Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. RESULTS: Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. CONCLUSIONS: Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.

Living-Donor Liver Transplantation Using Segment 2 Monosegment Graft: A Single-Center Experience.

BACKGROUND: In small infants, left lateral segment grafts are sometimes too large to overcome the problems of large-for-size grafts in the abdominal compartment. To address this problem, we have developed a safe living donor graftectomy for neonates, a so-called "S2 monosegment graft" to minimize graft thickness. We reviewed our single-center experience to evaluate the feasibility of this technique for reducing graft size. METHODS: Eleven living-donor liver transplants using S2 monosegment grafts were performed between October 2008 and September 2014 at our institution. Medical records of both donors and recipients were reviewed and data collected retrospectively. RESULTS: The mean age of recipients at the time of transplantation was 125.3 days, including 3 neonates. The average S2 monosegment graft weight was 127.4 g, and the graft-to-recipient body weight ratio was successfully reduced to 3.5%. The graft livers were reduced to 4.1 cm in thickness. Two recipients with grafts larger than 5 cm could not undergo primary abdominal closure. Portal vein stenosis and biliary stenosis was observed in 1 recipient, and hepatic artery complications were seen in 2 recipients; the clinical course for all donors were uneventful. Liver regeneration was seen in every patient. The graft and patient 1-year survival rate was 100%. CONCLUSIONS: Living-donor liver transplantation using S2 monosegment grafts offers a safe and useful option for treating smaller infants. Here, we introduce our method of S2 monosegment graft emphasizing the donor harvest and graft thickness.

Clinical characteristics and outcomes of adenovirus infection of the urinary tract after renal transplantation.

BACKGROUND: Urinary tract infection caused by human adenovirus (HAdV) after renal transplantation (RT) results in graft loss because of concomitant nephropathy and acute rejection and may result in death because of systemic dissemination. METHODS: We assessed the time period between RT and disease onset, symptoms, treatment details, disease duration, renal graft function, outcomes, and complications. RESULTS: HAdV infection of the urinary tract occurred in 8 of 170 renal transplant recipients. Symptoms were macrohematuria in all 8 patients, dysuria in 7, and fever in 5. The median period from RT to disease onset was 367 (range, 7-1763) days, and the median disease duration was 15 (range, 8-42) days. The mean serum creatinine (sCr) level prior to onset was 1.35 ± 0.48 mg/dL and the mean maximum sCr level during disease was 2.34 ± 1.95 mg/dL. These values were increased by ≥25% in 5 patients. The mean sCr levels when symptoms resolved was 1.54 ± 0.67 mg/dL, and no significant difference was seen before, during, or after disease onset (P = 0.069). Two patients were diagnosed with HAdV viremia and 1 with acute tubulointerstitial nephritis revealed on biopsy. In addition to a reduction in immunosuppressant dosage, 2 patients received gammaglobulins and 5 received ganciclovir. CONCLUSION: Symptoms of all patients were alleviated, although some patients developed nephritis or viremia. Hence, the possibility of exacerbation should always be considered. Adequate follow-up observation should be conducted, and diligent and aggressive therapeutic intervention is required to prevent the condition from worsening.

Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports.

OBJECTIVE: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). CASE SUMMARIES: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable". DISCUSSION: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. CONCLUSION: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.

Learning curve of laparoscopy-assisted gastrectomy using a standardized surgical technique and an established educational system.

BACKGROUND AND AIMS: The learning curve of a trainee for laparoscopy-assisted gastrectomy in a high volume center, in which an educational system and a standardized laparoscopic procedure are already established, remains unclear. MATERIAL AND METHODS: The early surgical outcomes of the patients of two trainees were investigated. Both trainees followed a training program where they performed at least 20 cases being the camera assistant, 20 cases being the first assistant, before performing the surgery as an operator. RESULTS: The average operation time, intraoperative bleeding, the number of retrieved lymph nodes, and morbidity rate were 240.2 min, 45.7 ml, 35.4, and 13.0%, respectively. There was no learning curve effect observed except with the operation time of one trainee. CONCLUSIONS: In a high volume center with an established educational system, trainees could perform laparoscopy-assisted gastrectomy safely, although there might be a -learning curve effect in operation time and the surgeries took longer operation time in trainee's initial cases.

