研究

研究課題

IGRA検査の歴史は短く、抗原特異的細胞性免疫反応を体外で正確に再現できる技術を要する検査法で有るため、技術者の技術精度や知識、或いはモラルが結果の特異度・感度に大きく影響します。
このため、検査技術の安定化や検体保管温度等について様々な改善すべき課題があります。また、IGRA検査は、最近の感染ばかりでなく過去に治療を終えた遠い昔の感染でも陽性を示す事が有ります。
何故こうした事が起こるのかという問いに対して明確な回答は得られていません。従って最近の結核、過去の結核との区別も今のIGRA検査では難しく、更にはIGRA検査陽性者のうちだれが発病する危険性を持っているか選択することは非常に難しい課題です。
RIIDはこうしたIGRAの課題について、免疫学的理論に基づいた検証実験を行いつつ新たな診断試薬の技術開発を目指しています。

IGRA検査の改良

1.活動性結核と潜在性結核感染の区別ができる検査法の開発

IGRA検査で陽性結果が出た場合、 IGRA検査結果のみでは被検者が活動性結核か潜在性結核かを区別することは困難です。この区別はその後の治療方針を決める上で重要です。この点については結核菌特異抗原と抗原特異的に反応するTリンパ球との関連を解析し、活動性結核において必須となるサイトカインを解析して、新しい検査法の開発を目指します。

2.休眠期結核感染を検出する検査法の開発

ヒトに感染した結核菌の中には、結核を発症せずに長い間ヒトの体の中で休眠したような状態になることがありますが、加齢等によりヒトの免疫が弱まると休眠期から目覚めて結核を発症させる事があります。もしこうした休眠期感染を発見し治療することができれば高齢者の結核発症は劇的に減少することが考えられます。結核の感染ステージに依って変化することが報告されているTリンパ球産生タンパクの解析研究から検査法の開発を目指します。

Tリンパ球の特殊な亜集団の抗結核作用の解析

近年、Tリンパ球の特殊な亜集団が結核菌感染後の発病を強力に阻止する能力のあることが発見されました。この亜集団を更に実用化に向けて解析研究を遂行します。

結核菌由来の免疫物質の解析

これまでの研究で、結核菌由来の非分泌性タンパクが成分ワクチンとして可能性の高いことを報告して来ましたが、理論的には免疫を介する難治性疾患において何らかの改善が期待されることが分かっています。今後はこうした事実に基づいて検証的研究成果を構築していきたいと考えています。

