INHIBITION OF IFN-γ PRODUCTION BY SOLUBLE FACTORS DERIVED FROM ORAL CANCER CELLS

The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432

Lactobacillus Acidophilus Strain L-92 Regulates the Production of Th1 Cytokine as well as Th2 Cytokines

ABSTRACTBackgroundThere is growing interest in probiotics such as lactic acid bacteria (LAB), not only for treatment of T helper type (Th) 1-mediated diseases but also for Th2-mediated diseases, including allergic diseases, since lactic acid bacteria may be able to modulate the Th1/Th2 balance, in addition to having an immunomodulative effect through induction of Th1 bias.MethodsThe effect of oral administration of heat-killed Lactobacillus acidophilus Strain L-92 (L-92) on ovalbumin (OVA)-specific immunoglobulin (Ig)E production was investigated in BALB/c mice. L-92 was orally administered to mice for 8 weeks from 2 weeks after initiation of OVA-immunization. Patterns of cytokine and Ig production in splenocytes and cells from Peyer’s patches (PPs) from these mice were examined after restimulation with OVA in vitro.ResultsL-92 significantly suppressed serum OVA-specific IgE levels for a long period. Cytokines such as interferon (IFN)-γ, interleukin (IL)-4 and IL-10 and Igs such as total IgE and OVA-specific IgE were produced at significantly lower levels by splenocytes of L-92-treated mice, compared with those of control mice. In contrast, transforming growth factor (TGF)-β and IgA levels produced by PPs from L-92-treated mice were significantly higher than in those from control mice.ConclusionsOral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-β production in PPs. TGF-β is known to be associated with activation of regulatory T (Treg) cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-β activity

Phase II Trial Using Romidepsin after Gemcitabine, Dexamethasone, and Cisplatin Therapy in Elderly Transplant-Ineligible Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma: Study Protocol

Romidepsin is an important therapeutic option for patients with peripheral T-cell lymphoma (PTCL). However, the timing of romidepsin administration remains controversial. Romidepsin was launched in Japan as a consolidation therapy agent after conventional salvage chemotherapy with gemcitabine, dexamethasone, and cisplatin (GDP). GDP therapy will be administered every 3 weeks. If complete response, partial response, or stable disease is confirmed after 2-4 GDP cycles, romidepsin will be administered every 4 weeks. The primary endpoint is a 2-year progression-free survival rate. Patients participating in this study and undergoing treatment can expect results similar to or better than those of conventional therapies

Development of New Functional Feed that Utilizes Yacon (\u3cem\u3eSmallanthus sonchifolius\u3c/em\u3e) and Rush (\u3cem\u3eJuncus effuses\u3c/em\u3e L.) in Japan

Yacon (Smallanthus sonchifolius) is acknowledged as a food as well as a medicinal plant and its cultivation in Ja-pan has recently expanded. Rush (Juncus effuses L.) which is widely distributed in the temperate regions in the north-ern hemisphere, has historically been used as a herbal medicine for nephritis and dermal disorders. However, there is a lot of harvest residue of both plants. This research was conducted to find out the way for the effective use of these residues as functional feed resources

Flash Controls of Proliferation and Senescence through p21

Dysregulation of the cell proliferation has been implicated in the pathophysiology of a number of diseases. Cellular senescence limits proliferation of cancer cells, preventing tumorigenesis and restricting tissue damage. However, the role of cellular senescence in proliferative nephritis has not been determined. The proliferative peak in experimental rat nephritis coincided with a peak in E2A expression in the glomeruli. Meanwhile, E12 (an E2A-encoded transcription factor) did not promote proliferation of Mesangial cells (MCs) by itself. We identified caspase-8-binding protein FLICE-associated huge protein (FLASH) as a novel E2A-binding partner by using a yeast two-hybrid screening. Knockdown of FLASH suppressed proliferation of MCs. This inhibitory effect was partially reversed by the knockdown of E2A. In addition, the knockdown of FLASH induced cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) expression, but did not affect p53 expression. Furthermore, overexpression of E12 and E47 induced p21, but not p53 in MCs, in the absence of FLASH. We also demonstrated that E2A and p21 expression at the peak of proliferation was followed by significant induction of FLASH in mesangial areas in rat proliferative glomerulonephritis. Moreover, we revealed that FLASH negatively regulates cellular senescence via the interaction with E12. We also demonstrated that FLASH is involved in the TNF-α-induced p21 expressions. These results suggest that the functional interaction of E2A and FLASH play an important role in cell proliferation and cellular senescence via regulation of p21 expression in experimental glomerulonephritis

SOCS1 Is a Suppressor of Liver Fibrosis and Hepatitis-induced Carcinogenesis

Hepatocellular carcinomas (HCCs) mainly develop from liver cirrhosis and severe liver fibrosis that are established with long-lasting inflammation of the liver. Silencing of the suppressor of the cytokine signaling-1 (SOCS1) gene, a negative regulator of cytokine signaling, by DNA methylation has been implicated in development or progress of HCC. However, how SOCS1 contributes to HCC is unknown. We examined SOCS1 gene methylation in >200 patients with chronic liver disease and found that the severity of liver fibrosis is strongly correlated with SOCS1 gene methylation. In murine liver fibrosis models using dimethylnitrosamine, mice with haploinsufficiency of the SOCS1 gene (SOCS1−/+ mice) developed more severe liver fibrosis than did wild-type littermates (SOCS1+/+ mice). Moreover, carcinogen-induced HCC development was also enhanced by heterozygous deletion of the SOCS1 gene. These findings suggest that SOCS1 contributes to protection against hepatic injury and fibrosis, and may also protect against hepatocarcinogenesis