Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice

Shigeru Tatebe, Hitoshi Unate, Frank A Sinicrope, Takashi Sakatani, Kenji Sugamura, Masato Makino, Hisao Ito, Niramol Savaraj, Nobuaki Kaibara, M. Tien Kuo

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 I μg HBV antigens or HCC-extracted proteins (50 μg protein) before vaccination with recombinant HBsAg. Splenocytes (2 × 106) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 107 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 mm3 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-γ 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.

Original languageEnglish (US)
Pages (from-to)52-57
Number of pages6
JournalInternational Journal of Cancer
Volume97
Issue number1
DOIs
StatePublished - Jan 1 2002

Fingerprint

Immune Tolerance
Neoplasm Antigens
Hepatitis B Surface Antigens
Hepatitis B virus
Hepatocellular Carcinoma
Hepatitis B Antigens
Growth
Adoptive Transfer
alpha-Fetoproteins
Nude Mice
Neoplasms
Serum
Antigens
Proteins
Adaptive Immunity
Tumor Burden
Weight Loss
Vaccination
Down-Regulation
Transplantation

Keywords

  • Hepatitis B surface antigen (HBsAg)
  • Hepatitis B virus
  • Hepatocellular carcinoma
  • Oral tolerance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice. / Tatebe, Shigeru; Unate, Hitoshi; Sinicrope, Frank A; Sakatani, Takashi; Sugamura, Kenji; Makino, Masato; Ito, Hisao; Savaraj, Niramol; Kaibara, Nobuaki; Kuo, M. Tien.

In: International Journal of Cancer, Vol. 97, No. 1, 01.01.2002, p. 52-57.

Research output: Contribution to journalArticle

Tatebe, S, Unate, H, Sinicrope, FA, Sakatani, T, Sugamura, K, Makino, M, Ito, H, Savaraj, N, Kaibara, N & Kuo, MT 2002, 'Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice', International Journal of Cancer, vol. 97, no. 1, pp. 52-57. https://doi.org/10.1002/ijc.1576
Tatebe, Shigeru ; Unate, Hitoshi ; Sinicrope, Frank A ; Sakatani, Takashi ; Sugamura, Kenji ; Makino, Masato ; Ito, Hisao ; Savaraj, Niramol ; Kaibara, Nobuaki ; Kuo, M. Tien. / Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice. In: International Journal of Cancer. 2002 ; Vol. 97, No. 1. pp. 52-57.
@article{1654b0e15d8b4fdda948a3336f9c6aae,
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 I μg HBV antigens or HCC-extracted proteins (50 μg protein) before vaccination with recombinant HBsAg. Splenocytes (2 × 106) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 107 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 mm3 and 2,500 ± 1,431 ng/ml in recipients of na{\"i}ve 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-γ 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.",
keywords = "Hepatitis B surface antigen (HBsAg), Hepatitis B virus, Hepatocellular carcinoma, Oral tolerance",
author = "Shigeru Tatebe and Hitoshi Unate and Sinicrope, {Frank A} and Takashi Sakatani and Kenji Sugamura and Masato Makino and Hisao Ito and Niramol Savaraj and Nobuaki Kaibara and Kuo, {M. Tien}",
year = "2002",
month = "1",
day = "1",
doi = "10.1002/ijc.1576",
language = "English (US)",
volume = "97",
pages = "52--57",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice

AU - Tatebe, Shigeru

AU - Unate, Hitoshi

AU - Sinicrope, Frank A

AU - Sakatani, Takashi

AU - Sugamura, Kenji

AU - Makino, Masato

AU - Ito, Hisao

AU - Savaraj, Niramol

AU - Kaibara, Nobuaki

AU - Kuo, M. Tien

PY - 2002/1/1

Y1 - 2002/1/1

N2 - 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 I μg HBV antigens or HCC-extracted proteins (50 μg protein) before vaccination with recombinant HBsAg. Splenocytes (2 × 106) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 107 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 mm3 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-γ 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.

AB - 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 I μg HBV antigens or HCC-extracted proteins (50 μg protein) before vaccination with recombinant HBsAg. Splenocytes (2 × 106) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 107 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 mm3 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-γ 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.

KW - Hepatitis B surface antigen (HBsAg)

KW - Hepatitis B virus

KW - Hepatocellular carcinoma

KW - Oral tolerance

UR - http://www.scopus.com/inward/record.url?scp=0036131962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036131962&partnerID=8YFLogxK

U2 - 10.1002/ijc.1576

DO - 10.1002/ijc.1576

M3 - Article

VL - 97

SP - 52

EP - 57

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 1

ER -