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Azoxystrobin (AZ) is one of the most widely used strobilurin fungicides in the world, and its residue has seriously endangered aquatic ecological security. Our previous data showed that AZ exposure may reduce the resistance of fish to rhabdovirus infection in aquatic environment. Here, we further reported a potential long-term adverse effect of AZ exposure on the antiviral and immunosuppressive recovery in fish, and observed that mitochondrial dynamic balance was disturbed by AZ in which excessive mitochondrial fission occurred in response to decreased ATP levels. When a recovery operation was performed in AZ-exposed cells and fish, infectivity of our model virus, spring viraemia of carp virus (SVCV), was significantly decreased in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using zebrafish) in a time-dependent manner. Also, the expression of eight innate antiviral immune genes (IFNs, ISG15, MX1, RIG-I, IRF3, Nrf2 and HO-1) showed a similar change to SVCV replication between the longer exposure period and the expression recovery. Additionally, AZ facilitated horizontal transmission of SVCV in a static cohabitation challenge model, predicting the increase of the potential for the viral outbreak. Therefore, our data suggest that long-term effect of AZ on irreparable impairment in fish made AZ residue potentially greater for ecological risks.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although many types of drug are used, clinical outcomes are still unsatisfactory. Previous studies have suggested that intestinal bacteria are involved in the pathogenesis of IBD. Accordingly, in an IBD model we evaluated the therapeutic effects of OPS-2071, a low-absorption quinolone antibacterial agent indicated for intestinal infection, and investigated its mechanism of action. Methods: The therapeutic effects of OPS-2071 and comparison therapies were evaluated using naive CD4 + T cell-transfer IBD model mice. In vitro inhibition of LPS-induced TNF-α production and inhibitory effects on T cell responses stimulated using anti-CD3/CD28 antibody-loaded beads were evaluated using mouse splenocytes and human peripheral blood mononuclear cells. In addition, in vitro activities against bacteria implicated in IBD pathogenesis were tested. Results: OPS-2071 dose-dependently decreased both colonic weight/length ratio and the colitis histological score as compared with the vehicle group. The therapeutic effect of OPS-2071 was equivalent to that of anti-IL-12/23 (p40) antibody. In vitro, OPS-2071 suppressed TNF-α production induced by LPS stimulation and T cell responses in a dose-dependent manner. At high concentrations, these effects were comparable to those of existing immunosuppressive agents, such as prednisolone, in both mouse and human cells. OPS-2071 also showed antibacterial activity against IBD-related bacteria. Conclusions: Our results suggest that OPS-2071 had both immunosuppressive and antibacterial effects. This dual effect makes OPS-2071 a unique and promising candidate for IBD. [ABSTRACT FROM AUTHOR]

Background: Identifying effective immunosuppressive strategies is critical for addressing immunological rejection following organ transplantation. This study explores the potential immunosuppressive effects and mechanisms of temsirolimus, a rapamycin derivative, in organ transplantation., Methods: A mouse cardiac allograft model was established using a cervical cannula technique with BALB/c donors and C57BL/6 recipients. Mice were administered temsirolimus intragastrically and graft survival was evaluated. Histological staining was used to assess pathological changes. The BrdU assay was used to measure splenic T cell proliferation. Flow cytometry was used to quantify regulatory T cells (Tregs), CD4+ T cells, and CD8+ T cells. ELISA and qPCR assays were used to determine Foxp3, IL-4, IFN-γ, and TGF-β expression., Results: Temsirolimus displayed potent immunosuppressive effects at 20 mg/kg/day, significantly inhibiting T cell proliferation (84.6%, P < 0.0001) and prolonging graft survival (median 49 days vs. 8.5 days in controls, P < 0.0001). However, median survival decreased to 34.5 days upon withdrawal. Temsirolimus also reduced splenic CD4+ and CD8+ T cells (2.85% and 2.92%, P < 0.001) and antibody levels (IgM, IgG1, IgG2) by 11.85-29.09% (P < 0.0001) and increased Tregs, Foxp3, IL-4 (P < 0.01), and TGF-β (P < 0.05), while decreasing IFN-γ (P < 0.001)., Conclusions: Temsirolimus exhibited potent immunosuppressive effects, emerging as a strong candidate to mitigate organ transplant rejection., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Sinomenine has been used as an antirheumatic drug in China. Glucocorticoid combined with sinomenine could be an alternative therapeutic approach. In this study, we evaluated the sinomenine potential effect on glucocorticoid pharmacodynamics in vitro using a human peripheral blood mononuclear cell (PBMC) culture system. We also disclosed the possible action mechanism of sinomenine with a focus on P-glycoprotein function and glucocorticoid receptor (GR) translocation into nucleus. The median (range) of methylprednisolone IC50 values against the PBMC proliferation was 3.18 (0.45-6.81) ng/mL, whereas the median (range) IC50 values of methylprednisolone combined with 0.03, 0.3, 3, and 30 μM sinomenine were 1.85 (0.05-5.15), 0.83 (0.10-3.90), 0.56(0.09-1.62), and 0.59(0.05-1.30) ng/mL, respectively. Sinomenine significantly decreased the IC50 values of methylprednisolone and enhanced the immunosuppressive effect of methylprednisolone (p < 0.05). Sinomenine alone regulated the GR translocation in both Jurkat T cells and normal human PBMCs, and the combination of sinomenine and methylprednisolone showed stronger GR-modulatory activity than methylprednisolone alone. Thus, the additive effect of sinomenine to promote the methylprednisolone immunosuppressive efficacy was suggested to be related to nuclear GR-translocation. However, sinomenine did not significantly inhibit the P-glycoprotein function in the activated PBMCs, suggesting that sinomenine's additive effect seemed to be unrelated with the P-glycoprotein inhibition. [ABSTRACT FROM AUTHOR]