研究業績

邦文論文リスト

  • 向山晴子、樋口一恵、原田登之：接触者健診におけるT-スポット.TBとQFT-3Gの比較.結核、2014; 89: 655-658.
  • 樋口一恵、原田登之：Interferon-gamma release assays (IGRA) の研究課題．結核、2009; 84: 173-86.
  • 徳永 修、村田祐樹、濱谷 舟、宮野前健、末永麻由美、宮川知士、錦戸知喜、吉田之範、亀田 誠、高松 勇、土居 悟、岡田賢司、樋口一恵、原田登之：小児活動性結核症例におけるクォンティフェロン®TB-2G応答性の検討. 日本小児呼吸器疾患学会雑誌、2008; 19: 112-121.
  • 樋口一恵、岡田賢司、原田登之、森 亨：小児における結核予防内服のクォンティフェロン®TB-2G応答に及ぼす影響. 結核、2008；83：603-609.
  • 中島由槻、尾形英雄、吉山 崇、御手洗聡、原田登之、樋口一恵、森 亨：結核病棟を有する医療施設における職員のQFT-2Gの経時的変化とツ反検査結果との対比. 結核、2008；83：445-450.
  • 増田宗義、森 亨、原田登之、樋口一恵：集団感染が懸念された大学での薬剤耐性結核事例におけるクォンティフェロン®TB-2Gの有用性. 結核、 2008；83：7-11.
  • 吉山 崇、原田登之、樋口一恵、尾形英雄：接触者検診のためのクォンティフェロン®TB-2G検査のタイミングについて. 結核、2007; 82: 655-658.
  • 樋口一恵、原田登之、長坂裕二、森 亨：結核感染診断法クォンティフェロン®TB-2Gを用いた外国人集団における集団感染疑い事例の検討. 結核、 2007；82：515-521.
  • 森 亨、原田登之：接触者健診におけるQuantiFERON®TB第二世代による感染診断の経費効果分析．結核、2005；80：675-686.
  • 宮下裕文、樋口一恵、東山典子、沖 智子、原田登之、関谷幸江、宍戸 眞司、森 亨： 接触者検診における全血インターフェロンγアッセイを用いた結核感染の診断 -QuantiFERON®TB-2Gを用いた検討-．結核、2005；80：557-564.
  • 原田登之、樋口一恵、関谷幸江、Jim Rothel、木藤 孝、森 亨：結核菌抗原ESAT-6およびCFP-10を用いた結核感染診断法QuantiFERON®TB-2Gの基礎的検討．結核、2004；79：725-735.
  • 原田登之、森 亨、宍戸 眞司、樋口一恵、関谷幸江：集団感染事例における新しい結核感染診断法QuantiFERON®TB-2Gの有効性の検討．結核、2004；79：637-643.
  • 須田 明、鈴木公典、志村昭光、中谷達廣、森 亨、原田登之、樋口一恵, 栗山喬之。高齢者における結核診断法の検討 -ツベルクリン反応二段階試験とインターフェロンアッセイ-．結核、2000；75：511-516.
  • 樋口一恵、原田登之、内山隆司、藤原 寛、上田千里、露口泉夫、中村玲子、小林和夫、青木正和。マクロファージのIL-12産生を高値に誘導する結核菌体成分の解析．結核、1998；73: 531-543.
  • 大友幸二、河端美則、宇田川忠、樋口一恵、山田博之、橋本尚子、岩井和郎。ディーゼル排出ガス粒子のラット肺内注入により形成された実験的肺腺癌および腺腫の免疫組織科学的検索．肺癌誌、1996；36：221-227.
  • 河端美則、岩井和郎、宇田川忠、樋口一恵、山田博之、高橋忠治、橋本尚子。ジーゼル排出ガス中の粒子成分の肺内注入による肺障害性と肺癌. 注入粒子量・反応関係について．大気汚染学会誌、1993；28：11-19.
  • 樋口一恵、石川隆俊、児玉顕一、河端美則、岩井和郎。ラット気管およびヒト気管上皮細胞の不定期DNA合成に及ぼすディーゼル排出粒子の影響について．大気汚染学会誌、1992；27：30-44.
  • 河端美則、宇田川忠、樋口一恵、山田博之、橋本尚子、岩井和郎。ディーゼル排ガス粒子の気管内注入による肺障害と発癌. 注入粒子量・反応関係について．大気汚染学会誌、1988；23：32-40.

