Immunoregulatory role of MΦ/DCs in the liver of murine malaria infected mice

• Project/Area Number: 16590343
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Parasitology (including Sanitary zoology)
• Research Institution: University of the Ryukyus
• Principal Investigator: WATANABE Hisami University of the Ryukyus, Center of Molecular Biosciences, Professor, 遺伝子実験センター, 教授 (50143756)
• Co-Investigator(Kenkyū-buntansha): MK Mannoor Division of Tropical Parasitology, Faculty of Medicine, Assistant Professor, 医学部, 助手 (70347136)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: Murine malaria / NKT cells / Dendritic cells (DC) / Myeloid DC / Plasmacytoid DC / Cytokine / Apoptosis inhibitor / Disease syndromes / 肝NKT細胞 / マクロファージ / 原虫の早期排除 / plasmocytoid DC / CD11c^<low> ClassII^-DC / parasitemia

Research Abstract

We have already reported that one subset of NKT cells, known as CD3^<int>IL-2Rβ+NK1.1-subset, expanded in the liver of P.yoelli 17XNL-infected C57BL/6(B6) mice and contributed to protection against malaria. On the other hand, accumulating results of our studies suggested that liver dendritic cells (DCs) might play a critical role in the regulation of immune responses through activation of liver NKT cells after malarial infection. However, this approach has not been clearly elucidated. In this study we attempted to analyze the phenotype and function of liver DCs in malaria infected mice.
DCs are classified into two majour subpopulations ; myeloid DC (mDC) and plasmacytoid DC (pDC). Murine liver had high absolute number of PDCA-1+CD11c^<low>I-A-B220+DC (pDC) which produced IFN-α by stimulation with CpG in vitro. PDCA-1-CD11c^<high>I-A+B220-DC (mDC) were dominant in the spleen. DCs of both phenotypes were able to produce IL-12, IL-10 and TNFα. CD11c^<low>I-A-DC isolated from malaria infect ed mice increased in the liver and spleen at acute phase (7 days). These cells showed high expression of CD86 but decreased PDCA-1 expression and IFN-α production. I-A-CD11c^<low>DCs isolated from infected mice showed impaired production of cytokines as compared with mDCs. PDCA-1^+ cells in CD11c^<low>I-A- fraction of liver and spleen reappeared at recovery phase (after 25 days) of malarial infection. These results indicate that while mDCs activate NKT cells via cytokines and that activated NKT cells promote the protective activity and disease syndromes in malaria infected mice. pDCs induce the immunosuppressive effects due to impaired production of IFN-α. AIM (apoptosis inhibitor expressed by MΦ) deficient mice lack some of MΦ and DC functions and were found to recover more quickly from malarial infection than B6 mice. γδT cells expanded in the liver and spleen, especially in the recovery phase. These findings clearly showed the phenotypical and functional change of DCs in the liver and may support the view that liver DC regulate the function of NKT cells in the liver after malarial infection.