A series of α, β-unsaturated carbonyl-based compounds (curcumin analogs and chalcone derivatives) and their pyrazoline derivatives were investigated for their in vitro inhibitory effects on the phagocytosis of human neutrophils. The effects of the compounds on the chemotactic migration, CD11a/18 expression, phagocytic activity, and reactive oxygen species (ROS) production by human whole blood cells (WBC) and isolated human polymorphonuclear neutrophils (PMNs) were assessed by using 24-well cell migration assay kit, flow cytometer, Phagotest assay kit, and luminol/lucigenin-based chemiluminescence assay, respectively. Compounds 4, 5, 6, 13, 23, 33, 39, and 41 showed strong inhibitory activity against PMNs chemotaxis with IC50 values, ranging from 0.22-1.68 µM which were much lower than those of ibuprofen and curcumin (IC50 values 11.02 and 5.0 µM, respectively). All compounds showed low or moderate inhibition of cell adhesion molecule expression except for compound 15, while compounds 4, 5, 8, and 21 at 100, 25, and 6.25 μg/mL showed strong inhibition of opsonized bacteria engulfment by neutrophils with the highest suppressive effects exhibited by compound 21 at 37.4%. Compounds 4, 11, 13, 14, 24, 25, 27, 33, and 34 significantly suppressed ROS generation by PMNs and WBC. Compounds with N-methyl 4-piperidone and 4-piperidone linkers (4, 13, 14, 23, 24) and 2-pyrazoline-1-carboxamide and 2-pyrazoline-1-carbothioamide derivatives showed strong inhibition on chemotactic and phagocytic activities, and ROS production. The results suggest that some of the α, β-unsaturated carbonyl-based compounds strongly modulated the innate immune responses of phagocytes at different steps, highlighting their potential as a source of new immunomodulatory agents. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus, leading to permanent renal damage and chronic kidney disease. Hydroxychloroquine (HCQ) serves a protective role against lupus-associated clinical manifestations and medical complications; however, it results in numerous adverse reactions, limiting its long‑term use. The aim of the present study was to investigate the combined effect of HCQ and artemisinin (ART) on LN, and to elucidate the underlying mechanisms. An in vivo LN mouse model was prepared, and the animals were administered prednisone (PDS; serving as a positive control), high‑dose HCQ (H‑HCQ) or low‑dose HCQ combined with ART (L‑HCQ + ART) once daily for 8 weeks. The body weight, serum biochemical parameters, immune and inflammatory indicators, renal and spleen histological alterations, and mRNA expression levels of Kruppel‑like factor 15 (KLF15) and nuclear factor‑κB (NF‑κB) were analyzed. It was observed that L‑HCQ + ART and H‑HCQ ameliorated the LN‑induced body weight decrease, and significantly decreased the levels of anti‑double stranded DNA, antinuclear antibodies, immunoglobulin G, interferon γ, tumor necrosis factor‑α and transforming growth factor‑β1, as well as improved the kidney and spleen pathology, when compared with the model group. In addition, L‑HCQ + ART and H‑HCQ treatments induced KLF15 upregulation and NF‑κB downregulation. These results indicated that treatment with L‑HCQ + ART exerted renoprotective effects by regulating the expression levels of cytokines, KLF15 and NF‑κB. This combination treatment may have a similar immunosuppressive effect as PDS and H‑HCQ, and may be a promising alternative for LN treatment. [ABSTRACT FROM AUTHOR]