英文論文リスト

  • Matsushita I, Hang NT, Hong LT, Tam DB, Lien LT, Thuong PH, Cuong VC, Hijikata M, Kobayashi N, Sakurada S, Higuchi K, Harada N, Keicho N. Dynamics of immune parameters during the treatment of active tuberculosis showing negative interferon-gamma response at the time of diagnosis. J Infect Dis. In press.
  • Yoshiyama T, Harada N, Higuchi K, Saitou M, Kato S. Use of the QuantiFERON®-TB Gold in Tube test for screening TB contacts and predictive value for active TB. Infect Dis. 2015; 47:542-549.
  • Satproedprai N, Wichukchinda N, Suphankong S, Inunchot W, Kuntima T, Kumpeerasart S, Wattanapokayakit S, Nedsuwan S, Yanai H, Higuchi K, Harada N, Mahasirimongkol S. Diagnostic value of blood gene expression signatures in active tuberculosis in Thais: a pilot study. Genes Immun. 2015; 16: 253-260.
  • Hang NT, Matsushita I, Shimbo T, Hong le T, Tam do B, Lien LT, Thuong PH, Cuong VC, Hijikata M, Kobayashi N, Sakurada S, Higuchi K, Harada N, Endo H, Keicho N. Association between tuberculosis recurrence and interferon-γ response during treatment. J Infect. 2014; 69: 616-626.
  • Wakao H, Yoshiko K, Koshimizu U, Furukawa T, Enomoto K, MaTsuda T, Tanaka T, Yasutomi Y, Yamada T, Minakami H, Tanaka J, Oda A, Sasaki T, Wakao R, Lantz O, Udagawa T, Sekiya Y, Higuchi K, Harada N, Nishimura K, Ohtaka M, Nakanishi M, Fujita H. Expansion of functional human mucosal-associated invariant T cells via reprogramming to pluripotency and redifferentation. Cell Stem Cell. 2013;12(5): 546-58.
  • Higuchi K, Sekiya Y, Igari H, Watanabe A, Harada N. Comparison of specificities between two interferon-gamma release assays in Japan. Int J Tuber Lung Dis. 2012; 16: 1190-1192.
  • Hang NT, Lien LT, Kobayashi N, Shimbo T, Sakurada S, Thuong PH, Hong LT, Tem DB, Hijikata M, Matsushita I, Hung VH, Higuchi K, Harada N, Keicho N. Analysis of factors lowering sensitivity of interferon-γ release assay for tuberculosis. PLoS One. 2011; 6(8): e23806.
  • Takayanagi K, Aoki M, Aman K, Mitarai S, Harada N, Higuchi K, Okumura M, Yoshiyama T, Ogata H, Mori T. Analysis of an interferon-gamma release assay for monitoring the efficacy of anti-tuberculosis chemotherapy. Jpn J Infect Dis. 2011; 64: 133-138.
  • Fujita A, Ajisawa A, Harada N, Higuchi K, Mori T. Performance of a Whole-Blood Interferon-Gamma Release Assay with Mycobacterium RD1-Specific Antigens among HIV-Infected Persons. Clin Dev Immunol. 2011; 2011. pii: 325295.
  • Yoshiyama T, Harada N, Higuchi K, Sekiya Y, Uchimura K. Use of the QuantiFERON-TB Gold test for screening tuberculosis contacts and predicting active disease. Int J Tuberc Lung Dis. 2010; 14: 819-827.
  • Ozeki Y, Sugawara I, Udagawa T, Aoki T, Osada-Oka M, Tateishi Y, Hisaeda H, Nishiuchi Y, Harada N, Kobayashi K, Matsumoto S. Transient role of CD4+CD25+ regulatory T cells in mycobacterial infection in mice. Int Immunol. 2010; 22: 179-189.
  • Lien LT, Hang NT, Kobayashi N, Yanai H, Toyota E, Sakurada S, Thuong PH, Cuong VC, Nanri A, Mizoue T, Matsushita I, Harada N, Higuchi K, Tuan LA, Keicho N. Prevalence and risk factors for tuberculosis infection among hospital workers in Hanoi, Viet Nam. PLoS One. 2009; 4: e6798.
  • Hang NT, Ishizuka N, Keicho N, Hong LT, Tam DB, Thu VT, Matsushita I, Harada N, Higuchi K, Sakurada S, Lien LT. Quality assessment of an interferon-gamma release assay for tuberculosis infection in a resource-limited setting. BMC Infect Dis. 2009; 9: 66.
