| Project/Area Number |
18591823
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KAWANA Kei The University of Tokyo, The University of Tokyo, Hospital, lecturer (60311627)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥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)
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| 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
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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. Less
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