Background: Maternal–fetal tolerance plays a fundamental role in the maintenance of pregnancy. However, this immunological tolerance can be influenced by intrauterine infections. Human amniotic epithelial cells (hAECs) have immunomodulatory effects and respond to invading pathogens through expressing various toll-like receptors (TLRs). We hypothesize that bacteria or bacterial products affect the immunosuppressive effects of hAECs through TLR stimulation. Here, we investigated how a successful pregnancy can be threatened by TLR4 activation on hAECs on lipopolysaccharide (LPS) engagement. Materials and Methods: hAECs were isolated from the amniotic membrane received from six healthy pregnant women. The immunophenotyping of hAECs was studied by flow cytometry. The isolated hAECs (4 × 105 cells/ml) were cultured in 24-well plates in the presence or absence of LPS (5 μg/ml). After 24, 48, and 72 h of incubation, the culture supernatants of hAECs were collected, and the levels of interleukin-5 (IL-5), IL-6, IL-1β, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), and prostaglandin E2 (PGE2) were measured by enzyme-linked immunosorbent assay. Results: TLR4 activation showed a stimulatory effect on TGF-β1 production of hAECs (P < 0.001–0.05). PGE2 production of LPS-stimulated hAECs was significantly increased (P < 0.01–0.05). Moreover, TLR4 could induce TNF-α and IL-1β production of hAECs (P < 0.0001–0.01), while this effect was not observed on IL-6 production of hAECs. The IL-5 was produced at a very low level in two culture supernatants of hAECs, in which its production was independent of LPS effect. Conclusion: TLR4 activation by bacterial components on hAECs may be a potential risk factor for pregnancy complications.

Eutypenoids A-C (1-3), pimarane diterpenoid alkaloid and two ring A rearranged pimarane diterpenoids, were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures, including absolute configurations, were authenticated on the basis of the mass spectroscopy (MS), nuclear magnetic resonance (NMR), X-ray crystallography, and electronic circular dichroism (ECD) analysis. The immunosuppressive effects of eutypenoids A-C (1-3) were studied using a ConA-induced splenocyte proliferation model, which suggested that 2 exhibited potent immunosuppressive activities. [ABSTRACT FROM AUTHOR]

Azoxystrobin (AZ) is one of the most widely used strobilurin fungicides in the world, and its residue has seriously endangered aquatic ecological security. Our previous data showed that AZ exposure may reduce the resistance of fish to rhabdovirus infection in aquatic environment. Here, we further reported a potential long-term adverse effect of AZ exposure on the antiviral and immunosuppressive recovery in fish, and observed that mitochondrial dynamic balance was disturbed by AZ in which excessive mitochondrial fission occurred in response to decreased ATP levels. When a recovery operation was performed in AZ-exposed cells and fish, infectivity of our model virus, spring viraemia of carp virus (SVCV), was significantly decreased in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using zebrafish) in a time-dependent manner. Also, the expression of eight innate antiviral immune genes (IFNs , ISG15 , MX1 , RIG-I , IRF3 , Nrf2 and HO-1) showed a similar change to SVCV replication between the longer exposure period and the expression recovery. Additionally, AZ facilitated horizontal transmission of SVCV in a static cohabitation challenge model, predicting the increase of the potential for the viral outbreak. Therefore, our data suggest that long-term effect of AZ on irreparable impairment in fish made AZ residue potentially greater for ecological risks. • Azoxystrobin alters mitochondrial dynamics in fish. • Azoxystrobin induces an immune damage in fish. • Azoxystrobin decreases fish resistance to virus infection. • Azoxystrobin potentially improve the outbreak of fish viral diseases. [ABSTRACT FROM AUTHOR]

