Studies on regulatory mechanism of Th1/Th2 cell differentiation by antigen presenting cell (APC) and onAPC-mediated immunotherapy

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 16208031
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Clinical veterinary science
• Research Institution: The University of Tokyo
• Principal Investigator: ONO Kenichiro The University of Tokyo, Graduate School of Agricultural and Life Sciences, Professor (50111480)
• Co-Investigator(Kenkyū-buntansha): MATSUMOTO Yoshitsugu The University of Tokyo, Graduate School of Agricultural and Life Sciences, Associate Professor (00173922) ; MATSUKI Naoaki The University of Tokyo, Graduate School of Agricultural and Life Sciences, Associate Professor (40251417) ; SHIMADA Terumasa Obihiro University, Department of Veterinary Science, Professor (00264812) ; WASHIZU Tsukimi Nippon Vetarinaiy and Life Science University, Department of Veterinary Science, Professor (20191736) ; BONKOBARA Mkoto Nippon Vetarinaiy and Life Science University, Department of Veterinary Science, Lecturer (50343611)
• Project Period (FY): 2004 – 2007
• Keywords: Antigen presenting cell / Dendritic cell / Established cell / Stimulating factor / Th1 / Th2 cell differentiation / Induction into Th1 / Th2 cell / Malignant melanoma / Babesiosis / Dndritic cell-mediated therapy

Research Abstract

Regulatory mechanisms of Th1/Th2 cell differentiation by antigen presenting cell (APC) and APC-mediated immunotherapy were investigated for 3 years (from 2004 to 2007) and following results were obtained.
1) Th1/Th2 cell differentiation in certain diseases, such as murine babesiosis, and canine malignant melanoma and histiocytic sarcoma:
a) IL-12p70 production from APC (included splenic macrophages) induced Th1 cell differentiation and closely related to transient parasitemia in Babesia microti infection. IL-12p70 was suggested to be an important factor for eliminating Babesia microti.
b) Seven novel cell lines from canine histiocytic sarcoma were established. All of them showed phagocytic and processing activities, suggesting to be a mononuclear phagocytic system cell and also APC.
2) Stimulatory factors for Th1/Th2 cell differentiation:
a) Stimulatory factors for IL-12 production, by which Th1 cell differentiation was introduced, from macrophages were isolated and purified from culture medium of Babesia microti and Babesia rodhaini infected erythrocytes. These factors were heat stable and soluble and their elution profiles were quite different between Babesia microti and Babesia rodhaini cultured medium.
3) APC-mediated immunotherapy
a) Against canine malignant melanoma: Canine APC from bone marrow were pulsed with lysate o canine melanoma cell lines and were transplanted into clinically healthy dogs. APC induced cell-mediated immunological responses against melanoma cells and prolonged survival period.
b) Against Babesia microti and Babesia rodhaini. Murine bone marrow-derived APC pulsed with Babesia microti infected erythrocytes induced decrease of parasitemia and increased survival rate in mice infected with Babesia rodhaini. These results suggested that APC-mediated therapy is an available manner for protozoan and cancer diseases.

