Studies on immunological strategy against gynecological cancers through mucosal immunity of reproductive tract mucosa.

• Project/Area Number: 18591823
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: KAWANA Kei The University of Tokyo, The University of Tokyo, Hospital, lecturer (60311627)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: gynecologic oncology / reproductive tract mucosa / mucosal lymphocyte / cervical cancer / CD1d / HPV therapeutic vaccine / 粘膜免疫 / ヒトパピローマウイルス(HPV) / 子宮頸部リンパ球 / CD1d

Research Abstract

Mucosal epithelia of human lower reproductive tract (vagina, cervix, and penile urethra) are exposed to sexually transmitted microbes, including Chlamydia trachomatis and Human papillomavirus (HPV). The in vivo susceptibility of each tissue to infection by Chlamydia trachomatis is quite distinct. CD Id is expressed on the surface of antigen presenting cells, including mucosal epithelial cells, and interacts specifically with invariant NKT cells. Invariant NKT cells play a role in both innate and adaptive immune responses to microbes. Immortalized epithelial cell lines from the human lower reproductive tract (vagina, endocervix, and penile urethra) were examined for CD1d expression and for ligand-induced cytokine production induced by CD1d crosslinking. CD1d expression in normal tissues was strong in the vagina but weak in endocervix and penile urethra. Flow cytometry revealed that cell-surface expression of CD1d was observed in the vaginal and penile urethral epithelial cells but not e ndocervical cells. Ligation of surface-expressed CD1d using monoclonal antibody crosslinking promoted IL-12 and IL-15, but not IL-10, production in vaginal and penile urethral cells. No induction was demonstrated in endocervical cells. Basal deficiency in CD1d-mediated immune responsiveness may result in susceptibility to sexually transmitted agents. Decreased CD1d-mediated signaling may help Chlamydia trachomatis and HPV evade detection by innate immune cells.
Previous therapeutic vaccines against human papillomavirus (HPV) E6/E7 oncogenic proteins have been administered intramuscularly or subcutaneously. We here addressed mucosal cytotoxic cellular immune response to HPV16 E7 on oral immunization of mice with Lactobacillus casei expressing HPV16E7 (LacE7). Cell-surface Integrin α4β7, a gut mucosal homing receptor, was expressed in 70-80% of murine intestinal mucosal lymphocyte and expressed in 15% of human cervical lymphocyte indicating that intestinal mucosal T cell homes to cervical mucosa in human. Oral immunization with LacE7 elicited IFNγ-producing Th1 cells recognizing E7 CTL epitope in the mucosal lymphocyte whereas that with vehicle alone did not. The induction of E7-specific Thl response was enhanced by boost immunization at week 8. Oral immunization with LacE7 induced E7-specific Thl response in the mucosal lymphocyte more strongly than splenocyte whereas intramuscularly immunization with GST-E7 did in splenocyte more strongly than mucosal lymphocyte. Oral immunization with LacE7 elicited E7-specific mucosal cytotoxic cellular immune response more effectively than intramuscularly immunization. This strategy may achieve more effective clinical clearance of high-grade CIN with mucosal cellular immune responses.