A series of novel scopariusicide derivatives were designed and synthesized starting from the main diterpenoid from the aerial parts of Isodon scoparius. Sis-25 was the most effective compound among them. The potential mechanism(s) of its immunosuppressive activity in vitro , as well as its effects on delayed type hypersensitivity (DTH) reaction and imiquimod-induced dermatitis in vivo were investigated in this study. Sis-25 inhibited anti-CD3/anti-CD28 mAbs, PHA or alloantigen-induced T cell proliferation without obvious cytotoxicity. Sis-25 was a highly selective inhibitor of GSK3-β and inhibited the mTOR/p70S6K pathway but not the PI3K/Akt, p38 MAPK/ERK 1/2 and JAK3/STAT5 pathways. Furthermore, Sis-25 significantly inhibited IFN-γ, IL-6 and IL-17 expression but not IL-10 expression in activated T cells. Finally, Sis-25 treatment mitigated the DNFB-induced DTH reaction and ameliorated imiquimod-induced dermatitis. In summary, Sis-25 exerted significant immunosuppressive activity by targeting GSK3β in vitro and in vivo. Sis-25 may guide the design of new drugs for more effective and safer treatments of autoimmune diseases and provide new insight into developing utilizations of Isodon scoparius. [Display omitted] • Sis-25 inhibits T cell proliferation without obvious cytotoxicity. • Sis-25 is identified as a highly selective inhibitor of GSK3-β. • Inhibition of GSK3-β by its inhibitor LiCl or SB415286 promotes T cell activation, but inhibits T cell proliferation. • Sis-25 treatment mitigates DNFB-induced DTH reaction and ameliorates imiquimod-induced dermatitis. [ABSTRACT FROM AUTHOR]

Cordyceps sinensis (CS) is an herbal tonic in traditional Chinese medicine and is used to treat a wide range of disorders, including immune, kidney, respiratory, lung and cardiovascular diseases, in China. Most studies are focused mainly on nucleotides and polysaccharides from CS and consider them to be the main active ingredients, while other ingredients are often disregarded. Hundreds of sphingolipids have been identified from CS and showed inhibitory effects on mouse splenic lymphocytes. This study aimed to establish a method for preparing a fraction of sphingolipids from the mycelial powder of CS and evaluate its immunosuppressive activity. Fraction of sphingolipids (Fr-SPLs) were prepared by silica gel chromatography and reversed-phase chromatography. Its components were identified and quantified by Quadrupole-Orbitrap UHPLC–MS/MS. PBMCs were prepared from human blood, and splenic lymphocytes, B cells, and T cells were prepared from mouse spleens. The inhibitory effect of Fr-SPLs on cell viability was evaluated by CCK-8 assay. PBMC apoptosis and the ratio of CD4+ T cells and CD8+ T cells were quantified by flow cytometry analysis. The expression of IL-2, IL-10, and TNF-α in PBMCs was detected by ELISA kits. A fraction containing 84.83% of sphingolipids (SPLs) was prepared from the mycelia of CS and named Fr-SPLs. 15 SPLs were identified from the Fr-SPLs. Fr-SPLs significantly inhibited the viability of human peripheral blood mononuclear cells (PBMCs) with an IC 50 value of 9.82 μg/mL and promoted PBMC apoptosis in a dose-dependent manner. Moreover, Fr-SPLs inhibited the viability of mouse splenocytes, as well as that of B cells and T cells derived from splenocytes. Furthermore, Fr-SPLs reduced the production of IL-2, IL-10, and TNF-α in PBMCs. Fr-SPLs show immunosuppressive activity, and this study will be useful for preparing immunosuppressive components from CS and its mycelia for hyperimmune disease. [Display omitted] 1. A fraction containing 15 sphingolipids (SPLs) with a content of 84.83% is prepared from the mycelia of Cordyceps Sinensis and named Fr-SPLs. 2. The wild Cordyceps Sinensis contains these 15 sphingolipids. 3. The Fr-SPLs exhibits an immunosuppressive activity. 4. The Fr-SPLs has the potential to alleviate the symptoms caused by the COVID-19 [ABSTRACT FROM AUTHOR]

