１．関節リウマチモデルマウス
・HTLV-I-pX トランスジェニックマウス
1) Iwakura, Y., Tosu, M., Yoshida, E., Takiguchi, M., Sato, K., Kitajima, I., Nishioka, K., Yamamoto, K., Takeda, T., Hatanaka, M., Yamamoto, H., and Sekiguchi, T. Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science, 253, 1026-1028 (1991).
2) Yamamoto, H., Sekiguchi, T., and Iwakura, Y. Polyarthritis in mice transgenic for human T-cell leukemia virus Type-I (HTLV-I). I. Histopathological characteristics of joints. Arth. Rheum., 36, 1612-1620 (1993).
3) Endo, T., Iwakura, Y., and Kobata, A. Structural changes in the N-linked sugar chains of serum immunoglobulin G of HTLV-I-trans-genic mice. Biochem. Biophys. Res. Commun., 192, 1004-1010 (1993).
4) Iwakura, Y., Saijo, S., Kioka, Y., Nakayama-Yamada, J., Itagaki, K., Tosu, M., Asano, M., Kanai, Y., and Kakimoto, K. Autoimmunity induction by human T-cell leukemia virus type I in transgenic mice that develop chronic inflammatory arthropathy resembling rheumatoid arthritis in humans. J. Immunol., 155, 1588-1598 (1995).
5) Fujisawa, K., Asahara, H., Okamoto, K., Aono, H., Hasunuma, T., Kobata, T., Iwakura, Y., Yonehara, S., Sumida, T., and Nishioka, K. Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-I tax transgenic mice. J. Clin. Invest., 98, 271-278 (1996).
6) Kishi, S., Saijo, S., Arai, M., Karasawa, S., Ueda, S., Kannagi, M., Iwakura, Y., Fujii, M., and Yonehara, S. Resistance to Fas-mediated apoptosis of peripheral T cells in human T lymphocyte virus type I (HTLV-I) transgenic mice with autoimmune arthropathy. J. Exp. Med., 186, 57-64 (1997).
7) Iwakura, Y., Itagaki, K., Ishitsuka, K., Yamazaki, Y., Matsuzawa, A., Yonehara, S., Karasawa, S., Ueda, S., and Saijo, S. The development of autoimmune inflammatory arthropathy in mice transgenic for the HTLV-I env-pX region is not dependent on H-2 haplotypes and modified by the expression levels of Fas antigen. J. Immunol., 161, 6592-6598 (1998).
8) Kotani, M., Tagawa, Y., and Iwakura, Y. Involvement of autoimmunity against type II collagen in the development of arthritis in mice transgenic for the human T cell leukemia virus type I tax gene. Eur. J. Immunol., 29, 54-64 (1999).
9) Habu, K., Nakayama-Yamada, J., Asano, M., Saijo, S., Itagaki, K., Horai, R., Yamamoto, H., Sekiguchi, T., Nosaka, T., Hatanaka, M., and Iwakura, Y. The HTLV-I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and non-inflammatory ankylotic arthropathy in transgenic mice. J. Immunol., 162, 2956-2963 (1999).
10) Kawakami, K., Miyazato, A., Iwakura, Y., and Saito, A. Induction of lymphocytic inflammatory changes in the lung interstitium by human T lymphotropic virus type I. Am. J. Respir. Crit. Care Med., 160, 995-1000 (1999).
11) Saijo, S., Kotani, M., Habu, K., Ishitsuka, C., Yamamoto, H., Sekiguchi, T. and. Iwakura, Y. Bone marrow derived cells are responsible for the development of autoimmune arthritis in HTLV-I transgenic mice and those of normal mice can suppress the disease. J. Immunol., 163, 5700-5707 (1999).
12) Miyazato, A., Kawakami, K., Iwakura, Y., and Saito, A. Chemokine synthesis and cellular inflammatory changes in lungs of mice bearing p40tax of human T-lymphotropic virus type 1. Clin. Exp. Immunol., 120, 113-124 (2000).
13) Saijo, S., Asano, M., Horai, R., Yamamoto, H., and Iwakura, Y. Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cells. Arth. Rheum., 46, 533-544 (2002).
14) Iwakura, Y. Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene. Gann Monograph on Cancer Research, 50, 197-218（2003).
15) Miyake-Nishijima, R., Iwata, S., Saijo, S., Kobayashi, H., Kobayashi, S., Souta-Kuribara, A., Hosono, O., Kawasaki, H., Tanaka, H., Ikeda, E., Okada, Y., Iwakura, Y., and Morimoto, C. Role of Crk-associated substrate lymphocyte type in the pathophysiology of the rheumatoid arthritis in tax transgenic mice and in humans. Arthritis Rheum., 48, 1890-1900 (2003).
16) Ono, Y., Ogihara, Y., Saijo, S., Iwakura, Y., and Inoue, M. Evaluation of Kampo medicines used ton treat rheumatoid arthritis in collagen-induced and pX transgenic mice. Mod. Rheumatol., 13, 50-56 (2003).