  • Yoshiyama T, Harada N, Higuchi K, Nakajima Y, Ogata H. Estimation of incidence of tuberculosis infection in health-care workers using repeated interferon-gamma assays. Epidemiol Infect. 2009; 137: 1691-1698.
  • Higuchi K, Kondo S, Wada M, Hayashi S, Ootsuka G, Sakamoto N, Harada N. Contact investigation in a primary school using a whole blood interferon-gamma assay. J Infect. 2009; 58: 352-357.
  • Higuchi K, Kawabe Y, Mitarai S, Yoshiyama T, Harada N, Mori T. Comparison of performance in two diagnostic methods for tuberculosis infection. Med Microbiol Immunol. 2009; 198: 33-37.
  • Harada N, Higuchi K, Mori T. Assessment of nosocomial transmission of tuberculosis in a psychiatric hospital using a whole blood interferon-gamma assay. Jpn J Infect Dis. 2008; 61: 415-418.
  • Higuchi K, Harada N, Mori T. Interferon-gamma responses after isoniazid chemotherapy for latent tuberculosis. Respirology. 2008; 13: 468-472.
  • Harada N, Higuchi K, Yoshiyama T, Kawabe Y, Fujita A, Sasaki Y, Horiba M, Mitarai S, Yonemaru M, Ogata H, Ariga H, Kurashima A, Wada A, Takamori M, Yamagishi F, Suzuki K, Mori T, Ishikawa N. Comparison of the sensitivity and specificity of two whole blood interferon-gamma assays for M. tuberculosis infection. J Infect. 2008; 56: 348-353.
  • Higuchi K, Harada N, Fukazawa K, Mori T. Relationship between whole-blood interferon-gamma responses and the risk of active tuberculosis. Tuberculosis. 2008; 88: 244-248.
  • Nishimura T, Hasegawa N, Mori M, Takebayashi T, Harada N, Higuchi K, Tasaka S, Ishizaka A. Accuracy of an interferon-gamma release assay to detect active pulmonary and extra-pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008;12: 269-274.
  • Mori T, Harada N, Higuchi K, Sekiya Y, Uchimura K, Shimao T. Waning of the specific interferon-gamma response after years of tuberculosis infection. Int J Tuberc Lung Dis. 2007; 11: 1021-1025.
  • Higuchi K, Harada N, Mori T, Sekiya Y. Use of QuantiFERON®-TB Gold to investigate tuberculosis contacts in a high school. Respirology. 2007; 12: 88-92.
  • Harada N, Nakajima Y, Higuchi K, Sekiya Y, Rothel J, Mori T. Screening for tuberculosis infection using whole-blood interferon-gamma and Mantoux testing among Japanese healthcare workers. Infect Control Hosp Epidemiol. 2006; 27: 442-448.
  • Mori T, Sakatani M, Yamagishi F, Takashima T, Kawabe Y, Nagao K, Shigeto E, Harada N, Mitarai S, Okada M, Suzuki K, Inoue Y, Tsuyuguchi K, Sasaki Y, Mazurek GH, Tsuyuguchi I. Specific detection of tuberculosis infection with an interferon-gamma based assay using new antigens. Am J Respir Crit Care Med. 2004; 170: 59-64.
  • Higuchi K, Sekiya Y, Harada N. Characterization of M. tuberculosis-derived IL-12-inducing material by alveolar macrophages. Vaccine. 2004; 22: 724-734.
  • Makino K, Yamamoto N, Higuchi K, Harada N, Ohshima H, Terada H. Phagocytic uptake of polystyrene microspheres by alveolar macrophages: effects of the size and surface properties of the microspheres. Colloids Surf B. 2003; 27: 33-39.
  • Higuchi K, Harada N, Yamada H, Kobayashi K, Takeda M. The invasion of Mycobacterium tuberculosis into non-phagocytic cells. Kekkaku. 2000; 75: 649-659.
