Authorship：Corresponding author   Language：English  

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This review examines associations of nutrients and dietary preferences with recurrent pregnancy loss (RPL), miscarriage, and infertility. Research articles, reviews, and meta-analyses of RPL and infertility that focused on nutrition, meals, and lifestyle were reviewed, and associations of nutrients and dietary preferences with pregnancy are discussed in relation to recent research findings. Studies related to RPL were given the highest priority, followed by those dealing with miscarriage and infertility. Multivitamin supplements-even when lacking folic acid or vitamin A-reduced total fetal loss. High-dose folic acid supplementation before conception reduced the risk of miscarriage and stillbirth. A meta-analysis revealed a strong association of vitamin D deficiency/insufficiency with miscarriage. Another meta-analysis revealed that seafood and dairy products reduced the risk of miscarriage, whereas a caffeine intake of 300 mg/day or more was associated with miscarriage. A balanced diet that included nutrients with antioxidant properties helped prevent miscarriage, whereas a diet that included processed foods and nutrients with proinflammatory effects increased the risk of miscarriage. Associations of nutrients with RPL warrant further research.

DOI： 10.1272/jnms.JNMS.2024_91-313

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The abdominal wall is an uncommon site for endometriosis that occurs in the soft tissues of the wound site after laparotomy. The present study reviewed cases of post-cesarean section abdominal wall endometriosis that were surgically treated at our institution from April 2007 to August 2020. We analyzed data from nine patients who were diagnosed with abdominal wall endometriosis and selected surgery after receiving sufficient explanation of hormone therapy and from patients who reported no improvement in symptoms with hormone therapy. Written consent for case reporting was obtained from all patients. The location of abdominal wall endometriosis was at the wound site in seven cases and outside the wound in two cases. In addition, 7/9 (78%) of post-cesarean cases of abdominal wall endometriosis were related to the cesarean procedure, and 6/9 (67%) of the cases had symptoms related to menstruation. Post-cesarean abdominal endometriosis was associated with pain (7/9; 78%) and a palpable mass (3/9; 33%). Surgical resection did not cause large tissue defects, and artificial repairs such as synthetic mesh were not required for any patient. In conclusion, women with a history of a cesarean section who present with recurrent pain or masses in the wound or abdominal wall that coincide with the menstrual cycle should be closely evaluated for abdominal wall endometriosis. Because surgical treatment often requires postoperative wound reconstruction, collaboration with plastic surgeons and dermatologists is essential.

DOI： 10.1272/jnms.JNMS.2024_91-604

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.placenta.2023.08.046

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DOI： 10.1016/j.placenta.2023.08.026

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

OBJECTIVE: Sterile inflammation, initiated by endogenous molecules such as high-mobility group box-1 (HMGB1), has come to be recognized as a critical mechanism in a variety of chronic diseases. To elucidate the involvement of sterile inflammation in neonatal disease, the association between serum HMGB1 levels and the development of bronchopulmonary dysplasia (BPD) was evaluated. STUDY DESIGN: Serum HMGB1 levels were measured in 25 premature infants born before 33 weeks of gestation, excluding any infection cases. Samples were collected at birth, two, and four weeks of age and compared according to BPD status. RESULTS: The serum HMGB1 levels in infants with BPD were maintained up to 4 weeks of age, while those without BPD declined with time. Postnatal cardiopulmonary and nutritional transition was delayed in infants with BPD. CONCLUSION: Sustained elevation of serum HMGB1 levels was associated with the development of BPD, suggesting that prolonged sterile inflammation may contribute to lung injury.

DOI： 10.1080/14767058.2021.1931102

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Preterm birth (PB) is the most-frequent complication occurring during pregnancy, with a significant impact on neonatal morbidity and mortality. Chorioamnionitis (CAM), the neutrophil infiltration into chorioamniotic membranes, is a major cause of PB. However, several cases of PB have also been reported without apparent pathogenic infection or CAM. Such cases are now attributed to "sterile inflammation." The concept of sterile inflammation has already attracted attention in various diseases, like cardiovascular diseases, diabetes, and autoimmune diseases; recently been discussed for obstetric complications such as miscarriage, PB, gestational hypertension, and gestational diabetes. Sterile inflammation is induced by alarmins, such as high-mobility group box 1 (HMGB1), interleukins (IL-33 and IL-1α), and S100 proteins, that are released by cellular damage without apparent pathogenic infection. These antigens are recognized by pattern-recognition receptors, expressed mainly on antigen-presenting cells of decidua, placenta, amnion, and myometrium, which consequently trigger inflammation. In reproduction, these alarmins are associated with the development of various pregnancy complications, including PB. In this review, we have summarized the development of PB related to acute CAM, chronic CAM, and sterile inflammation as well as proposed a new mechanism for PB that involves innate immunity, acquired immunity, and sterile inflammation.