In situ quantitative immunoprofiling of regulatory T cells using laser scanning cytometry.

Laser scanning cytometry (iCys; CompuCyte, Cambridge, Mass) has recently been developed to use fluorescence-based quantitative measurements on tissue sections or other cellular preparations at a single-cell level. The purpose of this study was to develop objective, quantitative immunoprofiling of regulatory T cells (T regs) on formalin-fixed/paraffin-embedded (FFPE) biopsy samples from transplanted allografts using iCys. We sought to evaluate the usefulness of iCys to analyzes the population of CD4 (+) Foxp3 (+) T regs among CD4 (+) T-cell and the entire T-cell (the total of CD4 [+] and CD8 [+] populations in human intestinal allograft biopsy samples. Primary antibodies (Foxp3 and CD4) which had been labeled using Alexa Fluoro 488 (Foxp3 Alexa488) and 647 (CD4 Alexa647) with polymer horseradish peroxidase and catalyzed signal amplification were incubated on 1 section. On the other section, CD8 and CD4 were labeled using Alexa488 and Alexa647 using the same protocol. Data acquisition was performed using iCys. The signal intensities of Alexa488 and Alexa647 were sufficient to analyze by iCys. Distribution of the integrals of Alexa488 and Alexa647 to visualize each cell population enabled calculation of the population of T reg among CD4 (+) T cells, CD4 (+) T cells among total T cells, and T reg among entire T cells. iCys and signal amplified immunofluorescent staining allowed objective quantitative immunoprofiling of in situ T reg populations, with precise quantitative analysis at a single-cell level on FFPE sections. This objective method may be applied on biopsy samples from various transplanted organs.

Purification method using iodixanol (OptiPrep)-based density gradient significantly reduces cytokine chemokine production from human islet preparations, leading to prolonged beta-cell survival during pretransplantation culture.

Purification is one of the most important steps in human islet isolation. Although Ficoll-based density gradients are widely used, OptiPrep-based density gradients are used in few centers. Cytokine/chemokine production from human islet preparations varies widely. Some cytokines/chemokines have been reported to have adverse effects on human islet preparations. Control of cytokine/chemokine production may be a key to improve islet quality and quantity, leading to better transplantation outcomes. The aim of the present study was to investigate the effects on islet preparations of purification methods using various density gradients on viability, cellular composition, and proinflammatory cytokine/chemokine production. After the digestion phase, the extracts were divided into 2 groups for purification using a semiautomated cell processor with Ficoll-based or OptiPrep-based density gradients. Islet preparations cultured for 2 days were assessed regarding islet cell viability (fluorescein diacetate/propidium iodide [FDA/PI]), fractional beta-cell viability by FACS, and beta-cell content using iCys. Cytokine/chemokine production from islet preparations was also measured by Bio-plex. After purification, the purity, islet equivalents (IEQ), and islet recovery rates were comparable between the 2 groups. Although FDA/PI and fractional beta-cell viability showed no significant difference, survival of beta cells during culture was significantly higher in the OptiPrep compared with the Ficoll-based density gradient group. There were significantly lower tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, IL-6, and MIP-1beta productions from the OptiPrep-based density gradient group. OptiPrep-based density gradients reduced cytokine/chemokine production by islet preparations. In addition, OptiPrep-based density gradient purification significantly reduced the loss of beta-cell mass during pretransplantation culture.

Effect of pituitary adenylate cyclase-activating polypeptide in islet transplantation.