  • Kariyone A, Higuchi K, Yamamoto S, Nagasaka-Kametaka A, Harada M, Takahashi A, Harada N, Ogasawara K, Takatsu K. Identification of amino acid residues of the T-cell epitope of Mycobacterium tuberculosis  antigen critical for V11+ Th1 cells. Infect Immun. 1999; 67: 4312-4319.
  • Izuhara K, Arinobu Y, Sumimoto H, Nunoi H, Takeya R, Higuchi K, Takashige K, Hamasaki N, Harada N. Association of the interleukin-4 receptor  chain with p47phox, an activator of the phagocyte NADPH oxidase in B cells. Mol Immunol. 1999; 36: 45-52.
  • Harada N, Higuchi K, Wakao H, Hamasaki N, Izuhara K. Identification of the critical portion on the human IL-4 receptor  chain for activation of STAT6. Biochem Biophys Res Commun. 1998; 246: 675-680.
  • Iwai K, Higuchi K, Udagawa T, Ohtomo K, Kawabata Y. Lung tumor induced by long-term inhalation or intratracheal instillation of diesel exhaust particles. Exp Toxic Pathol. 1997; 49: 393-401.
  • Izuhara K, Heike T, Otsuka T, Yamaoka K, Mayumi M, Imamura T, Niho Y, Harada N. Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X-linked severe combined immunodeficiency patients. J Biol Chem. 1996; 271: 619-622.
  • Machii K, Goto S, Yahagi N, Endo O, Fukuoka M, Higuchi K, Iwai K, Matsushita H. Evaluation of umu test using chemiluminescence. J. Environ. Chem. 1996; 6: 211-215.
  • Kawabata Y, Iwai K, Udagawa T, Tukagoshi T, Higuchi K. Effects of diesel soot on unscheduled DNA synthesis of tracheal epithelium and lung tumor formation. In : Carcinogenic and Mutagenic Effects of Diesel Engine Exhaust, N. Ishinishi, A. Koizumi, R.O. McClellan, and W. Stober, eds. Elsevier Science Publishers B.V.(Biomedical Division), p213-222, 1996.
  • Harada N, Izuhara K. (1995). CR2.3 IL-4 receptors (CDw124): structure and function. Leukocyte typing V, p1870-1873. Oxford University Press, Walton Street, Oxford ox2 6DP.
  • Schultz C, Izuhara K, Coffman R, Harada N. The critical region in the cytoplasmic domain of human IL-4 receptor for induction of IgE synthesis. Immunol Lett. 1995; 46: 215-219.
  • Izuhara K, Sakai M, Inaba R, Imamura T, Howard M, Harada N. A synthetic peptide corresponding to a critical intracellular signaling region of the human IL-4 receptor inhibits IL-4-induced proliferation. Cell Immunol. 1995; 163: 254-259.
  • Wakao H, Harada N, Kitamura T, Mui AL-F, Miyajima A. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J. 1995; 14: 2527-2535.
  • Mui AL-F, Wakao H, Harada N, O’Farrell A-M, Miyajima A. Interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 transduce signals through two forms of STAT5. J. Leukocyte Biol. 1995; 57: 799-803.
  • Mui AL-F, Wakao H, O’Farrell A-M, Harada N, Miyajima A. Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J. 1995; 14: 1166-1175.
  • Pruett W, Yuan Y, Rose E, Batzer AG, Harada N, Skolnik EY. Association between GRB2/Sos and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: implications for Ras activation by insulin. Mol Cell Biol. 1995; 15: 1778-1785.
  • Izuhara K, Feldman RA, Greer P, Harada N. Interaction of the c-fes proto-oncogene product with the interleukin-4 receptor. J Biol Chem. 1994; 269: 18623-18629.
  • Hara T, Harada N, Mitsui H, Miura T, Ishizaka T, Miyajima A. Characterization of cell phenotype by a novel cDNA library subtraction system: expression of CD8 in a mast cell-derived interleukin-4-dependent cell line. Blood. 1994; 84: 189-199.