DOI： 10.1016/j.jri.2022.103748

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Language：Japanese  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1272/manms.18.194

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

A few long noncoding RNAs (long ncRNAs, lncRNAs) exhibit trophoblast cell type-specific expression patterns and functional roles in mouse placenta. However, the cell- and stage-specific expression patterns and functions of most placenta-derived lncRNAs remain unclear. In this study, we explored mouse placenta-associated lncRNAs using a combined bioinformatic and experimental approach. We used the FANTOM5 database to survey lncRNA expression in mouse placenta and found that 1600012P17Rik (MGI: 1919275, designated P17Rik), a long intergenic ncRNA, was the most highly expressed lncRNA at gestational day 17. Polymerase chain reaction analysis confirmed that P17Rik was exclusively expressed in placenta and not in any of the adult organs examined in this study. In situ hybridization analysis revealed that it was highly expressed in spongiotrophoblast cells and to a lesser extent in glycogen trophoblast cells, including migratory glycogen trophoblast cells invading the decidua. Moreover, we found that it is a polyadenylated lncRNA localized mainly to the cytoplasm of these trophoblast cells. As these trophoblast cells also expressed the neighboring protein-coding gene, pappalysin 2 (Pappa2), we investigated the effects of P17Rik on Pappa2 expression using Pappa2-expressing MC3T3-E1 cells and found that P17Rik transfection increased the messenger RNA (mRNA) and protein levels of Pappa2. These results indicate that mouse placenta-specific lncRNA P17Rik modulates the expression of the neighboring protein-coding gene Pappa2 in spongiotrophoblast and glycogen trophoblast cells of mouse placenta during late gestation.

DOI： 10.1007/s00418-022-02109-w

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Other Link： https://link.springer.com/article/10.1007/s00418-022-02109-w/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

PURPOSE: Granulysin is a cytotoxic protein that simultaneously activates innate and cellular immunity. The authors aimed to evaluate whether granulysin is associated with the antiphospholipid antibody syndrome and whether heparin changes the granulysin levels. METHODS: A cohort study was performed with women with antiphospholipid antibody-positive recurrent pregnancy loss (RPL). The authors examined granulysin levels under RPL and evaluated the changes in serum granulysin levels before and 1 week after the commencement of heparin treatment. RESULTS: Serum granulysin levels before heparin treatment were significantly higher in women who tested positive for one or more types of antiphospholipid antibodies (2.75 ± 1.03 vs. 2.44 ± 0.69, p = 0.0341 by Welch's t test), particularly anti-phosphatidylethanolamine antibodies (IgG: 2.98 ± 1.09 vs. 2.51 ± 0.86, p = 0.0013; IgM: 2.85 ± 1.09 vs. 2.47 ± 0.77, p = 0.0024 by Welch's t test). After heparin treatment for 1 week, serum granulysin levels were significantly reduced (p = 0.0017 by the paired t test). The miscarriage rate was significantly higher in women whose serum granulysin levels were not reduced by heparin treatment (p = 0.0086 by Fisher's exact probability test). CONCLUSION: The results suggest that heparin may reduce the incidence of miscarriage by suppressing serum granulysin levels.

DOI： 10.1002/rmb2.12460

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

INTRODUCTION: Chronic alcohol consumption (CAC) can induce several deleterious effects on the body, including the promotion of osteoporosis; however, the immunological mechanism underlying alcohol-induced osteoporosis is still unclear. METHODS: We administered alcohol to mice for 4 weeks as the experimental CAC model and analyzed the bone and immune cells that are located in the vicinity of a bone. RESULTS: IL-4 is known to be a suppressive factor for osteoclastogenesis, and we found that natural killer T (NKT)-like cells, which showed NK1.1-positive, CD3-positive, and α-galactosylceramide-loaded CD1d tetramer-negative, produced IL-4 more effectively than CD4+ T and natural killer (NK) cells. The alcohol consumption facilitated a significant decrease of bone mineral density with the upregulation of nuclear factor of activated T cells 1 and receptor activator of NF-κB ligand expression. Meanwhile, we confirmed that alcohol consumption suppressed the activity of antigen-presenting cells (APCs) and NKT-like cells, leading to decreased IL-4 secretion. Moreover, these harmful effects of alcohol consumption were reduced by simultaneous treatment with a glycolipid antigen OCH. CONCLUSIONS: Our results indicate that the inactivation of innate immune cells, APCs, and NKT-like cells are likely to be crucial for alcohol-induced osteoporosis and provide a new therapeutic approach for preventing osteoporosis.