Background aims. Mesenchymal stromal cells (MSC) from several tissues have immunomodulatory properties that involve various immunosuppressive molecules. An example is human leukocyte antigen (HLA)-G, a non-classical major histocompatibility complex (MHC) class I molecule that induces tolerance via interactions with inhibitory receptors present on major immune effector cells. Recently, the molecular mechanisms that regulate MSC-mediated immunosuppression have come under investigation. Our goal was to determine whether HLA-G plays a crucial role in immunosuppression and whether human adipose tissure (hAT) MSC can be used as a tool for biologic immunosuppression with HLA-G in transplantation. Methods. MSC were characterized by fluorescence-activated cell sorting (FACS) analysis, reverse transcriptase (RT)-polymerase chain reaction (PCR) and staining for differentiation. The immunogenicity and immunomodulatory effects of MSC were monitored by peripheral blood mononuclear cell (PBMC) proliferation assay with or without phytohemagglutinin (PHA) stimulation. Stable expression of HLA-G1 in MSC was done using a lentiviral system. Results. MSC from different tissues had similar morphology, immunophenotypic characters and differentiation potential. We also found that the immunosuppressive effect of MSC was monitored along with their endogenous HLA-G mRNA and protein levels. Stable expression of HLA-G1 appeared to enhance the immunosuppressive effect of hAT MSC, and the function of HLA-G1 was significantly decreased by HLA-G antagonistic antibody in PBMC proliferation assays. Conclusions. Although the HLA-G molecule is not the sole factor for MSC-mediated immunosuppression, our data provide evidence that HLA-G plays an important role in immunosuppression and that hAT MSC can be used as a tool for biologic immunosuppression during transplantation procedures. [ABSTRACT FROM AUTHOR]

Abstract: Compounds having α,β-unsaturated lactones display a variety of biological activities. Many research groups have tested both natural and unnatural α,β-unsaturated lactones for as-yet undiscovered biological properties. We synthesized α,β-unsaturated lactones with various substituents at the δ-position and studied their immunosuppressive effects, that is, the inhibition of Interleukin-2 (IL-2) production. Among the compounds synthesized, the benzofuran-substituted α,β-unsaturated lactone 4h showed the best inhibitory activity toward IL-2 production in Jurkat e6-1 T lymphocytes (IC50 =66.9nM) without cytotoxicity at 10μM. The results indicated that 4h may be useful as a potent immunosuppressive agent, as well as in IL-2-related studies. [Copyright &y& Elsevier]

Purposes: To probe into immunosuppressive effect and cell cycle arrest effect of different dose of FTY720. Method: we study immunosuppressive effect and cell cycle arrest effect of different dose of FTY720 and time and dose dependence of FTY720 with control and random method in vivo, respectively. Results: (i) survival time of graft in rat cardiac transplantation model is prolonged in group treated with FTY720. It is longer in group treated with FTY720 10 mg/kg than that in group treated with FTY720 2 mg/kg. (ii) The mean sum of lymphocyte in periphery blood decrease obviously 2 h after administration, reaches its peak 4 h after administration, and then maintain at low level stably. The mean sum of lymphocyte shows a linear relationship with dose of FTY720 and decrease with increasing of dose of FTY720. (iii) The percent of cell in G1-G0 increased in group treated with FTY720, not only in thymus but also in lymph node; this is more prevalent in the group treated with FTY720 10 mg/kg than that in group treated with FTY720 2 mg/kg. Similarly, the percent of cell in S and G2-M decreased in group treated with FTY720, not only in thymus but also in lymph node, and this decrease is more associated with group treated with FTY720 10 mg/kg than the one treated with FTY720 2 mg/kg. Conclusion: FTY720 is an effective immunosuppressant and immunosuppressive effect of FTY720 show a tendency of time and dose dependent. Effect of cell cycle arrest of FTY720 is related to dose of this new immunosuppressant. [ABSTRACT FROM AUTHOR]

Cordyceps CS-4 (C.CS-4), a vegetative form of Cordyceps that contains the same active compounds as the fruit body, is widely used as a substitute of Cordyceps in China. A number of studies have shown that Cordyceps can positively stimulate the activation of T lymphocytes, B lymphocytes, natural killer cells, and macrophages. In our previous study, we found that C.CS-4 could inhibit the proliferation of CD4+ T cells in autoimmune diseases and prevent the lymphocyte infiltration in tissues. However, it is still unclear how the lymphocytes are regulated by C.CS-4. In this study, we investigate the effect of C.CS-4 on human monocyte-derived dendritic cells (Mo-DCs), which are generated from PBMCs by the treatment with GM-CSF and IL-4. It is observed that Mo-DCs pretreated with C.CS-4 show an immature phenotype. Moreover, C.CS-4 significantly inhibits proliferation of CD4+ T cells, attenuates the production of cytokines in Mo-DCs and balances the Th1 and Th2 response in immune system. Our findings indicate that C.CS-4 exerts the immunosuppressive effect through inhibiting the CD4+ T cells proliferation, regulating cytokine secretions of Th1 and Th2 response (Mo-DCs) and inducing phenotypic immature of Mo-DCs which may be related to the antigen presenting dysfunction. [ABSTRACT FROM AUTHOR]

