Takao Hidaka

Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer.

Foxp3+ CD4+CD25+ regulatory T (Treg) cells and immunoregulatory enzyme indoleamine 2,3‐dioxygenase (IDO) play an important role in immunoregulation. Accumulating evidence shows that IDO and Treg cells have potent regulatory properties for immune escape in cancer. To evaluate the expression of IDO and the localization of Foxp3+ Treg cells in the development and progression of uterine cervical cancer, IDO expression and Foxp3+ Treg cells in the primary and metastatic lesions were studied using immunohistochemistry. IDO expression in tumor cells appeared in cervical intraepithelial neoplasia (CIN)‐3 of the uterine cervix and marked expression in microinvasive cancer cells was observed. Interestingly, IDO expression in invasive cancer was confined to the cancer cells at the invasive front. Moreover, antigen‐presenting cells (APC) at the invasive front in primary and metastatic lesions were also expressing IDO. Stromal Foxp3+ Treg cells appeared in CIN‐3 and increased in microinvasive and invasive cancer. Intraepithelial Foxp3+ Treg cells were restricted within microinvasive and invasive cancer. No significant differences in the proportion of Foxp3+/CD4+ in the stroma or epithelium, or between non‐metastatic and metastatic invasive cancers, were observed in primary lesions of cervical cancer, while there was a significant increase (P < 0.005) in the proportion of Foxp3+/CD4+ in metastatic lymph nodes compared with non‐metastatic lymph nodes. Some of the Foxp3+ Treg cells in metastatic lymph nodes contacted the IDO+ APC. IDO expression at the invasive front of cancer cells and APC, and the localization of Foxp3+ Treg cells in front of cancer tissues, may create a network between IDO and Treg for the induction of immune escape. (Cancer Sci 2007; 98: 874–881)

Circulating and decidual Th17 cell levels in healthy pregnancy.

Citation Nakashima A, Ito M, Yoneda S, Shiozaki A, Hidaka T, Saito S. Circulating and decidual Th17 cell levels in healthy pregnancy. Am J Reprod Immunol 2010; 63: 104–109

Accumulation of IL-17-positive cells in decidua of inevitable abortion cases.

Citation Nakashima A, Ito M, Shima T, Bac ND, Hidaka T, Saito S. Accumulation of IL‐17‐positive cells in decidua of inevitable abortion cases. Am J Reprod Immunol 2010

A role for IL-17 in induction of an inflammation at the fetomaternal interface in preterm labour

Chorioamnionitis (CAM) is a major cause of preterm delivery. Inflammatory cytokines and chemokines play important roles in the pathogenesis of preterm delivery. Interleukin (IL)-17 is a key cytokine which induces inflammation and is critical to host defense. In this study, we examined the role of IL-17 in the pathogenesis of preterm delivery. The levels of cytokines including IL-17, IL-8 and tumor necrosis factor (TNF) alpha were measured by ELISA in amniotic fluid from 154 cases of preterm labor. Flow cytometry and immunohistochemical staining were performed to determine the distribution of IL-17-producing cells. IL-8 secretion was evaluated in primary cultured human amniotic mesenchymal (HAM) cells and human amniotic epithelial (HAE) cells stimulated with IL-17, TNFalpha or IL-1beta. We also studied the signaling pathway of IL-17 and TNFalpha in HAM cells. Levels of inflammatory cytokines in amniotic fluid were higher in preterm delivery cases than in term delivery cases. Furthermore, IL-8, IL-17 and TNFalpha levels were significantly higher in the preterm cases with CAM stage II or III than those without CAM. Flow cytometry and immunohistochemical staining revealed that CD3(+)CD4(+) T cells were the main source of IL-17 in the chorioamniotic membrane. Interestingly, TNFalpha-induced IL-8 secretion was enhanced by IL-17 in a dose-dependent manner in HAM cells. The IKK inhibitor BMS-345541 and mitogen-activated protein kinase (MAPK) inhibitors p38, JNK and p42/44 (ERK1/2 pathway) reduced IL-8 secretion by IL-17-stimulated and TNFalpha-stimulated HAM cells. These results indicate that IL-17, produced by T cells, promotes inflammation at the fetomaternal interface in preterm delivery.

