Trial of disease specific immunotherapy using antigen-specific T cells and immunoregulatory genes.

• Project/Area Number: 16590980
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kyoto University
• Principal Investigator: USUI Takshi Kyoto University, Faculty of Medicine, Assistant Professor (90362483)
• Co-Investigator(Kenkyū-buntansha): NISHIKOMORI Ryuta Kyoto University, Faculty of Medicine, Assistant Professor (70359800) ; WAKATSUKI Yoshio Kyoto University, Faculty of Medicine, Lecturer (40220826)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: helper T cell / Th1 / Th2 / T-bet / STAT4 / STAT1 / IFN-gamma / レトロウイルス / 関節リウマチ / TGF-beta / 細胞移入療法 / type II collagen / 制御性T細胞 / IL-10 / TGF-β / 自己免疫疾患 / 関節リマウチ

Research Abstract

The aim of this re-search is to establish disease-specific immunotherapy using antigen-specific T cells and immunoregulatory genes. To perform this, it is very important to know what is the critical factor for helper T cells to work as regulatory cells. Therefore, we investigate the molecular mechanism of helper T cell development in the context of Th1 and Th2 cells. T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT) 4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet -/- mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti-interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet -/- mice manifest IFNG promoter accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet -/- cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/1L-12Rβ2 chain unless GATA-3 levels or function is regulated by T-bet Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene.

Research Products

• [Journal Article] Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopathic inflammatory myopathies (2006)
  • Author(s): Yoshifuji H, Fujii T, Kobayashi S, Imura Y, Fujita Y, Kawabata D, Usui T, Tanaka M, Nagai S, Umehara H, Mimori T
  • Journal Title: Autoimmunity 39 Pages: 233-41
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription (2006)
  • Author(s): Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O'Shea JJ, Strober W.
  • Journal Title: J Exp Med 203 Pages: 755-66
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopathic inflammatory myopathies (2006)
  • Author(s): Yoshifuji H, Fujii T, Kobayashi S, Imura Y, Fujita Y, Kawabata D, Usui T, Tanaka M, Nagai S, Umehara H, Mimori T.
  • Journal Title: Autoimmunity 39(3) Pages: 233-41
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription (2006)
  • Author(s): Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O'Shea JJ, Strober W.
  • Journal Title: J Exp Med. 203(3) Pages: 755-66
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. (2006)
  • Author(s): Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O'shea JJ, Strober W.
  • Journal Title: J Exp Med. 203(3) Pages: 755-766
• [Journal Article] Host factors are important in determining clinical outcomes of Helicobacter pylori infection. (2006)
  • Author(s): Chiba T, Seno H, Marusawa H, Wakatsuki Y, Okazaki K.
  • Journal Title: J Gastroenterol. 41(1) Pages: 1-9
  • NAID: 10017328156
• [Journal Article] Plasma ghrelin levels in healthy elderly volunteers : the levels of acylated ghrelin in elderly females correlate positively with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure. (2006)
  • Author(s): Akamizu T, Murayama T, Teramukai S, Miura K, Bando I, Irako T, Iwakura H, Ariyasu H, Hosoda H, Tada H, Matsuyama A, Kojima S, Wada T, Wakatsuki Y, Matsubayashi K, Kawakita T, Shimizu A, Fukushima M, Yokode M, Kangawa K.
  • Journal Title: J Endocrinol. 188(2) Pages: 333-344
• [Journal Article] Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation : a case report. (2006)
  • Author(s): Mizumoto H, Hata D, Yamamoto K.Shirakawa R, Kumakura A, Shiota M, Yokoyama A, Matsubara H, Kobayashi M, Nishikomori R, Adachi S, Nakahata T, Kita T, Horiuchi H, Yasukawa M, Ishii E.
  • Journal Title: Eur J Pediatr. 14 Pages: 1-5
• [Journal Article] Immune and inflammatory reaction to Helicobacter pylori in the stomach (2005)
  • Author(s): Wakatsuki Y.
  • Journal Title: Nippon Rinsho 63 Suppl 11 Pages: 150-155
• [Journal Article] Th response to Helicobacter pylori differs between patients with gastric ulcer and duodenal ulcer. (2005)
  • Author(s): Itoh T, Seno H, Kita T, Chiba T, Wakatsuki Y.
  • Journal Title: Scand J Gastroenterol 40(6) Pages: 641-647
• [Journal Article] CD4+CD25+ T cells regulate colonic localization of CD4 T cells reactive to a microbial antigen. (2005)
  • Author(s): Watanabe T, Yamori M, Kita T, Chiba T, Wakatsuki Y.
  • Journal Title: Inflamm Bowel Dis. 11(6) Pages: 541-550
• [Journal Article] Somatic mosaicism of CIASI in a patient with chronic infantile neurologic, cutaneous, articular syndrome. (2005)
  • Author(s): Saito M, Fujisawa A, Nishikomori R, Kambe N, Nakata-Hizume M, Yoshimoto M, Ohmori K, Okafuji I, Yoshioka T, Kusunoki T, Miyachi Y, Heike T, Nakahata T.
  • Journal Title: Arthritis Rheum. 52(11) Pages: 3579-3585
• [Journal Article] The cytosolic pattern-recognition receptor Nod2 and inflammatory granulomatous disorders. (2005)
  • Author(s): Kambe N, Nishikomori R, Kanazawa N.
  • Journal Title: J Dermatol Sci. 39(2) Pages: 71-80
  • NAID: 10018031497
• [Journal Article] SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. (2005)
  • Author(s): Kusunoki T, Okafuji I, Yoshioka T, Saito M, Nishikomori R, Heike T, Sugai M, Shimizu A, Nakahata T.
  • Journal Title: J Allergy Clin Immunol. 115(3) Pages: 636-638