Two new cyclolanostane diglycosides, cimifoetiside A ( 1) and cimifoetiside B ( 2), were isolated from an 80% ethanolic extract of the aerial part of Cimicifuga foetida L. (Ranuculaceae). Using spectral data and chemical analysis, the structures of 1 and 2 were identified as (23 R, 24 S) cimicigenol 3-O- β-D-glucopyranosyl-(1″→3′)- β-D-xylopyranoside and (23 R, 24 S) cimicigenol 3-O- β-D-glucopyranosyl-(1″→2′)- β-D-xylopyranoside, respectively. The in vitro immunosuppressive effects of the two new compounds 1 and 2, as well as four other known cyclolanostane saponins 3–6 on T cells were evaluated. All the agents tested effectively inhibited the proliferation of murine splenocytes induced by Concanavalin A (ConA), with IC50 values ranging from 12.7 nM to 33.3 nM. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have received much attention because of their capabilities of differentiating into multiple mesenchymal lineages and supporting hematopoiesis. Recently, MSCs have gained further interests after the demonstration of an immunosuppressive role. However, it's still unclear whether the immunosuppressive capability of MSCs will be altered with disease state. In this study, our results showed that MSCs derived from patients with lymphoblastic leukemia (ALL), Hodgkin disease (HD), and non-Hodgkin lymphoma (NHL) capable of suppressing the proliferation of T-lymphocyte stimulated in a mixed-lymphocyte reaction (MLR). The immunosuppressive effect of MSCs derived from ALL, HD and NHL on T-cell proliferation was dose-dependent. The supernatants of MSCs derived from ALL, HD and NHL had effect on T-cell proliferation. By using neutralising monoclonal antibodies, we found that transforming growth factor β1 (TGFβ1) and hepatocyte growth factor were major mediators of T-cell suppression by MSCs derived from ALL, HD and NHL. Although MSCs derived from patients with myelodysplastics syndromes (MDS) could inhibit T-cell proliferation stimulated with mitogen or in MLR, the inhibitory effect of MDS-MSCs was impaired. However, adherent cells derived from patients with acute myeloid leukemia (AML) showed abnormal immunomodulatory functions. Adherent cells derived from AML failed to suppress the proliferation of T-cell stimulated in MLR. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of differentiating into multiple mesenchymal lineages and supporting hematopoiesis. Recently, MSCs have gained further interests after the demonstration of an immunosuppressive role. However, it is still unclear whether the immunosuppressive capability of MSCs will be altered with disease state. In this study, we obtained and expanded MSCs from bone marrow of patients with chronic myeloid leukemia (CML). Our results showed that MSCs derived from CML do not express costimulatory molecules CD40, CD80, and CD86. When MSCs derived from CML were added back to T cells stimulated by mitogens, a significant inhibition of T-cell proliferation was evident. MSCs differentiated into various mesenchymal lineages did not alter their immunosuppressive effect on T-cell proliferation. A significant T-cell inhibition was found in a transwell system, in which cell-cell contact between MSCs and effector cells was prevented. Furthermore, we found that transforming growth factor β1 (TGF β1) and hepatocyte growth factor (HGF) were major mediators of T-cell suppression by MSCs derived from CML. These results demonstrated that autologous MSCs derived from CML could effectively suppress T-cell proliferation. [ABSTRACT FROM AUTHOR]