17) Kobari, Y., Misaki, Y., Setoguchi, K., Zhao, W., Komagata, Y., Kawahata, K., Iwakura, Y., and Yamamoto, K. T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression. Int. Immunol., 16, 131-138 (2004).
18) Ishihara, K., Sawa, S.I., Ikushima, H., Hirota, S., Atsumi, T., Kamimura, D., Park, S.J., Murakami, M., Kitamura, Y., Iwakura, Y., and Hirano, T. The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-I pX in promoting rheumatoid arthritis-like arthritis. Int. Immunol., 16, 455-465 (2004).
19) Fujikado, N., Saijo, S., and Iwakura, Y. Identification of arthritis-related gene clusters by microarray analysis of two independent mouse models for rheumatoid arthritis. Arthritis Res. Ther., 8, R100 (2006).
20) Murakami, M., Iwai, S., Hiratsuka, S., Yamauchi, M., Nakamura, K., Iwakura, Y., and Shibuya, M. Signaling of vascular endothelial growth factor receptor- 1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages. Blood, 108, 1849-1856 (2006).
21) Ashino, T., Arima, Y., Shioda, S., Iwakura, Y., Numazawa, S., and Yoshida, T. Effect of interleukin-6 neutralization on CYP3A11 and metallothionein-1/2 expressions in arthritic mouse liver. Eur. J. Pharmacol., 558, 199-207 (2007).
22) Teruya, H., Tomita, M., Senba, M., Ishikawa, C., Tamayose, M., Miyazato, A., Yara, S., Tanaka, Y., Iwakura, Y., Fujita, J., and Mori, N. Human T-cell leukemia virus type I infects human lung epithelial cells and induces gene expression of cytokines, chemokines and cell adhesion molecules. Retrovirology, 5, 86 (2008).
23) Ohtaki, H., Yofu, S., Nakamachi, T., Satoh, K., Shimizu, A., Mori, H., Sato, A., Iwakura, Y., Matsunaga, M., and Shioda, S. Nucleoprotein Diet Ameliorates Arthritis Symptoms in Mice Transgenic for Human T-Cell Leukemia Virus Type I (HTLV-1). J. Clin. Biochem. Nutr., 46, 93-104 (2010).
・HTLV-I LTR-tax トランスジェニックマウス
・fms-tax トランスジェニックマウス
・CD4-tax トランスジェニックマウス
１）Habu, K., Nakayama-Yamada, J., Asano, M., Saijo, S., Itagaki, K., Horai, R., Yamamoto, H., Sekiguchi, T., Nosaka, T., Hatanaka, M., and Iwakura, Y. The HTLV-I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and non-inflammatory ankylotic arthropathy in transgenic mice. J. Immunol., 162, 2956-2963 (1999).
ｂ）IL-1レセプターアンタゴニストノックアウトマウス
1) Horai, R., Saijo, S., Tanioka, H., Nakae, S., Sudo, K., Okahara, A., Ikuse, T., Asano, M., and Iwakura, Y. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice. J. Exp. Med., 191, 313-320 (2000).
2) Iwakura, Y. Roles of IL-1 in the development of rheumatoid arthritis: Consideration from mouse models. Cytokine Growth Factor Rev., 13, 341-355 (2002).
3) Nakae, S., Saijo, S., Horai, R., Sudo, K., Mori, S., and Iwakura, Y. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl. Acad. Sci. USA, 100, 5986-5990 (2003).
4) Isoda, K., Shiigai, M., Ishigami, N., Matsuki, T., Horai, R., Nishikawa, K., Kusuhara, M., Nishida, Y., Iwakura, Y., and Ohsuzu, F. Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury. Circulation, 108, 516-518 (2003).
5) Matsuki, T., Horai, R., Sudo, K., and Iwakura, Y. IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions. J. Exp. Med., 198, 877-888 (2003).
6) Isoda, K., Sawada, S., Ishigami, N., Matsuki, T., Miyazaki, K., Kusuhara, M., Iwakura, Y., and Ohsuzu, F. Lack of Interleukin-1 Receptor Antagonist Modulates Plaque Composition in Apolipoprotein E-Deficient Mice. Arterioscler. Thromb. Vasc. Biol., 24, 1068-1073 (2004).
7) Uekawa, N., Nishikimi, A., Isobe, K., Iwakura, Y., and Maruyama, M. Involvement of IL-1 family proteins in p38 linked cellular senescence of mouse embryonic fibroblasts. FEBS Lett., 575, 30-34 (2004).
8) Horai, R., Nakajima, A., Habiro, K., Kotani, M., Nakae, S., Matsuki, T., Nambu, A., Saijo, S., Kotaki, H., Sudo, K., Okahara, A., Tanioka, H., Ikuse, T., Ishii, N., Schwartzberg, P. L., Abe, R., and Iwakura, Y. TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J. Clin. Invest., 114, 1603-1611 (2004).