DOI： 10.1002/iid3.485

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Endometriosis is a chronic inflammatory disease often associated with dysmenorrhea, infertility, adenomyosis, and endometrial ovarian cyst (EOC). In particular, EOC can sometimes become malignant in a longitudinal follow-up. This study aimed to investigate the involvement of high-mobility group box-1 (HMGB1) in an inflammatory milieu and the characteristics of immune cells in EOC. The samples were obtained from patients who underwent ovarian cystectomy for benign ovarian cyst. The participants were divided into two groups: patients with EOC (EOC group) and those without EOC (nEOC group). We divided a part of the removed ovary into small sections and isolated the tissue cells. Thereafter, the cytoplasmic HMGB1 levels in DCs, macrophages, and non-immune cells were analyzed by flow cytometry. We also evaluated the proportions of immune, T, NK, iNKT, NK, and regulatory T (Treg) cells. Results showed that the DCs, macrophages, and non-immune cells of EOC had significantly higher cytoplasmic HMGB1 levels than those of nEOC. The expression of CD69 and CD107a on CD8+ T and CD4+ T cells of EOC was also more enhanced than that of nEOC. Furthermore, the M2 macrophages and Tregs highly accumulated in EOC. These results indicate that HMGB1 may aggravate chronic inflammation related to T-cell activation and simultaneously facilitate development of the immunosuppressive milieu in EOCs.

DOI： 10.1016/j.jri.2021.103292

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PROBLEM: Acute chorioamnionitis (aCAM) associated with microbial infection is a primary cause of preterm birth (PB). However, recent studies have demonstrated that innate immunity and sterile inflammation are causes of PB in the absence of aCAM. Therefore, we analyzed immune cells in the decidua of early to moderate PB without aCAM. METHOD OF STUDY: Deciduas were obtained from patients with PB at a gestational age of 24+0 to 33+6  weeks without aCAM in pathological diagnosis. The patients were divided into two groups as follows: patients with labor and/or rupture of membrane (ROM) (no aCAM with labor and/or ROM: nCAM-w-LR), and patients without labor and/or ROM (no aCAM without labor and/or ROM: nCAM-w/o-LR). The immune cells and high mobility group box 1 (HMGB1) levels in the decidua were analyzed using flow cytometry. Co-culture of CD56+ cells with dendritic cells (DCs) and macrophages obtained from the decidua was also performed in the presence of HMGB1. RESULTS: The nCAM-w-LR group demonstrated an accumulation of iNKT cells, and increased expression of HMGB1, TLR4, receptors for advanced glycation end products, and CD1d on DCs and macrophages. HMGB1 facilitated the proliferation of iNKT cells co-cultured with DCs and macrophages, which was found to be inhibited by heparin. CONCLUSIONS: Inappropriate activation of innate immune cells and increased HMGB1 expression may represent parturition signs in human pregnancy. Therefore, control of these cells and HMGB1 antigenicity may be represent a potential therapeutic target for the prevention of PB.

DOI： 10.1111/aji.13330

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

In reproduction, inflammatory processes play important roles in the development of many pregnancy complications such as preterm labor/birth, recurrent pregnancy loss, recurrent implantation failure, and preeclampsia. Inflammation can be initiated by both microbial and non-microbial causes. Bacterial infection in the feto-maternal interface and uterus can provoke preterm labor/birth, miscarriage, and chronic endometritis. By contrast, inflammation without infection, or 'sterile inflammation,' can also lead to many kinds of complications, such as preterm labor/birth, miscarriage, or preeclampsia. Aberrant inflammation is facilitated by immune cells such as macrophages, dendritic cells, natural killer cells, and invariant natural killer T cells. In addition, cytokines, chemokines, and several kinds of inflammatory mediators are involved. On the other hand, appropriate inflammation is required for a successful offspring during the progression of the entire pregnancy. Herein, we discuss the relation between pregnancy and inflammation with immunological alterations. Understanding the role of inflammation in complications during pregnancy may establish new perspectives of the progress of normal pregnancy as well as treatments during pregnancy complications.

DOI： 10.1080/25785826.2020.1809951

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PROBLEM: Septate uterus is associated with spontaneous abortion. Surgical intervention of the uterine septa (US) is frequently performed following spontaneous abortion; however, immunological mechanisms for spontaneous abortion in patients with septate uterus remain completely unknown. METHOD OF STUDY: A total of 12 women with septate uterus who underwent hysteroscopic metroplasty and 10 women with uterine leiomyoma who underwent total hysterectomy were enrolled as the experimental and control groups, respectively. Immune cells, dendritic cells (DCs), macrophages, T cells, natural killer cells, invariant natural killer cells, and chemokine receptors in US and uterine myometrium tissue (UMT) were analyzed using flow cytometry and immunohistochemical staining. Additionally, the chemokine production of macrophage inflammatory protein 1 alpha (MIP-1α), regulated upon activation normal T-cell express sequence (RANTES), and macrophage inflammatory protein 3 beta (MIP-3β) from the viable cells obtained from the US and UMT samples was evaluated in an ex vivo study. RESULTS: The percentage of CD141+ DCs in US was significantly lower than that in UMT. Both US and UMT showed CCR1 and CCR5 expression on CD141+ DCs; however, the production of chemokines, MIP-1α, RANTES, and MIP-3β was abundant in UMT-obtained viable cells. CONCLUSION: The accumulation of CD141+ DCs was lower in US than that in UMT. This phenomenon may be caused by low chemokine productions in US. Our findings support the benefit of surgical intervention for septate uterus-that is, the elimination of inappropriate implantation sites.