Research Products

• [Journal Article] Induction of dendric cell-mediated immune response against canine malignant melanoma cells. (2008)
  • Author(s): Tamura, K. et al.
  • Journal Title: Vet. J. 175 Pages: 126-129
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of canine Kdap in normal, hyperplastic and neoplastic epidermis. (2008)
  • Author(s): Yagihara, H. et al.
  • Journal Title: Vet. J. (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Strain differences on splenic IL-12p70 concentration ahd immunological responsesin mice infected with Babesia microti and Babesia rodhaini (2008)
  • Author(s): Ohmori, T. et al.
  • Journal Title: J. Protozool. Res. (準備中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Immunological responses in anti-IL-12p70 serum treated and in IL-12 knock out mice infected muth Babesia microti and Babesia rodhaini. (2008)
  • Author(s): Ohmori, T. et al.
  • Journal Title: J. Protozool. Res. (準備中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Comparison of surface markers among among 7 cell lines from canine histiocytic sarcoms. (2008)
  • Author(s): Azagami, D. et al.
  • Journal Title: J. Vet. Med. Sci. l. (準備中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Induction of dendritic cell-mediated immune response against Babesia microti and Babesia rodhaini. (2008)
  • Author(s): Tokushuge, H. et al.
  • Journal Title: J. Protozool. Res. (準備中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Changes surface markers on 7 canine histiocytic sarcoma cell lines by cultivation with GM-CSF and IL-4. (2008)
  • Author(s): Azagami, D. et al.
  • Journal Title: J. Vet. Med. Sci. (準備中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effects of pulsed dendritic cell treatment on paraistemia and survival rate in mice infected with Babesia microti and Babesia rodhaini (2008)
  • Author(s): Tokushuge, H. et al.
  • Journal Title: J. Protozool. Res. (準備中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Induction of dendric cell-mediated immune response against canine malignant melanoma cells (2008)
  • Author(s): Tamura, K., Yamada, M., Isotani, M., Arai, H., Yagihara, H., Ono, K., Washizu, T., Bonkobara, M.
  • Journal Title: Vet. J. 175 Pages: 126-129
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of canine Kdap in normal, hyperplastic and neoplastic epidermis (2008)
  • Author(s): Yagihara, H., Kinjo, E., Kobayashi, Y., Tsuji, A., Nishimura, Y., Shinozaki, N., Tamura, K., Isotani, M., Nakagaki, K., Takahashi, K, Ono, K, Washizu, T., Bonkobara, M.
  • Journal Title: Vet. J. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Strain differences on splenic IL-12p70 concentration and immunological responses in mice infected with Babesia microti and Babesia rodhaini (2008)
  • Author(s): Ohmori, T., Tamahara, S., Pham, N. T., Tomihari, M., Matsuki, N., Ono, K.
  • Journal Title: J. Protozool. Res. (submitted)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunological responses in anti-IL-12p70 serum treated and in IL-12p70 knockout mice infected with Babesia microti and Babesia rodhaini (2008)
  • Author(s): Ohmori, T., Tamahara, S., Tomihari, M., Matsuki, N., Ono, K.
  • Journal Title: J. Protozool. Res. (submitted)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of surface markers among 7 cell lines from canine histiocytic sarcoma (2008)
  • Author(s): Azakami, D., Bonkobara, Washizu, T., Matsuki, N., Ono, K.
  • Journal Title: J. Vet. Med. Sci. (submitted)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of dendric cell-mediated immune response against Babesia microti and Babesia rodhaini (2008)
  • Author(s): Tokushige, H., Ohmori, T., Tamahara, S., Tomihari, M., Matsuki, N., Ono, K.
  • Journal Title: J. Protozool. Res. (submitted)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Changes of surface markers on 7 canine histiocytic sarcoma cell lines by cultivation with GM-CSF and IL-4 (2008)
  • Author(s): Azakami, D., Bonkobara, Washizu, T., Matsuki, N., Ono, K.
  • Journal Title: J. Vet. Med. Sci. (submitted)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of pulsed dendric cell treatment on parasitemia and survival rate in mice infected with Babesia microti and Babesia rodhaini (2008)
  • Author(s): Tokushige, H., Ohmori, T., Tamahara, S., Tomihari, M., Matsuki, N., Ono, K.
  • Journal Title: J. Protozool. Res. (submitted)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression pattern of the BRCA1 splicing variants in canine normal tis sues and mammary tumor. (2007)
  • Author(s): Sugiura, T. et al.
  • Journal Title: J. Vet. Med. Sci. 69 Pages: 587-592
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Comparison of dendric cell-mediated immune responses among canine malignant cells (2007)
  • Author(s): Tamura, K. et al.
  • Journal Title: J. Vet. Med. Sci. 69 Pages: 925-930
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression pattern of the BRCA1 splicing variants in canine normal tissues and mammary gland tumor (2007)