9) Isoda, K., Sawada, S., Ayaori, M., Matsuki, T., Horai, R., Kagata, Y., Miyazaki, K., Kusuhara, M., Okazaki, M., Matsubara, O., Iwakura, Y., and Ohsuzu, F. Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice. J. Biol. Chem., 280, 7002-7009 (2005).
10) Matsuki, T., Isoda, K., Horai, R., Nakajima, A., Aizawa, Y., Suzuki, K., Ohsuzu, F., and Iwakura, Y. Involvement of TNFα in the development of T cell-dependent aortitis in IL-1 receptor antagonist-deficient mice. Circulation, 112, 1323-1331 (2005).
11) Ishigame, H., Nakajima, A., Saijo, S., Komiyama, Y., Matsuki, T., Nakae, S., Horai, R., Kakuta, S., and Iwakura, Y. The role of TNFα and IL-17 in the development of excess IL-1 signaling-induced inflammatory diseases in IL-1 receptor antagonist-deficient mice. In "Cytokines as Potential Therapeutic Targets for Inflammatory Skin Disease", (eds. Numerof, R., Dinarello, C.A., and Asadullah, K.), Ernst Schering Research Foundation Workshop 56, pp.129-153, (2006).
12) Zhou, F., He, X., Iwakura, Y., Horai, R., and Stuart, JM. Arthritis in mice that are deficient in interleukin-1 receptor antagonist is dependent on genetic background. Arthritis Rheum., 52, 3731-3738 (2005).
13) Matsuki, T., Nakae, S., Sudo, K., Horai, R., and Iwakura, Y. Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int. Immunol., 18, 399-407 (2006).
14) Kotani, M., Hirata, K., Ogawa, S., Habiro, K., Ishida, Y., Tanuma, S., Horai, R., Iwakura, Y., Kishimoto, H., and Abe, R. CD28-dependent differentiation into the effector/memory phenotype is essential for induction of arthritis in interleukin-1 receptor antagonist-deficient mice. Arthritis Rheum., 54, 473-481 (2006).
15) O'Sullivan, BJ., Thomas, HE., Pai, S., Santamaria, P., Iwakura, Y., Steptoe, RJ., Kay, TWH., and Thomas, R. IL-1β Breaks Tolerance through Expansion of CD25+ Effector T Cells. J. Immunol., 176, 7278-7287 (2006).
16) Fujikado, N., Saijo, S., and Iwakura, Y. Identification of arthritis-related gene clusters by microarray analysis of two independent mouse models for rheumatoid arthritis. Arthritis Res. Ther., 8, R100 (2006).
17) Onodera, S., Ohshima, S., Tohyama, H., Yasuda, K., Nishihira, J., Iwakura, Y., Matsuda, I., Minami, A., and Koyama, Y. A novel DNA vaccine targeting macrophage migration inhibitory factor protects joints from inflammation and destruction in murine models of arthritis. Arthritis Rheum., 56, 521-530 (2007).
18) Krelin, Y., Voronov, E., Dotan, S., Elkabets, M., Reich, E., Fogel, M., Huszar, M., Iwakura, Y., Segal, S., Dinarello, CA., and Apte, RN. Interleukin-1β-Driven Inflammation Promotes the Development and Invasiveness of Chemical Carcinogen-Induced Tumors. Cancer Res., 67, 1062-1071 (2007).
19) Kagari, T., Tanaka, D., Doi, H., Iwakura, Y., and Shimozato, T. Anti-type II collagen antibody accelerates arthritis via CXCR2-expressing cells in IL-1 receptor antagonist-deficient mice. Eur. J. Immunol., 37, 2753-2763 (2007). Correction: 37, 2991 (2007).
20) Chida, D., Hashimoto, O., Kuwahara, M., Sagara, H., Osaka, T., Tsubone, H., and Iwakura, Y. Increased fat:carbohydrate oxidation ratio in Il1ra-/- mice on a high fat diet is associated with increased sympathetic tone. Diabetologia, 51, 1698-706 (2008).
21) Elkabets, M., Krelin, Y., Dotan, S., Cerwenka, A., Porgador, A., Lichtenstein, R.G., White, M.R., Zoller, M., Iwakura, Y., Dinarello, C.A., Voronov, E., and Apte, R.N. Host-derived interleukin-1α is important in determining the immunogenicity of 3-methylcholantrene tumor cells. J. Immunol., 182, 4874-4881 (2009).
22) Isoda, K., Matsuki, T., Kondo, H., Iwakura, Y., and Ohsuzu, F. Deficiency of Interleukin-1 Receptor Antagonist Induces Aortic Valve Disease in BALB/c Mice. Arterioscler. Thromb. Vasc. Biol., 30, 708-715 (2010).
c）Dcir欠損マウス
1) Fujikado, N., Saijo, S., Yonezawa, T., Shimamori, K., Ishii, A., Sugai, S., Kotaki, H., Sudo, K., Nose, M., and Iwakura, Y. DCIR deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat. Med., 14, 176-180 (2008).