DOI： 10.1111/aji.13241

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Immunotherapy for cancer cells induced by interfering with PD-1/PD-L1 engagement via check-point blockades was initiated by tumour-specific PD-1+ CD8+ cytotoxic T lymphocytes (CTLs) within a tumour mass and eliminate the tumour. Here, we used C57BL/6 (B6) mice implanted with the syngeneic hepatoma cell line Hepa1-6-1, and confirmed that the dendritic cells (DCs) within Hepa1-6-1 tumour mass were tolerogenic with downmodulated co-stimulatory molecules by tumour-derived factors. Although Hepa1-6-1 cells did not prime tumour-specific CTLs within the tumour, specific CTLs primed in the regional lymph nodes seemed to be invaded into the tumour mass. The specific CTLs gained PD-1+ expression when associated with PD-L1+ Hepa1-6-1 cells within the tumour mass. Their cytotoxic activity in vivo was revitalised after intraperitoneal (i.p.) administration of the anti-PD-1 monoclonal antibody (mAb), indicating that PD-1/PD-L1 engagement within the tumour was abrogated by check-point blockade. Nonetheless, the tolerogenic DCs within the Hepa1-6-1 tumour mass remained tolerogenic even after three shots of PD-1-blockade administration, and the suppressed Hepa1-6-1 growth was revisited. In this study, we show here an excellent therapeutic effect consisting of three injections of anti-PD1 mAb and the sequential administration of the CD1d molecule-restricted ligand α-galactosylceramide (α-GalCer), an immuno-potent lipid/glycolipid, which converts tolerogenic DCs into immunogenic DCs with upregulated expression of co-stimulatory molecules. The α-GalCer-activated DCs secreted a large amount of IL-12, which can activate tumour-specific CTLs in vivo. The check-point blockade was not sufficiently effective, but the dose needed for tumour eradication was reduced by 90% when tumour-bearing mice were also administered i.p. α-GalCer.

DOI： 10.1016/j.imbio.2019.10.009

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DOI： 10.1007/s00262-019-02396-8

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DOI： 10.1111/jog.13759

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-VCH Verlag  

Unexpected fetal loss is one of the common complications of pregnancy
however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC-205+ dendritic cells (DCs) and NK1.1+ invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of α-galactosylceramide (α-GalCer). Here we demonstrate that the adoptive transfer of DEC-205+ bone marrow-derived DCs cocultured with α-GalCer (DEC-205+ BMDCs-c/w-α-GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (♀) × BALB/c (♂)), which was accompanied by the accumulation of activated iNKT cells in the myometrium. Further, the adoptive transfer of NK1.1+ iNKT cells obtained from B6 mice injected with α-GalCer facilitated miscarriages in syngeneic Jα18(−/−) (iNKT cell-deficient) mice. These results suggest that DEC-205+ DCs and NK1.1+ iNKT cells play crucial roles required for the initiation of fetal loss associated with stimulation by glycolipid antigens and sterile inflammation.

DOI： 10.1002/eji.201747162

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Language：English   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.jri.2017.10.007

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Cancer immunity is mediated through the effective priming and activation of tumour-specific class I MHC molecule-restricted CD8(+) cytotoxic T lymphocytes (CTLs). DEC-205(+) dendritic cells (DCs) can cross-present the epitope(s) of captured tumour antigens associated with class I MHC molecules alongside co-stimulatory molecules to prime and activate tumour-specific CD8(+) CTLs. Immunosuppressive tolerogenic DCs with reduced co-stimulatory molecules may be a cause of impaired CTL induction. Hepa1-6-1 cells were established from the mouse hepatoma cell line Hepa1-6; these cells grow continuously after subcutaneous implantation into syngeneic C57BL/6 (B6) mice and do not prime CD8(+) CTLs. In this study, we show that the growth of ongoing tumours was suppressed by activated CD8(+) CTLs with tumour-specific cytotoxicity through the administration of the glycolipid -galactosylceramide (-GalCer), which is a compound known to stimulate invariant natural killer T (iNKT) cells and selectively activate DEC-205(+) DCs. Moreover, we demonstrated that sequential repetitive intraperitoneal inoculation with -GalCer every 48 hr appeared to convert tolerogenic DEC-205(+) DCs into immunogenic DCs with a higher expression of co-stimulatory molecules and a stronger cross-presentation capacity, which primed CTL precursors and induced tumour-specific CD8(+) CTLs within the tumour environment without activating iNKT cells. These findings provide a new basis for cancer immunotherapy to convert tolerogenic DEC-205(+) DCs within tumours into immunogenic DCs through the sequential administration of an immuno-potent lipid/glycolipid, and then activated immunogenic DCs with sufficient expression of co-stimulatory molecules prime and activate tumour-specific CD8(+) CTLs within the tumour to control tumour growth.