INTRODUCTION: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion similar to exendin-4. It has been reported that systemic administration of PACAP maintained beta-cell mass, delayed the onset of hyperglycemia, and protected beta cells from glucose toxicity. Moreover, PACAP increases glucose-stimulated insulin release in vitro and in vivo. In this study, we investigated the possibility of PACAP use in human islet transplantation. METHODS: Human islets were cultured in the presence or absence of PACAP (10(-12) mol/L) for 48 hours. We assessed beta-cell viability using FACS, cellular composition analysis by iCys/LSC, and glucose-stimulated insulin secretion. In vivo, islets were transplanted beneath the kidney capsule of Streptozotocin-induced diabetic immunodeficient mice. An intravenous glucose tolerance test (IVGTT) was also performed in the presence or absence of PACAP (Peptide International, Louisville, Ky, United States; 1.3 nmol/kg). RESULTS: There were significant improvements in terms of beta-cell viability and cellular composition between islets cultured with or without PACAP, respectively (P < .05). Moreover, glucose-stimulated insulin secretion significantly improved in islets cultured with PACAP compared with controls, respectively (P < .05). Treatment of recipient mice with PACAP resulted in beneficial effects on insulin secretion (PACAP vs control, 13.2 vs 1.9 mU/L), in IVGTT. However, no significant difference was observed in glucose levels between the 2 groups. CONCLUSIONS: Our study indicated that PACAP significantly improved beta-cell viability and survival during culture, and increased insulin secretion in vitro and in vivo. However, blood glucose levels in vivo after an IVGTT did not significantly improve, probably due to increased glucagon secretion from alpha cells. PACAP supplementation to culture medium could be of assistance to improve clinical islet transplantation outcomes.

Effect of human islet rescue gradient purification on islet yield and fractional Beta cell viability.

It is difficult to consistently obtain sufficient postpurification islet numbers from younger donors because of the higher proportion of trapped islets after pancreas digestion. Continuous gradient purification (CGP), which is currently used in several islet processing centers, sometimes is not efficient in the purification of trapped islets. Rescue gradient purification (RGP) could improve postpurification islet yields, resulting in an increased number of islet cell products that could be transplanted. Sixty-eight human islet isolations, in which CGP was followed by RGP were analyzed. The quality of islets from CGP and RGP was assessed by beta-cell fractional viability (betaFV) and ADP/ATP ratio. Donor age negatively correlated with the proportion of the islets rescued by RGP (R = -0.52; P < .01) and to the percentage of trapped islets (R = -0.46; P < .01). Age-related differences were observed in pancreas weight, digestion time, and islet yields from CGP, respectively. Importantly, islets from RGP had an 11% higher betaFV compared with islets from CGP. ADP/ATP ratio was also lower in RGP islets versus CGP islets. RGP improved the efficiency of islet purification from younger pancreata and did not affect islet cell viability, which was actually higher in RGP fractions, indicating that rescued trapped islets from the pellet and lower purity layers are not damaged by the extra purification step and may actually be more viable. RGP could be used to rescue high-quality islets from less than 30% pure islet fractions, which are often discarded in the clinical setting.

Laparoscopic and endoscopic cooperative surgery for gastrointestinal stromal tumor dissection.

BACKGROUND: Laparoscopic wedge resections are increasingly applied for gastric submucosal tumors such as gastrointestinal stromal tumor (GIST). Despite this, no defined strategy exists to guide the surgeon in choosing the appropriate laparoscopic technique for an individual case on the basis of tumor characteristics such as location or size. This study aimed to introduce a laparoscopic and endoscopic cooperative surgery (LECS) for gastric wedge resection that is applicable for submucosal tumor resection independent of tumor location and size. METHODS: Seven patients underwent LECS for the resection of gastric submucosal tumors. Both mucosal and submucosal layers around the tumor were circumferentially dissected using endoscopic submucosal dissection via intraluminal endoscopy. Subsequently, the seromusclar layer was laparoscopically dissected on the exact three-fourths cut line around the tumor. The submucosal tumor then was exteriorized to the abdominal cavity and dissected with a standard endoscopic stapling device. RESULTS: In all cases, the LECS procedure was successful for dissecting out the gastric submucosal tumor. In four of seven cases, the tumor was located in the upper gastric portion near the esophagogastric junction. The remaining three tumors were in the posterior gastric wall. In two cases, the tumors were more than 5 cm in diameter, and one was a GIST of the remnant stomach. The mean operation time was 169 +/- 17 min, and the estimated blood loss was 7 +/- 2 ml. The postoperative course was uneventful in all cases. CONCLUSIONS: The LECS procedure for dissection of gastric submucosal tumors such as GIST may be performed safely with reasonable operation times, less bleeding, and adequate cut lines. In addition, the success of the procedure does not depend on the tumor location such as the vicinity of the esophagogastric junction or pyloric ring.