  • Heath AW, Chang R, Harada N, Santos-Argumedo L, Gordon J, Hannum C, Campbell D, Shanafelt AB, Clark EA, Torres R, Howard M. Antibodies to murine CD40 stimulate normal B lymphocytes but inhibit proliferation of B lymphoma cells. Cell Immunol. 1993; 152: 468-480.
  • Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedman MC, Miyajima A, Puri RK, Paul WE, Leonard WJ. Interleukin-2 receptor  chain: functional component of the interleukin-4 receptor. Science. 1993; 262: 1880-1883.
  • Izuhara K, Yang G, Miyajima A, Howard M, Harada N. Structure of the IL4 receptor and signal transduction mechanism of IL4. Res Immunol. 1993; 144: 584-590.
  • Harada N, Santos-Argumedo L, Chang R, Grimaldi JC, Lund FE, Brannan CI, Copeland NG, Jenkins NA, Heath AW, Parkhouse RM, Howard M. Expression cloning of a cDNA encoding a novel murine B cell activation marker. J Immunol. 1993; 151: 3111-3118.
  • Sakamaki K, Wang H-M, Miyajima I, Kitamura T, Todokoro K, Harada N, Miyajima A. Ligand-dependent activation of chimeric receptors with the cytoplasmic domain of the interleukin-3 receptor  subunit (IL3). J Biol Chem. 1993; 268: 15833-15839.
  • Izuhara K, Harada N. Interleukin-4 (IL-4) induces protein tyrosine phosphorylation of the IL-4 receptor and association of phosphatidylinositol 3-kinase to the IL-4 receptor in a mouse T cell line, HT2. J Biol Chem. 1993; 268: 13097-13102.
  • Izuhara K, Miyajima A, Harada N. The chimeric receptor between interleukin-2 receptor  chain and interleukin-4 receptor transduces interleukin-2 signal. Biochem Biophys Res Commun. 1993; 190: 992-1000.
  • Harada N, Yang G, Miyajima A, Howard M. Identification of an essential region for growth signal transduction in the cytoplasmic domain of the human interleukin-4 receptor. J Biol Chem. 1992; 267: 22752-22758.
  • Wrighton N, Campbell LA, Harada N, Miyajima A, Lee F. The murine interleukin-4 receptor gene: genomic structure, expression and potential for alternative splicing. Growth Factors 1992; 6: 103-118.
  • Harada N, Howard M, Miyajima A. (1992). IL-4 receptor. In “IL-4: structure and function” (ed. Spits, H.), p33-54. CRC Press, Inc. Boca Raton, FL.
  • Miyajima A, Kitamura T, Harada N, Yokota T, Arai K. Cytokine receptors and signal transduction. Annu Rev Immunol. 1992; 10: 295-331.
  • Higuchi K, Ishikawa T, Kodama K, Kawabata Y, Iwai K. Effect of diesel soot particle to unscheduled DNA synthesis in rat tracheal epithelium and human bronchial epithelium. J. Japan Soc. Air Pollut. 1992; 27: 30-44.
  • Ishida H, Yang G, Harada N, Hastings RL, Castle BE, Kastelein R, Miyajima A, Howard M. Evaluation of murine interleukin 4 (IL-4) receptor expression using anti-receptor monoclonal antibodies and S1 nuclease protection analyses. Cell Immunol. 1991; 136: 142-154.
  • Galizzi J-P, Zuber CE, Harada N, Gorman DM, Djossou O, Kastelein R, Banchereau J, Howard M, Miyajima A. Molecular cloning of a cDNA encoding the human interleukin 4 receptor. Int Immunol. 1990; 2: 669-675.
  • Zuber CE, Galizzi J-P, Harada N, Durand I, Banchereau J. Interleukin-4 receptors on human blood mononuclear cells. Cell Immunol. 1990; 129: 329-340.
  • Zuber CE, Galizzi J-P, Valle A, Harada N, Howard M, Banchereau J. Interleukin 4 receptors on normal human B lymphocytes: characterization and regulation. Eur J Immunol. 1990; 20: 551-555.