DOI： 10.1111/imm.12733

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Problem: Acute chorioamnionitis (aCAM) is an important cause of pre-term birth. However, little is known about the pathogenesis of late pre-term birth without aCAM that was the most common category of pre-term birth. Here we analyze the kinetics of immune cells obtained from the decidua of women with late pre-term births with and without aCAM.
Method of study: Deciduas were obtained from women who underwent labor with late pre-term birth without aCAM (PB-n/aCAM) or with aCAM (PB-w/aCAM). The population of DEC-205(+) dendritic cells (DCs), macrophages, invariant natural killer T (iNKT) cells, NK cells, CD8(+) T cells, and CD4(+) T cells were analyzed by flow cytometry.
Results: The number of iNKT cells was higher in the decidua obtained from women with PB-n/aCAM than PB-w/aCAM. DEC-205(+) DCs obtained from women with PB-n/aCAM preferentially induced iNKT cell proliferation.
Conclusion: iNKT cell accumulation with DEC-205(+) DCs in PB-n/aCAM suggests that iNKT cells contribute to the onset of PB-n/aCAM.

DOI： 10.1111/aji.12658

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DOI： 10.1016/j.jri.2016.10.043

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Innate immunity, which is unable to discriminate self from allo-antigens, is thought to be important players in the induction of miscarriages. Here, we show that the administration of IL-12 to syngeneic-mated C57BL/6 mice on gestation day 7.5 (Gd 7.5), drives significant miscarriages in pregnant females. Furthermore, the administration on Gd 7.5 of a-galactosylceramide (alpha-GalCer), which is known to activate invariant natural killer T (iNKT) cells, induced miscarriages in both syngeneic-mated C57BL/6 mice and allogeneic-mated mice (C57BL/6 (female) x BALB/c (male)). Surprisingly, the percentages of both DEC-205(+) DCs and CD1d-restricted NK1.1(+) iNKT cells were higher in the myometrium of pregnant mice treated i.p. with alpha-GalCer than in the decidua. IL-12 secreted from alpha-GalCer-activated DEC-205(+) DCs stimulated the secretion of cytokines, including IL-2, IL-4, IFN-gamma, TNF-alpha, perforin, and granzyme B, from the NK1.1(+) iNKT cells in the myometrium, leading to fetal loss in pregnant mice. Finally, the i.p. administration of IL-12 and/or alpha-GalCer in iNKT-deficient J alpha 18(-/-) (J alpha 18 KO) mice did not induce miscarriages. This study provides a new perspective on the importance of the myometrium, rather than the decidua, in regulating pregnancy and a mechanism of miscarriage mediated by activated DEC-205(+) DCs and NK1.1(+) iNKT cells in the myometrium of pregnant mice.

DOI： 10.1002/eji.201545923

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

Langerhans cells (LCs), a subset of dendritic cells (DCs), reside in body surface presenting antigens from various pathogens and activate immune system after migrating to vicinal lymph nodes. We recently demonstrated that the E-cadherin interaction allowed peripheral blood (PB) CD14(+) cells to differentiate into LC-like cells that closely resemble primary LCs. Here, with a combination of GM-CSF, TGF-beta, and TNF-alpha, we induced LC-like cells from umbilical cord blood (UCB)derived CD34(+) cells and compared them with those induced from PB CD14(+) cells. In contrast to PB CD14(+) cell-derived LC-like cells with an undetectable surface level of toll-like receptor (TLR) 4 and an unresponsiveness feature to bacterial lipopolysaccharide (LPS), CB CD34(+) cells-derived LC like cells expressed a low, but apparent, surface level of TLR4 and a reduced level of intracellular TLR3. Consistent with this result, they responded to bacterial LPS, but poorly to poly(I: C) reflecting viral RNA. These findings suggest that LC-precursors from circulating PB CD14(+) cells seem to be arranged in the outer barrier of skin, while LC-precursors from local undifferentiated UCB-derived CD34(+) cells may be arranged in the inner barrier of mucosal tissues and work together to combat against external pathogens as well as internal malignancies throughout body surface.