SHORT COMMUNICATION: Circulating and Decidual Th17 Cell Levels in Healthy Pregnancy

Citation Nakashima A, Ito M, Yoneda S, Shiozaki A, Hidaka T, Saito S. Circulating and decidual Th17 cell levels in healthy pregnancy. Am J Reprod Immunol 2010; 63: 104–109

Absence of estrogen receptor-α expression in human ovarian clear cell adenocarcinoma compared with ovarian serous, endometrioid, and mucinous adenocarcinoma

The mechanism that regulates growth in ovarian clear cell adenocarcinoma (CCA) is not well understood. A high incidence of concurrent endometriosis with CCA may indicate that estrogen is a growth promotor in CCA. To determine estrogen as a growth promotor, the authors investigated the presence or absence of estrogen receptor-&agr; (ER-&agr;), ER-&bgr;, progesterone receptor, and dioxin receptor (i.e., aromatic hydrocarbon receptor) in clinically resected ovarian CCA, serous adenocarcinoma (SAC), endometrioid adenocarcinoma (EAC), and mucinous adenocarcinoma (MAC) specimens using an immunohistochemical method. Expression of ER-&agr; and ER-&bgr; messenger ribonucleic acid was examined by reverse transcription–polymerase chain reaction in three established CCA cell lines: KK, RMG-1, and HAC-II. None of the surgically resected CCA and CCA cell lines showed positive staining for ER-&agr;. Conversely, 97.2% of SACs, 100% of EACs, and 70% of MACs showed positive nuclear staining for ER-&agr; (p <0.001). Conversely, positive ER-&bgr; staining for CCA (39.3%) was similar to that of SAC (41.7%) and MAC (30.0%). EAC (75%) showed a higher expression of ER-&bgr; (p <0.02). Progesterone receptor was detected in only 10.7% of CCA, compared with SAC and EAC (SAC, 86.1%; EAC, 91.7%; p <0.01). Aromatic hydrocarbon receptor was detected in all histologic types at an incidence of approximately 50% to 60%. Messenger ribonucleic acid of ER-&agr; and ER-&bgr; was not detected in the three CCA cell lines. These findings indicate biologic characteristics that distinguish CCA from other types of ovarian epithelial cancer.

HER2 Is Frequently Over‐expressed in Ovarian Clear Cell Adenocarcinoma: Possible Novel Treatment Modality Using Recombinant Monoclonal Antibody against HER2, Trastuzumab

Ovarian clear cell adenocarcinoma (CCA) is generally chemo‐resistant. Recently the poor prognosis and resistance to chemotherapeutic agents of HER2/neu over‐expressing tumors have become clear. Thus, we investigated the expression level of HER2 in surgically resected CCA and ovarian serous adenocarcinoma, endometrioid adenocarcinoma, and mucinous adenocarcinoma specimens, as well as CCA cell lines, by an immunohistochemical method. HER2 was over‐expressed in 42.9% of CCA (P=0.026, vs. ovarian serous adenocarcinoma), 20.8% of ovarian serous adenocarcinoma, 23.1% of ovarian endometrioid adenocarcinoma, and 30.0% of mucinous adenocarcinoma specimens. Three CCA cell lines, RMG‐1, HAC‐II and KK were also positively stained for HER2. A flow‐cytometric study of HER2 revealed 7.2‐, 6.4‐ and 4.5‐fold greater expression of HER2 than that of normal mammary gland, respectively. Trastuzumab, a humanized recombinant monoclonal antibody against HER2 significantly and dose‐dependently reduced the growth of CCA cell lines in vitro. The extent of the inhibitory effect of trastuzumab was dependent on the expression level of HER2. Trastuzumab also dose‐dependently inhibited the growth of xenografted RMG‐1 tumor. The survival period of trastuzumab‐treated mice was longer than that of the control group. From these findings, trastuzumab appears to be a candidate as a treatment modality for HER2 over‐expressing ovarian CCA.

Herbal medicine Shakuyaku-kanzo-to reduces paclitaxel-induced painful peripheral neuropathy in mice.

Objectives: Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors such as breast, ovarian and lung cancer. However, it sometimes induces moderate to severe muscle pain, and impairs the patients’ quality of life. An appropriate method for relieving this pain is not well established. Shakuyaku‐kanzo‐to, a herbal medicine, is known to relieve menstrual pain, muscle spasm, and muscle pain, and its effectiveness is expected. To ascertain the effectiveness of Shakuyaku‐kanzo‐to on paclitaxel‐induced pain, we investigated the effects of Shakuyaku‐kanzo‐to and its constituent herbal medicines in a mouse model.

Interleukin‐8 and glucose in amniotic fluid, fetal fibronectin in vaginal secretions and preterm labor index based on clinical variables are optimal predictive markers for preterm delivery in patients with intact membranes

Aim:  Various predictive markers for preterm delivery have been proposed in previous studies. We investigated which marker is most reliable.

Prediction of exact delivery time in patients with preterm labor and intact membranes at admission by amniotic fluid interleukin‐8 level and preterm labor index

Aim:  To examine whether delivery time for preterm labor can be predicted by clinical and biochemical markers at admission.