Partial liver resections are the treatment of choice for patients with a malignant liver or bile duct tumor. The most frequent indications for partial liver resections are colorectal metastasis, hepatocellular carcinoma (HCC) and cholangiocarcinoma. Liver resection is the only therapy with a chance for cure in these patients. Refinements in surgical technique and increasing experience have contributed to a reduction in perioperative morbidity and mortality in recent years. Despite these improvements, partial liver resections remain a major surgical procedure and carry the risk for excessive blood loss and a subsequent need for blood transfusion. Blood transfusions have been associated with systemic side effects, such as depression of the immune system. Several studies have suggested that perioperative blood loss or transfusions have a negative impact on postoperative outcome. However, it has been debated whether this is due to a real cause-effect relationship or merely the result of more complicated surgery. We have reviewed the literature concerning studies focusing on the relationship between blood loss and blood transfusion during liver surgery for malignant tumors and postoperative outcome. Most studies were based on a retrospective analysis of single center experiences, using uni- and multivariate statistical methods. Most studies have demonstrated a significant and clinically relevant association between blood transfusion and postoperative mortality and morbidity, especially postoperative infectious complications. The effect of blood transfusions on tumor recurrence and more long-term mortality is much less clear and evidence varies depending on the type of malignancy. The strongest indication that blood transfusion may have an impact on tumor recurrence has been found for patients with early stages of HCC. However, overall, no such effect could be demonstrated for patients undergoing partial liver resection for late stages of HCC, colorectal liver metastasis or cholangiocarcinoma. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The avidity for CD80Ig/CD86Ig and the in vitro immunosuppressive effect of recombinant human cytotoxic T lymphocyte-associated antigen 4-immunoglobulin, produced by transgenic rice cell suspension cultures (hCTLA4IgP) with CHO-derived recombinant hCTLA4Ig (hCTLA4IgM), were measured. Surface plasmon resonance (SPR) was used for kinetic binding analysis: hCTLA4IgP and hCTLA4IgM had higher avidity for CD80Ig/CD86Ig than for CD28Ig, and the avidity for CD80Ig/CD86Ig was similar. hCTLA4IgP and hCTLA4IgM had similar in vitro immunosuppressive activity against the expression of T cell-derived cytokines, such as IL-2, IL-4, and IFN-γ, but did not suppress the expression of macrophage-derived cytokines, including TNF-α and IL-1β, as well as NO. Thus the immunosuppressive mechanism of hCTLA4IgP is also T cell-specific and it could therefore be used as an immunosuppressive agent with an equivalent potency to that of hCTLA4IgM. [ABSTRACT FROM AUTHOR]

Abstract: Clematis mandshurica Rupr (Ranunculaceae) roots are used in traditional Korean medicine to treat inflammation-related diseases. Therefore, we undertook to investigate their inhibitory effect on inflammation under non-cytotoxic conditions. The ethanolic extract of Clematis mandshurica at 100μg/ml was found to significantly block the production of the pro-inflammatory mediators, nitric oxide (NO) and prostaglandin E2 (PGE2), in lipopolysaccharide (LPS)/interferon(IFN)-γ-stimulated mouse peritoneal macrophages, by up to 77% and 59%, respectively. In addition, it significantly inhibited cell proliferation and cytokine production (interleukin (IL)-2 and IFN-γ) in splenocytes stimulated with Con A (concanavalin A; 5μg/ml). Furthermore, when splenocytes from extract fed mice (200mg/kg for 2 weeks) were activated with Con A, cell proliferation and the production of IL-2 and IFN-γ were significantly inhibited. In addition, the extract reduced in vivo inflammation in oxazolone-induced delayed type hypersensitivity (DTH) model mice. Taken together, these data suggest that Clematis mandshurica is able to ameliorate inflammatory disease by exerting an anti-inflammatory effect in cases of proinflammatory and cell-mediated inflammation. [Copyright &y& Elsevier]

Two lignans, isochaihulactone and chaihunaphthone, together with eleven known compounds were isolated from the root of Bupleurum scorzonerifolium. Their structures were established on the basis of spectral evidence. In biological testing, eugenin and saikochromone potently inhibited CD28-costimulated activation of human peripheral blood T cells. [Copyright &y& Elsevier]

The immunosuppressive effect of hepatocytes was examined experimentally by heart allograft and delayed-type-hypersensitivity (DTH) reactions. The hepatocyte inoculation (1×10) of BDE (of the major histocompatibility complex haplotype RT1), LEW (RT1), and DA (RT1) into the spleens of LEW rats significantly prolonged the survival of BDE heart allografts to 14.3±2.7 (mean±SD), 9.2±0.8, and 10.8±2.3 days respectively, compared with 6.7±0.8 days in controls (p<0.01). Moreover, the BDE hepatocytes had a significantly prolonged survival compared to the LEW (p<0.01) and DA (0.02