DOI： 10.2220/biomedres.37.271

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The major effector cells for cellular adaptive immunity are CD8(+) cytotoxic T lymphocytes (CTLs), which can recognize and kill virus-infected cells and tumor cells. Although CTLs exhibit strong cytolytic activity against target cells in vitro, a number of studies have demonstrated that their function is often impaired within tumors. Nevertheless, CTLs can regain their cytotoxic ability after escaping from the tumor environment, suggesting that the milieu created by tumors may affect the function of CTLs.
As for the tumor environment, the patho-physiological situation present in vivo has been shown to differ from in vitro experimental conditions. In particular, low pH and hypoxia are the most important microenvironmental factors within growing tumors. In the present study, to determine the effect of these factors on CTL function in vivo, we examined the cytolytic activity of CTLs against their targets using murine CTL lines and the induction of these cells from memory cells under low pH or hypoxic conditions using antigen-primed spleen cells. The results indicated that both cytotoxic activity and the induction of functional CTLs were markedly inhibited under low pH. In contrast, in hypoxic conditions, although cytotoxic activity was almost unchanged, the induction of CTLs in vitro showed a slight enhancement, which was completely abrogated in low pH conditions.
Therefore, antigen-specific CTL functions may be more vulnerable to low pH than to the oxygen concentration in vivo. The findings shown here provide new therapeutic approaches for controlling tumor growth by retaining CM cytotoxicity through the maintenance of higher pH conditions. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of European Federation of Immunological Societies.

DOI： 10.1016/j.imlet.2015.07.003

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Background: Two major distinct subsets of dendritic cells (DCs) are arranged to regulate immune responses: DEC-205+ DCs drive Th1 polarization and 33D1+ DCs establish Th2 dominancy. Th1 polarization can be achieved either by depletion of 33D1+ DCs with a 33D1-specific monoclonal antibody (mAb) or by activation of DEC-205+ DCs via intraperitoneal injection of alpha-galactosylceramide (alpha-GalCer). We studied the effect of 33D1+ DC depletion or DEC-205+ DC activation in vivo using an established mouse model of allergic rhinitis (AR). Methods: Mice were injected intraperitoneally with OVA plus alum and challenged 4 times with daily intranasal administration of OVA. Immediately after the last challenge, allergic symptoms such as sneezing and nasal rubbing as well as the number of cells in the bronchoalveolar lavage fluid (BALF) and nasal lavage fluid (NALF) were counted. The levels of serum OVA-specific IgG1, IgG2a, and IgE were also determined by ELISA. Results: The allergic symptom scores were significantly decreased in 33D1+ DC-depleted or DEC-205+ DC-activated AR mice. The levels of OVA-specific IgG1, IgG2a, and IgE, and the number of NALF cells, but not BALF cells, were reduced in 33D1+ DC-depleted but not in DEC-205+ DC-activated AR mice. Moreover, the activated DEC-205+ DCs suppressed histamine release from IgE-sensitized mast cells, probably through IL-12 secretion. Conclusions: The manipulation of innate DC subsets may provide a new therapeutic strategy for controlling various allergic diseases by reducing histamine release from IgE-sensitized mast cells by driving the immune response towards Th1 dominancy via activation of DEC-205+ DCs in vivo. (C) 2016 The Author(s) Published by S. Karger AG, Basel

DOI： 10.1159/000443237

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Tumor infiltrating dendritic cells (TIDCs) are thought to be potent antigen-presenting cells able to activate tumor-specific cytotoxic T lymphocytes (CTLs) or tolerogenic DCs that suppress immune reaction against tumors to escape. We have recently reported that majority of these TIDCs were DEC-205(+) DCs having a cross-presenting ability of captured tumor antigens to CD8(+) T cells via class I MHC (MHC-I) molecules, nevertheless, when the TIDCs expressed down-modulated costimulatory molecules, such as CD80 and CD86, they will inhibit the priming and activation of immune effectors (Immunol. Cell Biol., 91: 545-555, 2013). Here, we show that DC-precursors (preDCs) but not the established DCs become tolerogenic DCs expressing down-regulated costimulatory molecules having low responsiveness to LPS or tumor cells, when exposed to soluble factors released from the encountered ovarian tumors in the early phase of their development. However, we found that we could reduce the secretion of those soluble factors with a low, nontoxic concentration of paclitaxel (PTX) and we could stop the preDCs to be tolerogenic DCs and maintain DC functions. These findings indicate that we could prevent the induction of tolerogenic DCs from preDCs by using low, non-toxic doses of anti-cancer drugs to establish DCs that effectively elicit tumor-specific CTLs.

DOI： 10.2220/biomedres.35.369

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Paraneoplastic cerebellar degeneration is a paraneoplastic neurological syndrome caused by the remote effect of certain systemic cancers and is characterized by subacute cerebellar symptoms. A 62-year-old woman suffering from unidentified cerebellar symptoms was admitted to our hospital. Paraneoplastic cerebellar degeneration was suspected and ovarian cancer was detected after the systemic examination for malignancy. The symptoms of vertigo and dysarthria were improved a little after surgical operation and treatments of -globulin, steroid pulse and tacrolimus hydrate. The cerebellar symptoms of paraneoplastic cerebellar degeneration are often evident prior to detection of malignancy. It is important to perform systemic examination for malignancy in case of unidentified cerebellar symptoms.