Herbal medicines, Sairei-to and Tokishakuyaku-san, differently modulate the release of cytokines from decidual versus peripheral blood mononuclear cells.

PROBLEM AND METHOD OF STUDY: We have shown that Tokishakuyaku-san (Toki) and Sairei-to (Sai) enhance T helper-1 (Th1) cytokine release from peripheral blood mononuclear cells (PBMCs): thereby, they could be a therapeutic means in the treatment of autoimmunity related recurrent abortion in which T helper-2 (Th2) polarization is exaggerated, the condition purported to benefit from these herbal medicines. However, an open question is whether these medicines might enhance Th1 cytokine release in decidual tissues and thereby stimulate the killer activity, thus, working counterproductively by accelerating maternal alloimmune reactions toward fetal tissues. To address this, we examined the effects of these medicines on the release of cytokines from decidual mononuclear cells (DMCs) in comparison with PBMCs on the assumption that they might act differently on these cell types. The effects of these medicines were investigated as related to human leukocyte antigen (HLA)-G, a nonclassical HLA class I antigen expressed on trophoblasts and a putative crucial player involved in fetomaternal immune interplay. RESULTS: Regarding Th1 cytokines. Toki marginally increased the release of tumor necrosis factor (TNF)-alpha, but not interferon (IFN)-gamma from DMCs while Sai did not affect the release of both. Both Toki and Sai were without effect in modulating the release of interleukin (IL)-4, a member of Th2 cytokines. Interestingly, the presence of HLA-G reduced the release of Th1 cytokines from DMCs regardless of the addition of Toki, Sai or none. These findings are in sharp contrast with PBMCs on which these medicines seem to act so as to enhance Th1 polarization and attenuate Th2 polarization. CONCLUSION: Differential effects of Toki and Sai on the release of Th1/Th2 cytokines between DMCs and PBMCs may afford the rationale of these medicines in the treatment of autoimmunity-related recurrent abortion.

Soluble HLA-G influences the release of cytokines from allogeneic peripheral blood mononuclear cells in culture.

Exquisitely regulated cytokine balance during early pregnancy is thought to be necessary for promoting survival of the fetal allograft. Our previous studies have demonstrated that membrane-bound human leukocyte antigen (mHLA-G) expressed on trophoblasts is one of the key factors in regulating cytokine balance by shifting the Th1/Th2 balance toward Th2 polarization, a favourable milieu for the maintenance of pregnancy. Given that trophoblasts secrete soluble HLA-G (sHLA-G), we examined its biological roles in comparison with mHLA-G. We cultured peripheral blood mononuclear cells (PBMC) with either the HLA-A and -B-deficient B lymphoblast cell line (721.221 cells) or the same cell line transfected with mHLA-G (721.221-G1 cells), in the presence or absence of recombinant sHLA-G. Cytokine concentrations in the culture media were determined by enzyme-linked immunosorbent assay. In contrast to mHLA-G protein, sHLA-G stimulated the release of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, whereas it reduced the release of interleukin (IL)-3, regardless of the presence of the presence of a stimulatory effect of the mHLA-G-expressing cells. Although mHLA-G reduced the release of IL-4, sHLA-G did not have any effect. Conversely, sHLA-G stimulated the release of IL-10 whereas mHLA-G was without effect. These results suggest that sHLA-G regulates the release of cytokines from PBMC chiefly by counterbalancing mHLA-G, and thereby may play a role in maintaining pregnancy.