  • Author(s): Sugiura, T., Matsuyama, S., Akiyoshi, H., Yamate, J., Kuwamura, M., Aoki, M., Shimada, T., Ohashi, F., Kubo, K.
  • Journal Title: J. Vet. Med Sci. 69 Pages: 587-592
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of dendric cell-mediated immune responses among canine malignant cells (2007)
  • Author(s): Tamura, K., Arai, H., Ueno, E., Saito, C., Yagihara, H., Isotani, M., Ono., K, Washizu, T., Bonkobara, M.
  • Journal Title: J. Vet. Med. Sci. 69 Pages: 925-930
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification and cornification-related gene expression of canine keratinocyte differentiation-associated protein, Kdap. (2006)
  • Author(s): Yagihara, H. et al.
  • Journal Title: Vet. J. 172 Pages: 141-146
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Efficient generation of canine bone marrow-derived dendric cells (2006)
  • Author(s): Isotani, M. et al.
  • Journal Title: J. Vet. Med. Sci. 68 Pages: 809-814
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Establishment and biological characterization of canine histiocytic sarcoma cell lines. (2006)
  • Author(s): Azagami, D. et al.
  • Journal Title: J. Vet. Med. Sci. 68 Pages: 1343-1346
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Identification and cornification-related gene expression of canine keratinocyte differentiation-associated protein, Kdap (2006)
  • Author(s): Yagihara, H., Terada, Y., Sugimoto, S., Hidaka, F., Yamada, O., Ono, K., Washizu, T., Ariizumi, K., Bonkobara, M.
  • Journal Title: Vet. J. 172 Pages: 141-146
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Efficient generation of canine bone marrow-derived dendric cells (2006)
  • Author(s): Isotani, M., Katsuma, K, Tamura, K., Yamada, M., Yagihara, H., Azagami, D., Ono, K., Washizu, T., Bonkobara, M.
  • Journal Title: J. Vet. Med. Sci. 68 Pages: 809-814
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Establishment and biological characterization of canine histiocytic sarcoma cell lines (2006)
  • Author(s): Azakami, D., Bonkobara, M., Iida, A., Hiraiwa, M., Kato, R., Niikura, Y., Iwaki, S., Washizu, T., Matsuki, N., Ono, K.
  • Journal Title: J. Vet. Med. Sci. 68 Pages: 1343-1346
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Changes of splenic interleukin-12p70 1evels in mice infected with Babesia microti and Babesia rodhaini. (2005)
  • Author(s): Ohmori, T. et al.
  • Journal Title: J. Protozool. Res. 15 Pages: 41-47
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Stimulatory, factors for InterIeukin-12 Production from murine splenic macrophages co-cultured with Babesia rodhaini and Babesia microti infected erythrocytes. (2005)
  • Author(s): Hashiguchi-Kato, R. et al.
  • Journal Title: J. Protozool. Res. 15 Pages: 48-56
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Changes of splenic interleukin-12p70 levels in mice infected with Babesia microti and Babesia rodhaini (2005)
  • Author(s): Ohmori, T., Tamahara, S., Pham, N. T., Tomihari, M., Matsuki, N., Ono, K.
  • Journal Title: J. Protozool. Res. 15 Pages: 41-47
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Stimulatory factors for Interleukin-12 Production from murine splenic macrophages co-cultured with Babesia rodhaini and Babesia microti infected erythrocytes (2005)
  • Author(s): Hashiguchi-Kato, R., Pham, N. T., Ohmori, T., Tamahara, S., Katayama, N., Shimada, T., Matsuki, N., Ono, K.
  • Journal Title: J. Protozool. Res. 15 Pages: 48-56
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum interleukin-12 1evels and splenic helper T cell subpopulation in Babesia rodhaini inoculated mice preimmunized with Babesia microti. (2004)
  • Author(s): Hashiguchi-Kato, R. et al.
  • Journal Title: J. Protozool. Res. 14 Pages: 50-54
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Primary hepatic plasma cell tumor in a dog. (2004)
  • Author(s): Aoki, M. et al.
  • Journal Title: J. Vet. Med. Sci. 66 Pages: 445-447
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Serum interleukin-12 levels in mice infected with Babesi microti and Babesia rodhaini (2004)
  • Author(s): Hashiguchi-Kato, R., Pham, N. T., Ohmori, T., Tamahara, S., Tomihari, M., Shimada, T., Matsuki, N., Ono, K.
  • Journal Title: J Protozool. Res. 14 Pages: 50-54
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum interleukin-12 levels and splenic helper T cell subpopulation in Babesia rodhaini inoculated mice preimmunized with Babesi microti (2004)
  • Author(s): Hashiguchi-Kato, R., Pham, N. T., Ohmori, T., Tamahara, S., Tomihari, M., Shimada, T., Matsuki, N., Ono, K.
  • Journal Title: J Protozool. Res. 14 Pages: 43-49
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Primary hepatic plasma cell tumor in a dog (2004)
  • Author(s): Aoki, M., Kim T., Shimada, T., Kuwamura, M., Ohashi, F.
  • Journal Title: J. Vet. Med. 66 Pages: 445-447
  • Description: 「研究成果報告書概要(欧文)」より