       Document 0490
 DOCN  M9640490
 TI    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.
 DT    9604
 AU    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.
 SO    Int Immunol. 1995 Jul;7(7):1135-45. Unique Identifier : AIDSLINE
       MED/96134437
 AB    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.
 DE    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

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