DOI： 10.1111/jog.12212

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Dendritic cells (DCs) play an important role in providing an appropriate fetal/maternal balance between Th1 and Th2 during pregnancy. The Th1/Th2 balance seems to be regulated mainly by two distinct DC subsets, DEC-205(+) DCs having the capacity to establish Th1 polarization and 33D1(+) DCs to induce Th2 dominance. Pregnancy is established and maintained by maternal hormones, such as progesterone and estrogen, and the balance of DC subtypes was affected mainly by progesterone, which induced a dose-dependent reduction of the DEC-205/33D1 ratio together with/without a stable amount of estrogen. The DEC-205/33D1 ratio decreased gradually with the progress of pregnancy and rapid augmentation of the ratio was seen around delivery in vivo. Here, we demonstrate that depletion of 33D1(+) DCs during the perinatal period caused substantial fetal loss probably mediated through Th1 up-regulation via transient IL-12 secretion, and pre-administration of progesterone could rescue the fetal loss. Similar miscarriages were also observed when pregnant mice were intraperitoneally (i.p.) injected twice with IL-12 on Gd 9.5 and 10.5. Moreover, prior inoculation of progesterone suppressed the enhanced serum IL-12 production in mice treated with 33D1 antibody, indicating that progesterone might inhibit temporal IL-12 secretion around Gd 10.5 and miscarriage was avoided. These findings suggest the importance of balancing DC subsets during pregnancy and reveal that we can avoid miscarriage by manipulating the activity of the DC subpopulation of pregnant individuals with maternal hormones. (c) 2012 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.imbio.2012.01.011

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim: To evaluate postoperative declines in serum human chorionic gonadotropin (hCG) levels (percentages of preoperative hCG levels) to rule out persistent ectopic pregnancy (PEP).
Methods: A retrospective study was conducted on 50 patients who underwent laparoscopic salpingotomy between April 1995 and March 2008. The postoperative course was divided into four periods: (period A: days 1-2; period B: days 3-4; period C: days 5-6; and period D: days 7-8), and the postoperative serum hCG declines in the PEP and control groups (successfully treated patients) were compared. A cutoff value of serum hCG decline to rule out PEP was established by receiver operating characteristic (ROC) analysis.
Results: Ten of the 50 patients (20%) were diagnosed with PEP. There were no differences in clinical findings or preoperative serum hCG levels between the two groups. From period C, the serum hCG decline in the control group was significantly greater than in the PEP group, and all individual serum hCG declines in the PEP group were outside the 95% confidence interval of the control group. Furthermore, analysis by ROC using a 14% decline in postoperative serum hCG as a cutoff revealed that the specificity and sensitivity of the test were equal to 100% from period C.
Conclusion: Declines in serum hCG during period C (days 5-6) constitute an important marker of the presence or absence of PEP. Decisions regarding a second intervention for PEP should be made by this time postoperatively.

DOI： 10.1111/j.1447-0756.2009.01073.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim: To examine the efficacy of local methotrexate (MTX) administration following linear salpingostomy for tubal pregnancy in the prevention of persistent ectopic pregnancy (PEP).
Methods: Patients who underwent a laparoscopic linear salpingostomy between January 1996 and December 2006 were enrolled in the study. Patients who were assigned to the prophylaxis group were administered MTX (50 mg) into the tubal wall in the vicinity of the lesion immediately following linear salpingostomy (n = 41). Patients who were treated without MTX were assigned to the control group (n = 40). Serum human chorionic gonadotrophin levels were followed in both groups postoperatively once every 3 days until they became undetectable. The incidence of PEP was compared between the two groups.
Results: Persistent ectopic pregnancy occurred in seven patients (17.5%) in the control group compared with zero patients in the prophylaxis group (P < 0.05). There were no side-effects attributable to MTX in the prophylaxis group.
Conclusion: A single prophylactic intratubal injection of MTX following laparoscopic linear salpingostomy is a safe and effective regimen for the prevention of PEP.

DOI： 10.1111/j.1447-0756.2008.00746.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

A 33-year-old primigravida experienced a delayed eclamptic convulsion. Following the convulsion, an i.v. administration of magnesium sulfate was utilized in response to cerebroarterial vasospasms, which were seen before and 1 week after the convulsion. Our findings confirm that the appropriate use of magnesium sulfate is necessary in such cases.