Human leukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells present in the decidua versus peripheral blood.

PROBLEM: To better understand the role of human leukocyte antigen (HLA)-G in regulating the T helper (Th)1/Th2 cytokine balance, one of key conditions in determining the fate of pregnancy, we asked whether the presence of HLA-G protein altered the release of cytokines from both decidual mononuclear cells and peripheral blood mononuclear cells (PBMCs). METHOD OF STUDY: The amounts of cytokines released from decidual mononuclear cells and PBMCs were compared in the presence or absence of HLA-G-expressing cells. RESULTS: When cocultured with HLA-G-expressing cells, the amounts of tumor necrosis factor-alpha and interferon-gamma released from decidual mononuclear cells and PBMCs were decreased, while the amounts of interleukin (IL)-4 from PBMCs was increased, with IL-4 release from decidual mononuclear cells being unchanged. CONCLUSIONS: Upon contact with HLA-G, decidual mononuclear cells, and PBMCs as well, modulate their ability to release cytokines in a way that may shift the Th1/Th2 balance towards relative Th2 dominance, suggesting a role for HLA-G in maintaining pregnancy.

Functional MRI in children with congenital structural abnormalities of the occipital cortex.

Functional MRI techniques were used to map the position of visual cortex in an awake and a sedated child with congenital anomalies of the posterior hemispheres. In one subject with cortical heterotopia, an activated cortex was found distinct from the structurally abnormal area detected on conventional MRI. In a sedated patient with holoprosencephaly, activated cortical areas in the posterior-medial portions of the hemispheres were identified. This study demonstrates the utility of functional MRI in such patients, both awake and sedated.

Immunotherapy prevents recurrent abortion without influencing natural killer receptor status.

PROBLEM: We assessed the expression of natural killer (NK) receptors in recurrent aborters before and after immunotherapy using their husbands' peripheral blood mononuclear cells (PBMCs). METHOD OF STUDY: Using stored PBMCs from recurrent aborters before and after the immunotherapy, the expression of NK receptors, CD158a, CD158b, CD159 and CD94, were analyzed using monoclonal antibodies for respective receptors. The diversity of killer activatory receptors (KARs) and killer inhibitory receptors (KIRs) was also examined using reverse transcriptase-polymerase chain reaction (RT-PCR)-single strand conformation polymorphism (SSCP) method. RESULTS: In recurrent aborters, no apparent changes in NK receptor expression and the balance between KARs and KIRs were found before and after the immunotherapy. CONCLUSION: The allo-human leukocyte antigen (HLA)-stimulation caused by the immunotherapy for recurrent aborters did not affect the expression of NK receptors and the ratio of KARs to KIRs regardless of the outcome of subsequent pregnancies, suggesting that recurrent aborters may benefit from the immunotherapy through mechanisms unrelated to alteration in NK receptor status.

Decrease of suppressor-inducer (CD4+ CD45RA) T lymphocytes and increase of serum immunoglobulin G due to perceived job stress in Japanese nuclear electric power plant workers.