Research Products

• [Journal Article] Reasons why DBA/2 mice are resistant to malarial infection : expansion of CD3^int B220^+ gammadelta T cells with double-negative CD4^- CD8^- phenotype in the liver. (2006)
  • Author(s): Bakir, H.Y., Tomiyama-Miyaji, C., Watanabe, H., Nagura, T., Kawamura, T., Sekikawa H, Abo, T.
  • Journal Title: Immunology 117 Pages: 127-135
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reasons why DBA/2 mice are resistant to malarial infection : expansion of CD3^<int> B220^+ gammadelta T cells with double-negative CD4^- CD8^- phenotype in the liver. (2006)
  • Author(s): Bakir, H.Y., Tomiyama-Miyaji, C., Watanebe, H., Nagura, T., Kawamura, T., Sekikawa H, Abo, T.
  • Journal Title: Immunology 117 Pages: 127-135
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protection against malaria by anti-erythropoietin antibody due to suppression of erythropoiesis in the liver and at other sites. (2005)
  • Author(s): Tsubata, S., Ebe, K., Kawamura, T., Ishimoto, Y., Tomiyama-Miyaji, C., Watanabe, H., Sekikawa, H., Aoyagi, Y., Abo, T.
  • Journal Title: Immunology and Cell Biology 83 Pages: 638-642
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immunologic states of autoimmune diseases. (2005)
  • Author(s): Abo, T., Kawamura, T., Watanabe, H.
  • Journal Title: Immunologic Research 33 Pages: 23-34
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Protection against malaria by anti-erythropoietin antibody due to suppression of erythropoiesis in the liver and at other sites. (2005)
  • Author(s): Tsubata, S., Ebe, K., Kawamura, T., Ishimoto, Y., Tomiyama-Miyaji, C., Watanabe.H., Sekikawa, H., Aoyagi, Y., Abo, T.
  • Journal Title: Immuno Cell Biol 83 Pages: 638-642
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunologic states of autoimmune diseases. (2005)
  • Author(s): Abo, T., Kawamura, T., Watanabe.H.
  • Journal Title: Immunol Res 33 Pages: 23-34
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pyrimethamine-Sulfadoxine treatment of uncomplicated Plasmodium falciparum malaria in Lao PDR. (2005)
  • Author(s): Mannoor, M.K., Vanisaveth, V., Keokhamphavanh, B., Toma, H., Watanabe, H., Kobayashi, J., Hatabu, T., Taguchi, N., Hongvangthong, B., Phetsouvanh, R., Phompida, S., Kano, S., Sato, Y.
  • Journal Title: Southeast Asian J.Trop.Med.Public Health 36 Pages: 1092-1095
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Reasons why DBA/2 mice are resistant to malaria infection : expansion of CD 3^<int> B220^+ γδ T cells with double-negative CD4^-CD8^- phenotype in the liver. (2005)
  • Author(s): Bakir, H.Y.
  • Journal Title: Immunology 117 Pages: 127-135
• [Journal Article] Immunologic states of autoimmune diseases. (2005)
  • Author(s): Abo, T.
  • Journal Title: Immunologic research 33 Pages: 23-34
• [Journal Article] Protection against malaria by anti-erythropoietin antibody due to suppression of erythropoiesis in the liver and at other sites. (2005)
  • Author(s): Tsubata, S.
  • Journal Title: Immunology and Cell Biology 83 Pages: 638-642
• [Journal Article] Pyrimethamine-Sulfadoxine treatment of uncomplicated Plasmodium falciparum malaria in Lao PDR. (2005)
  • Author(s): Mannoor, M.K.
  • Journal Title: Southeast Asian Journal of Tropical Medicine and Public Health 36 Pages: 1092-1095
• [Journal Article] A pilot field survey on the in vitro drug susceptibility of Plasmodium falciparum in Lao PDR. (2005)
  • Author(s): Hatabu, T.
  • Journal Title: Tropical Medicine and Health 33 Pages: 103-104
• [Journal Article] Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe Concanavalin A-induced hepatitis. (2004)
  • Author(s): Saito, T., Okumura, A., Watanabe, H., Asano, M., Ishida-Okawara, A., Sakagami, J., Sudo, K., Hatano-Yokoe, Y., Bezbradica, J.S., Joyce, S., Abo, T., Iwakura, Y., Suzuki, K., Yamagoe, S.
  • Journal Title: Journal of Immunology 173 Pages: 579-585
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pleiotropic role of AIM in lymphocyte apoptosis and inflamation. (2004)
  • Author(s): Kuwata, K., Watanabe, H., Miyazaki, T., Naito, M.
  • Journal Title: Journal of Clinical and Experimental Hematopathology 44 Pages: 1-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially NKT cells, double-positive CD4^+8^+ cells and B220^+T cells, in mice. (2004)
  • Author(s): Ishimoto, Y., Tomiyama-Miyaji, C., Watanabe, H., Yokoyama, H., Ebe, K., Tsubata, S., Aoyagi, Y., Abo, T.
  • Journal Title: Immunology 113 Pages: 371-377
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe Concansvalin A-induced hepatitis. (2004)
  • Author(s): Saito, T., Okumura, A., Watanabe, H., Asano, M., Ishida-Okawara, A., Sakagami, J., Sudo, K., Hatano-Yokoe, Y., Bezbradica, J.S., Joyce, S., Abo, T., Iwakura, Y., Suzuki, K., Yamagoe, S.
  • Journal Title: J.Immunol 173 Pages: 579-585
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pleiotropic role of AIM in lymphocyte apoptosis and inflamation. (2004)
  • Author(s): Kuwata, K., Watanabe, H., Miyazaki, T., Naito, M.
  • Journal Title: J.Clin.Exp.Hematopathol 44 Pages: 1-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially NKT cells, double-positive CD4^+8^+ cells and B220^+T cells, in mice. (2004)
  • Author(s): Ishimoto, Y., Tomiyama-Miyaji, C., Watanabe.H., Yokoyama, H., Ebe, K., Tsubata, S., Aoyagi, Y., Abo, T.
  • Journal Title: Immunology 113 Pages: 371-377
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe Concanavalin A-induced hepatitis. (2004)
  • Author(s): Saito, T.
  • Journal Title: Journal of Immunology 173 Pages: 579-585
• [Journal Article] Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially NKT cells, double-positive CD4^+8^+ cells and B220^+T cells, in mice. (2004)
  • Author(s): Ishimoto, Y.
  • Journal Title: Immunology 113 Pages: 371-377
• [Journal Article] Pleiotropic role of AIM in lymphocyte apoptosis and inflamation. (2004)
  • Author(s): Kuwata, K.
  • Journal Title: Journal of Clinical and Experimental Hematology 44 Pages: 1-9
• [Journal Article] Wall shear stress and intrahepatic leukocytes of graft in living related donor liver transplantation. (2004)
  • Author(s): Sato, Y.
  • Journal Title: Hepatogastroenterology 51 Pages: 329-333
• [Journal Article] Estimation of effector cytotoxic lymphocytes against male H-Y antigens induced by two-stepstimulations as CD8^+NK1.1^-TCR^<int> and CD8^+NKI1.1^+TCR^<int> cells. (2004)
  • Author(s): Yokoyama, Y.
  • Journal Title: Biomedical Research 25 Pages: 93-100
• [Journal Article] Comparative characterization of double-positive CD4^+8^+ cells in the thymus and small intestine of mice. (2004)
  • Author(s): Ebe, K.
  • Journal Title: Biomedical Research 25 Pages: 201-207