  • Tominaga A, Takahashi T, Kikuchi Y, Mita S, Naomi S, Harada N, Yamaguchi N, Takatsu K. Role of carbohydrate moiety of IL-5: effect of tunicamycin on the glycosylation of IL-5 and the biologic activity of deglycosylated IL-5. J Immunol. 1990; 144: 1345-1352.
  • Harada N, Castle BE, Gorman DM, Itoh N, Schreurs J, Barrett RL, Howard M, Miyajima A. Expression cloning of a cDNA encoding the murine interleukin 4 receptor based on ligand binding. Proc Natl Acad Sci USA. 1990; 87: 857-861.
  • Galizzi J-P, Castle B, Djossou O, Harada N, Cabrillat H, Yahia SA, Barrett R, Howard M, Banchereau J. Purification of a 130-kDa T cell glycoprotein that binds human interleukin 4 with high affinity. J Biol Chem. 1990; 265: 439-444.
  • Yamaguchi N, Takahashi T, Harada N, Takatsu K. Mechanisms of the interleukin 5-induced differentiation of B cells. J Biochem. 1989; 106: 837-843.
  • O’Garra A, Barbis D, Harada N, Lee F, Howard M. Constitutive production of lymphokines by cloned murine B-cell lymphomas-CH12 B lymphoma produces interleukin-4. J Mol Cell Immunol. 1989; 4: 149-158.
  • Murakami S, Ono S, Harada N, Hara Y, Katoh Y, Dobashi K, Takatsu K, Hamaoka T. T-cell-derived factor B151-TRF1/IL-5 activates blastoid cells among unprimed B cells to induce a polyclonal differentiation into immunoglobulin M-secreting cells. Immunology. 1988; 65: 221-228.
  • Mita S, Harada N, Naomi S, Hitoshi Y, Sakamoto K, Akagi M, Tominaga A, Takatsu K. Receptors for T cell-replacing factor/interleukin 5: specificity, quantitation, and its implication. J Exp Med. 1988; 168: 863-878.
  • Koyama N, Harada N, Takahashi T, Mita S, Okamura H, Tominaga A, Takatsu K. Role of recombinant interleukin-1 compared to recombinant T-cell replacing factor/interleukin-5 in B-cell differentiation. Immunology. 1988; 63: 277-283.
  • Takatsu K, Mita S, Harada N, Matsumoto R, Nishikawa S, Tominaga A. (1988). Role of T cell-replacing factor (TRF)/interleukin 5 (IL-5) in the B cell growth and differentiation. In “B cell development” (eds. Howard, M., Witte, O., and Klinman, N.), p173-187. Alan R. Liss, Inc. New York.
  • Takatsu K, Tominaga A, Harada N, Mita S, Matsumoto M, Takahashi T, Kikuchi Y, Yamaguchi N. T cell-replacing factor (TRF)/interleukin 5 (IL-5): molecular and functional properties. Immunol Rev. 1988; 102: 107-135.
  • Tominaga A, Matsumoto M, Harada N, Takahashi T, Kikuchi Y, Takatsu K. Molecular properties and regulation of mRNA expression for murine T cell-replacing factor/IL-5. J Immunol. 1988; 140: 1175-1181.
  • Rasmussen R, Takatsu K, Harada N, Takahashi T, Bottomly K. T cell-dependent hapten-specific and polyclonal B cell responses require release of interleukin 5. J Immunol. 1988; 140: 705-712.
  • Yamaguchi Y, Suda T, Suda J, Eguchi M, Miura Y, Harada N, Tominaga A, Takatsu K. Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors. J Exp Med. 1988; 167: 43-56.
  • Alderson MR, Pike BL, Harada N, Tominaga A, Takatsu K, Nossal GJ. Recombinant T cell replacing factor (interleukin 5) acts with antigen to promote the growth and differentiation of single hapten-specific B lymphocytes. J Immunol. 1987; 139: 2656-2660.
  • Loughnan MS, Takatsu K, Harada N, Nossal, GJ. T-cell-replacing factor (interleukin 5) induces expression of interleukin 2 receptors on murine splenic B cells. Proc Natl Acad Sci USA. 1987; 84: 5399-5403.
