title: Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice.
abstract: Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) was previously shown to facilitate suppression of experimental human hepatocellular carcinoma (HCC) expressing HBsAg in athymic mice. We have shown that oral tolerance induces antigen-specific immune suppression of HBsAg by feeding hepatitis B virus (HBV) antigens. In the present study we evaluated the effect of oral tolerance induction toward HBV or HCC antigens on the growth of experimental HCC-expressing HBsAg in mice. Tolerance induction was induced in mice by 5 oral feedings of 1 microg HBV antigens or HCC-extracted proteins (50 microg protein) before vaccination with recombinant HBsAg. Splenocytes (2 x 10(6)) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 10(7) human hepatoma Hep3B cells. Adoptive transfer of splenocytes immunized toward HBsAg prevented tumor growth. At 4 weeks after splenocyte transplantation, tumor volume and serum alpha-fetoprotein (AFP) levels in athymic mice transplanted with splenocytes immunized to HBsAg were undetectable as compared with 1,048 +/- 738 mm(3) and 2,500 +/- 1,431 ng/ml in recipients of naïve splenocytes (p < 0.0001). Mice receiving splenocytes tolerized toward Hep3B cells, as manifested by reduced serum HBs antibody levels, reduced HBV-specific stimulation index and reduced HBV-specific-IFN gamma spot-forming cells, had early tumor growth evident by elevated AFP serum levels, weight loss and mortality, which were suppressed at 6 weeks. Mice transplanted with splenocytes tolerized toward HBV antigens did not have direct evidence of tumor growth. Induction of oral tolerance toward HCC-extracted proteins enabled transient tumor growth in this model. This effect was mediated through downregulation of the anti-HBV immune response.
authors.affiliation: Liver Unit Division of Medicine, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Gotsman
authors.forename: David
authors.initials: D
authors.lastname: Israeli
authors.forename: Ruslana
authors.initials: R
authors.lastname: Alper
authors.forename: Elazar
authors.initials: E
authors.lastname: Rabbani
authors.forename: Dean
authors.initials: D
authors.lastname: Engelhardt
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology*; D005260:Female; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D013154:Spleen / Q000276:immunology; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: D000951:Antigens, Neoplasm; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D000509:alpha-Fetoproteins; D007371:Interferon-gamma