DOI： 10.1111/j.1447-0756.2008.00898.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Objctive: To investigate the effect of serum on the interaction between natural killer (NK) cells and endothelial cells in pre-eclampsia.
Methods: Seven severely pre-eclamptic patients, five normal pregnant women, and four normal non-pregnant women were included in this study. Freshly isolated NK cells labeled with Chromium-51 were incubated on an endothelial cell monolayer in the presence of patient serum. In regard to the characteristics of adhesive molecules, the endothelial cells were blocked by monoclonal antibodies (mAbs) to intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1); the NK cells were blocked by mAbs to leukocyte function-associated antigen (LFA-1) and very late antigen-4 (VLA-4) before co-incubation. After incubation, the adherent cells were solubilized with 1% Triton X. The lysates were collected and counted in a gamma counter.
Results: The adhesion of NK cells to the endothelium in the normal pregnancy group decreased significantly in comparison to the non-pregnant group (7% vs 72%; P < 0.01). Adhesion in the severe pre-eclamptic group was significantly higher in comparison to the normal pregnant group (44% vs 7%; P < 0.01). The blocking percentages of mAbs on NK adhesion in the severe pre-eclampsia group were 49 +/- 4% to LFA-1, 61 +/- 48%, 67 +/- 39% to VLA-4, ICAM-1, and 68 +/- 7% to VCAM-1.
Conclusion: Sera from normal pregnant women suppress the adhesion between NK cells and endothelial cells, whereas the suppressive effect of sera from pre-eclamptic patients has a diminished affect.

DOI： 10.1111/j.1447-0756.2006.00444.x

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.jri.2018.09.005

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J-GLOBAL

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Language：Japanese   Publisher：日本生殖免疫学会  

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DOI： 10.1016/j.jri.2015.09.010

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Language：Japanese   Publisher：日本生殖免疫学会  

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DOI： 10.1016/j.jri.2014.09.039

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：日本生殖免疫学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本生殖免疫学会  

Dendritic cells (DCs) play a crucial role in providing an appropriate immune balance during pregnancy. It has recently been reported that two distinct types of DCs are arranged in the murine system. One subtype is the DCs bearing the C-type lectin CD205 (DEC-205) having the capacity to establish Th1 polarization. The other is the DCs expressing 33D1, recognizing DC inhibitory receptor-2 (DCIR-2), having the capacity to induce Th2 polarization. In addition, we found that the balance of DC subtypes was affected mainly by progesterone, which induced a dose-dependent reduction of the DEC-205/33D1 ratio together with/without a stable amount of estrogen(1). The DEC-205/33D1 ratio decreased gradually with the progress of pregnancy and rapid augmentation of this ratio was seen around delivery period. Here, we demonstrated that the fetal loss could be induced by the depletion of 33D1+ DCs during perinatal period mediated through the transient IL-12 secretion, and pre-administration of progesterone could rescue this fetal loss. Similar miscarriages were also observed when pregnant mice were intraperitoneally (i.p.) injected twice with IL-12 on Gd 9.5 and 10.5. Moreover, prior inoculation of progesterone suppressed the enhanced serum IL-12 production in mice treated with 33D1 antibody, indicating that progesterone might inhibit temporal IL-12 secretion around Gd 10.5 and thus miscarriage was prevented. These findings suggest that the balance of DC subsets is crucial for maintaining pregnancy and we can prevent miscarriage by manipulating the activity of the DC subpopulation of pregnant individuals by progesterone administration.

DOI： 10.3192/jsirib.28.26

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DOI： 10.1016/j.jri.2012.03.393

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Language：Japanese   Publisher：日本産科婦人科学会  

CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=448458

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CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=448809

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CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=444990

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=443359

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Language：Japanese   Publisher：日本医科大学医学会  

症例は26歳の初回妊娠で、妊娠経過中に特に異常所見は認めず、妊娠36週の超音波断層検査では推定体重2600gで、羊水指数は16と正常であった。妊娠40週6日の未明から胎動感消失を主訴に来院し、腹部超音波検査では胎児の心拍を認めず子宮胎児死亡の診断にて緊急入院となった。入院時、妊娠高血圧症候群は否定され、腹部超音波検査では胎盤の異常所見も認めず、翌朝経腟分娩となった。児は2748gの女児で、臍帯頸部巻絡を2回認めたもの外表奇形は認めず、付属物肉眼所見では臍帯には骨盤付着部から約32cmの部位に真結節を認め、単一臍帯動脈を認めた。胎盤には全体的に小石灰化が認められたが特に異常を認めず、胎盤・臍帯の病理組織学的所見では絨毛膜に及ぶ各1本の臍帯動静脈の血管壁に僅かに好中球を認める以外の異常は認めなかった。新生児の解剖学的検査は家族の同意が得られず、本症例の子宮内胎児死亡の原因として単一臍帯動脈との関連性が示唆されたものの確定診断には至らなかった。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J04260&link_issn=&doc_id=20070228290004&doc_link_id=%2Fcw1nimed%2F2007%2F000301%2F006%2F0020-0024%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw1nimed%2F2007%2F000301%2F006%2F0020-0024%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=439106

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=434062

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