  • Naomi S, Umeda T, Sato T, Harada N, Tominaga A, Takatsu K. Production and characterization of monoclonal antibodies against amino-terminus of human -atrial natriuretic polypeptide. Hybridoma 1987; 6: 433-440.
  • Harada N, Takahashi T, Matsumoto M, Kinashi T, Ohara J, Kikuchi Y, Koyama N, Severinson E, Yaoita Y, Honjo T, Yamaguchi N, Tominaga A, Takatsu K. Production of a monoclonal antibody useful in the molecular characterization of murine T-cell-replacing factor/B-cell growth factor II. Proc Natl Acad Sci USA. 1987; 84: 4581-4585.
  • Harada N, Matsumoto M, Koyama N, Shimizu A, Honjo T, Tominaga A, Takatsu K. T cell replacing factor/interleukin 5 induces not only B-cell growth and differentiation, but also increased expression of interleukin 2 receptor on activated B-cells. Immunol Lett. 1987; 15: 205-215.
  • Takatsu K, Kikuchi Y, Takahashi T, Honjo T, Matsumoto M, Harada N, Yamaguchi N, Tominaga A. Interleukin 5, a T-cell-derived B-cell differentiation factor also induces cytotoxic T lymphocytes. Proc Natl Acad Sci USA. 1987; 84: 4234-4238.
  • Matsumoto M, Tominaga A, Harada N, Takatsu K. Role of T cell-replacing factor (TRF) in the murine B cell differentiation: induction of increased levels of expression of secreted type IgM mRNA. J Immunol. 1987; 138: 1826-1833.
  • Tominaga A, Matsumoto M, Takahashi T, Harada N, Takatsu K. Establishment of an assay system for the detection of translated materials of T-cell-replacing factor mRNA in Xenopus oocytes. Microbiol Immunol. 1986; 30: 789-798.
  • Kanashi T, Harada N, Severinson E, Tanabe T, Sideras P, Konishi M, Azuma C, Tominaga A, Bergstedt-Lindqvist S, Takahashi M, Matsuda F, Yaoita Y, Takatsu K, Honjo T. Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. Nature. 1986; 324: 70-73.
  • Sano Y, Harada N, Takatsu K. Three functionally distinct helper T-cell clones: the roles for antigen non-specific helper factors in B-cell activation through two different pathways. Immunology 1985; 56: 585-596.
  • Harada N, Kikuchi Y, Tominaga A, Takaki S, Takatsu K. BCGFII activity on activated B cells of a purified murine T cell-replacing factor (TRF) from a T cell hybridoma (B151K12). J Immunol. 1985; 134, 3944-3951.
  • Takatsu K, Harada N, Hara Y, Takahama Y, Yamada G, Dobashi K, Hamaoka T. Purification and physicochemical characterization of murine T cell replacing factor (TRF). J Immunol. 1985; 134: 382-389.
  • Okamoto M, Nakamura H, Harada N, Shirasaka T, Fujii S. Characterization of the activity of growth factor from AH-130 tumor cells. Gann. 1984; 75: 136-142.
  • Nakamura H, Yu-Qin W, Miyauchi S, Nishioka N, Tanaka H, Harada N, Shirasaka T, Fujii S. Studies on the mechanism of antitumor activity of 5-FU and its derivatives–relationship between the inhibition of tumor growth and the inhibition of thymidylate synthetase in vivo. Gan to Kagaku Ryoho. 1984; 11: 1049-1055.
  • Chiba T, Kawai K, Ikenaka K, Nakamura H, Okamoto M, Harada N, Tanaka H, Shirasaka T, Fujii S. Effect of an exogenous energy source and amino acids on DNA synthesis in regenerating rat liver. Biochim. Biophys. Acta. 1983; 755: 420-427.
  • Harada N, Okamoto M, Ogata Y, Shirasaka T, Fujii S. Growth factor from tumor cells. Gann. 1982; 73: 391-397.
  • Harada N, Shirasaka T, Fujii S. DNA synthesis in tumor-bearing rats: purification of liver thymidine kinase stimulating factor from Yoshida sarcoma. Gann. 1980; 71: 173-180.