Research Products

• [Journal Article] Expression of CDld and ligand-induced cytokine productionare tissue-specific in mucosal epithelia of the human lower reproductive tract. (2008)
  • Author(s): Kawana K. Matsumoto J, Miura S, Shen L, Kawana Y, Nagamatsu T, Yasugi T, Fujii T, Yang H, Quayle AJ, Taketani Y, Schust DJ
  • Journal Title: Infection and Immunity 76 Pages: 3011-3018
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prolactin can modulate CD4^+ T cell response through receptor-mediated alterations in the expression of T-bet. (2008)
  • Author(s): Tomio A, Schust DJ, Kawana K, Yasugi T, Kawana Y, Mahalingaiah S, Fujii T, Taketani Y
  • Journal Title: Immunology and Cell Biology 86 Pages: 616-621
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of surface CDld in the extra-villous trophoblast cells of early gestation placenta is downregulated through TGF-β1 in a manner dependent on trophoblast differentiation. (2008)
  • Author(s): Matsumoto J, Kawana K, Nagamatsu T, Schust DJ, Fujii T, Sato H, Yasugi T, Kozuma S, Taketani Y
  • Journal Title: Biochemical and Biophysjological Research Commumcation 371 Pages: 236-241
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cyclic Regulation of T-Bet and GATA-3 in Human Endometrium. (2008)
  • Author(s): Inman DA, Kawana K, Schust DJ, Lininger RA, Young SL
  • Journal Title: Reproductive Sciences 15 Pages: 83-90
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of CD Id and ligand-induced cytokine production are tissue-specific in mucosal epithelia of the human lower reproductive tract. (2008)
  • Author(s): Kawana K. Matsumoto J, Miura S, Shen L, Kawana Y, Nagamatsu T, Yasugi T, Fujii T, Yang H, Quayle AJ, Taketani Y, Schust DJ
  • Journal Title: InfectImmun 76 Pages: 3011-3018
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prolactin can modulate CD4^+ T cell response through receptor-mediated alterations in the expression of T-bet. (2008)
  • Author(s): Tomio A, Schust DJ, Kawana K. Yasugi T, Kawana Y, Mahalingaiah S, Fujii T, Taketani Y
  • Journal Title: Immunol Cell Biol 86 Pages: 616-621
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cyclic Regulation of T-Bet and GATA-3 in Human Endometrium. (2008)
  • Author(s): Inman DA, Kawana K. Schust DJ, Lininger RA, Young SL
  • Journal Title: Reproductive Sciences 15 Pages: 83-90
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of surface CD Id in the extra-villous trophoblast cells of early gestation placenta is downregulated through TGF-J31 in a manner dependent on trophoblast differentiation. (2008)
  • Author(s): Matsumoto J, KawanaK, Nagamatsu T, Schust DJ, Fujii T, Sato H, Yasugi T, Kozuma S, Taketani Y
  • Journal Title: Biochem Biophys Res Commun 371 Pages: 236-241
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human papillomavirus type 16 capsid proteins : Immunogenicity and possible use as prophylactic vaccine antigens. (2008)
  • Author(s): Kanda T, Kawana K, Yoshikawa H
  • Journal Title: Structure-based study of viral replication, Chapter 19 (World Scientific Publishing Co.) Pages: 517-538
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CDld degradation in Chlamydia trachomatis-infected epithelial cells is a result of both cellular and chlamydial proteasomal activity. (2007)
  • Author(s): Kawana K, Quayle AJ, Ficarra M. Ibana JA, Shen L, Kawana Y, Greene S, Yang H, Yavagal S, Marrero L, Zhang YX, Pyles RB, Blumberg RS, Schust DJ
  • Journal Title: Journal of Biological Chemistry 282 Pages: 7368-7375
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. (2007)
  • Author(s): Arimoto T, Nakagawa S, Yasugi T, Yoshikawa H, Kawana K, Yano T, Taketani Y.
  • Journal Title: Gynecologic Oncology 104 Pages: 32-35
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] CD1d degradation in Chlamydia trachomatis-infected epithelial cells is a result of both cellular and chlamydial proteasomal activity. (2007)
  • Author(s): Kawana K. Quayle AJ, Ficarra M, Ibana JA, Shen L, Kawana Y, Greene S, Yang H, Yavagal S, Marrero L, Zhang YX, Pyles RB, Blumberg RS, Schust DJ
  • Journal Title: J Biol Chem 282 Pages: 7368-7375
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CDld degradation in Chlamydia trachomatis-infected epithelial cells is a result of both cellular and chlamydial proteasomal activity. (2007)
  • Author(s): Kawana, Quayle AJ, Ficarra M, Ibana JA, Shen L, Kawana Y, Greene S, Yang H, Yavagal S, Marrero L, Zhang YX, Pyles RB, Blumberg RS,
  • Journal Title: Journal of Biological Chemistry 282(10) Pages: 7368-7375
  • Peer Reviewed
• [Journal Article] Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. (2007)
  • Author(s): Arimoto T, Nakagawa S, Yasugi T, Yoshikawa H, Kawana K, Yano T, Taketani Y
  • Journal Title: Gynecologic Oncology 104 Pages: 32-35
  • Peer Reviewed
• [Journal Article] CD1d degradation in Chlamydia trachomatis-infected epithelial cells is a result of both cellular and chlamydial proteasomal activity. (2007)
  • Author(s): Kawana K, Quayle AJ, Ficarra M, Ibana JA, Shen L, Kawana Y, Greene S, Yang H, Yavagal S, Marrero L, Zhang YX, Pyles RB, Blumberg RS, Schust DJ
  • Journal Title: Journal of Biological Chemistry 282(10) Pages: 7368-7375
• [Journal Article] Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. (2007)
  • Author(s): Arimoto T, Nakagawa S, Yasugi T, Yoshikawa H, Kawana K, Yano T, Taketani Y
  • Journal Title: Gynecologic Oncology. 104 Pages: 32-35
• [Presentation] Oral Immunization with Lactobacillus casei expressing HPV E7 elicits strong mucosal CTL response to HPV16 E7. (2008)
  • Author(s): Kawana K, Yokoyama T, Yasugi T, Sewaki T, Fujii T, Yano, T, Osanai Y, Taketani Y.
  • Organizer: 3^<rd> Biennial conference of Asia Oceania Research Organization on Genital Infections and Neoplasia
  • Place of Presentation: Seoul
  • Year and Date: 2008-05-30
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] シンポジウム3 性感染症における母子感染対策[4]HPV (2007)
  • Author(s): 川名敬
  • Organizer: 第20回日本性感染症学会
  • Place of Presentation: 東京
  • Year and Date: 2007-12-01
• [Presentation] CDld degradation in Chlatnydia trachomatis-infected epithelial cells is the resultof both cellular and Chlamydial proteasomal activities. (2007)
  • Author(s): Kawana K, Kawana Y, Matsumoto J, Sato H, Nagamatsu T, Fujii T, Yasugi T, Schust DJ, Taketani Y.
  • Organizer: 20^<th> Asia and Oceania Congress of Obstetrics and Gynecology
  • Place of Presentation: Tokyo
  • Year and Date: 2007-09-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] CD Id degradation in Chlamydia trachomatis-infected epithelial cells is the result of both cellular and Chlamydial proteasomal activities. (2007)
  • Author(s): Kawana K, Kawana Y, Matsumoto J, Sato H, Nagamatsu T, Fujii T, Yasugi T, Schust DJ, Taketani Y.
  • Organizer: 20^<th> Asia and Oceania Congress of Obstetrics and Gynecology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Structure-based study of viral replication (2008)
  • Author(s): Kanda T, Kawana K. Yoshikawa H
  • Publisher: World Scientific Publishing Co.
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Structure-based study of viral replication, Chapter 19: Human papillomavirus type 16 capsid proteins: Immunogenicity and possible use as prophylactic vaccine antigens. (2008)
  • Author(s): Kanda T, Kawana K, Yoshikawa H
  • Total Pages: 638
  • Publisher: World Scientific Publishing Co.