initial lymphokine-producing capacity decreased. Here, we investigated the ability of IL-12 to (i) restore suppressed IFN-gamma production, (ii) cause tumor regression and (ii) induce anti-tumor protective immunity. Addition of rIL-12 to spleen cell cultures from 4- to 10-week-old tumor-bearing mice resulted in a striking enhancement in the production of IFN-gamma compared with cultures of these cells in the absence of rIL-12 or of normal spleen cells in the presence of rIL-12. Five i.p. injections of rIL-12 into mice bearing s.c. tumors induced complete tumor regression. This was found when rIL-12 was given at early (1-2 weeks), intermediate (4-5 weeks) or even late (7 weeks) stages of tumor growth. Furthermore, IL-12-treated mice which rejected the primary tumor exhibited complete resistance to a rechallenge with the same tumor but did not reject a second syngenetic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T cells infiltrate the tumor. More importantly, IFN-gamma mRNA expression was observed in fresh tumor masses from tumor-bearing mice receiving IL-12 treatment. The importance of IFN-gamma was further demonstrated by the observation that the systemic administration of anti-IFN-gamma mAb prior to IL-12 treatment completely abrogated the anti-tumor effect of IL-12. Thus, these results indicate that administration of modest levels of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving reversal of suppressed IFN-gamma production by anti-tumor T cells and the establishment of a tumor-specific protective immune response.
Keywords: Animal CD4-Positive T-Lymphocytes/IMMUNOLOGY CD8-Positive T-Lymphocytes/IMMUNOLOGY Fibrosarcoma/IMMUNOLOGY/PATHOLOGY/*THERAPY Immune Tolerance/*DRUG EFFECTS Immunity, Natural/DRUG EFFECTS Immunophenotyping Injections, Intraperitoneal Interferon Type II/*ANTAGONISTS & INHIB/BIOSYNTHESIS/PHYSIOLOGY Interleukin-12/ADMINISTRATION & DOSAGE/PHARMACOLOGY/*THERAPEUTIC USE Lymphokines/BIOSYNTHESIS Male Mice Mice, Inbred BALB C Recombinant Proteins/ADMINISTRATION & DOSAGE/THERAPEUTIC USE Remission Induction Spleen/METABOLISM Support, Non-U.S. Gov't T-Lymphocytes/*IMMUNOLOGY/METABOLISM Tumor Cells, Cultured JOURNAL ARTICLE 960430
M9640839
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Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