To clarify the effects of perceived job stress on the immune system, a cross-sectional study was conducted in 116 male Japanese workers of a nuclear electric power plant (age, 20 to 39; mean, 31 years). Perceived job stress, i.e., psychological job demand, job control, worksite social support, and job strain, was assessed by means of the Japanese version of the Job Content Questionnaire. The job strain score was calculated as the ratio of the job demand score to the job control score. Blood samples were taken from all workers, and numbers of T and natural killer cell subpopulations, B lymphocytes, total lymphocytes and white blood cells, and serum concentrations of immunoglobulins (IgG, IgM, IgA, IgE and IgD) in their blood were measured. The workers were divided into higher and lower strain groups according to their job strain scores. The number of CD4+ CD45RA+ T lymphocytes in the higher strain group having the job strain score of 0.5 or more (41 workers) was significantly smaller than that in the lower strain group having the score of less than 0.5 (75 workers). In contrast, the serum IgG concentration in the former group was significantly higher than that in the latter group (analysis of covariance with age and smoking as covariates). Also, the numbers of total CD4+ T and total T (CD3+) lymphocytes and of white blood cells in the former group were significantly smaller than those in the latter group. After controlling for age and smoking by the partial correlation coefficient in all 116 workers, the number of CD57+ CD16+ natural killer cells was inversely correlated with job demand and with job strain; the number of CD8+ T lymphocytes was positively correlated with worksite social support; and serum IgG and IgM concentrations were positively correlated with job strain. It is suggested that higher job strain decreases the number of CD4+ CD45RA+ T lymphocytes in male Japanese workers but increases serum IgG concentrations.

Theoretical basis for herbal medicines, Tokishakuyaku-san and Sairei-to, in the treatment of autoimmunity-related recurrent abortion by correcting T helper-1/T helper-2 balance.

PROBLEM AND METHOD OF STUDY: To get insight into the basis for the empirical usage of herbal medicines in the treatment of recurrent abortion, we examined whether Tokishakuyaku-san (Toki) and Sairei-to (Sai) modulate T helper-1 (Th1) and T helper-2 (Th2) cytokine release from peripheral blood mononuclear cells (PBMCs). The effects of these medicines were investigated as related to human leukocyte antigen (HLA)-G, a non-classical HLA class I antigen expressed on trophoblasts and a putative crucial player involved in fetomaternal immune interplay. RESULTS: Toki and Sai increased the release of Th1 group cytokines, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma while preserving the inhibitory effect of HLA-G on the release of these cytokines. As for Th2 group cytokine release, Toki was without effect in modulating interleukin (IL)-4 release, regardless of the presence of HLA-G, whereas Sai nullified the effect of the presence of HLA-G to stimulate the release of IL-4 without affecting its release in the absence of HLA-G. CONCLUSION: Toki and Sai may have therapeutic potential, particularly in autoimmunity-related recurrent abortion where Th2 response is pathologically enhanced, but not in recurrent abortion involving alloimmune fetomaternal derangement, a condition of, rather, an enhanced Thl response.

Effects of sairei-to and tokishakuyaku-san on cytokine release from peripheral blood mononuclear cells upon recognition of HLA-G protein in the treatment of recurrent abortion.

Human leukocyte antigen (HLA)-G has been shown to play a role in establishing pregnancy through the mechanism of modulating cytokine secretion from maternal lymphocytes. To elucidate the mechanisms of actions of the herbal medicines, Sairei-to and Tokishakuyaku-san, in the treatment of recurrent abortion, we investigated whether these medicines modulate cytokine secretion from peripheral blood mononuclear cells (PBMCs) upon recognition of HLA-G protein on trophoblasts. Sairei-to and Tokishakuyaku-san increased the interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha secretion and decreased the IL-3 secretion from PBMCs regardless of whether these cells recognized HLA-G protein or not. Accordingly, Sairei-to nullified the effects of HLA-G to reduce the secretion of IL-1 beta and TNF-alpha and to enhance the secretion of IL-3. Tokishakuyaku-san also abolished the effect of HLA-G to reduce IL-1 beta and TNF-alpha secretion but did not affect the increase in IL-3 secretion. Thus, it is conceivable that Sairei-to may normalize Th1/Th2 balance by enhancing Th1 polarization in autoimmunity-related recurrent abortion in which Th1/Th2 balance might be shifted towards Th2 polarization. However, the mechanisms of action of Tokishakuyaku-san when used in treating unexplained recurrent abortion, cannot be explained only by the Th1/Th2.