The first stereoselective total synthesis of the immunosuppressive decalin derivative monascusic acid B has been accomplished from (R)-(+)-pulegone involving Horner-Wadsworth- Emmons and Julia-Kocienski olefination reactions and Lewis acid catalyzed intramolecular Diels-Alder cyclization. [ABSTRACT FROM AUTHOR]

The first stereoselective total synthesis of the immunosuppressive decalin derivative monascusic acid B has been accomplished from (R)-(+)-pulegone involving Horner-Wadsworth- Emmons and Julia-Kocienski olefination reactions and Lewis acid catalyzed intramolecular Diels-Alder cyclization. [ABSTRACT FROM AUTHOR]

B cells play a major role in the pathophysiology of myasthenia gravis (MG) with their ability to produce disease specific, pathogenic antibodies. However, their status during disease development and follow-up stages of the disease in the peripheral blood may need further studies to determine useful markers. In this study, we aimed to detect B cell associated factors concerning immunosuppressive treatment in generalized non-thymomatous MG patients. Although CD19+ B cell distribution did not vary among disease subgroups, expressions of both CD38 and BAFFR were altered on B cells in MG patients under immunosuppressive therapy. Serum levels of BAFF were elevated in untreated MG patients as compared to treated MG patients and healthy controls. B cell activation factors may show profound alterations due to immunosuppression. • We investigated B cell associated factors for immunosuppressive treatment in MG patients. • Expressions of CD38 and BAFFR were altered on B cells under immunosuppressive therapy. • Serum levels of BAFF were elevated in untreated patients as compared to treated patients. • B cell activation factors may show profound alterations due to immunosuppression. [ABSTRACT FROM AUTHOR]

Background: Maternal–fetal tolerance plays a fundamental role in the maintenance of pregnancy. However, this immunological tolerance can be influenced by intrauterine infections. Human amniotic epithelial cells (hAECs) have immunomodulatory effects and respond to invading pathogens through expressing various toll-like receptors (TLRs). We hypothesize that bacteria or bacterial products affect the immunosuppressive effects of hAECs through TLR stimulation. Here, we investigated how a successful pregnancy can be threatened by TLR4 activation on hAECs on lipopolysaccharide (LPS) engagement. Materials and Methods: hAECs were isolated from the amniotic membrane received from six healthy pregnant women. The immunophenotyping of hAECs was studied by flow cytometry. The isolated hAECs (4 × 105 cells/ml) were cultured in 24-well plates in the presence or absence of LPS (5 μg/ml). After 24, 48, and 72 h of incubation, the culture supernatants of hAECs were collected, and the levels of interleukin-5 (IL-5), IL-6, IL-1β, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), and prostaglandin E2 (PGE2) were measured by enzyme-linked immunosorbent assay. Results: TLR4 activation showed a stimulatory effect on TGF-β1 production of hAECs (P < 0.001–0.05). PGE2 production of LPS-stimulated hAECs was significantly increased (P < 0.01–0.05). Moreover, TLR4 could induce TNF-α and IL-1β production of hAECs (P < 0.0001–0.01), while this effect was not observed on IL-6 production of hAECs. The IL-5 was produced at a very low level in two culture supernatants of hAECs, in which its production was independent of LPS effect. Conclusion: TLR4 activation by bacterial components on hAECs may be a potential risk factor for pregnancy complications. [ABSTRACT FROM AUTHOR]

Background: In vitro and in vivo immunosuppressive properties have been described for mesenchymal stem cells (MSCs), as they are able to modulate the function of all major immune cell populations. They represent important candidates for tissue regeneration and manipulation of the immune response in graft rejection, graft vs. host disease, and autoimmune disorders. Objective: To evaluate effect of autologous bone marrow stem cell on panel reactive antibodies in patients with chronic and progressive renal failure. Methods: This is a pilot study on 17 patients with CFR (9 in the intervention group and 8 in the control group). Panel reactive anti-bodies before and after injections of stem cells from bone marrow that containing acceptable percent of MSCs in the intervention group compared with the control group. 200-400 mL bone marrow was aspirated; then nucleated cells were separated from red blood cells; those cells were then injected to patients via a peripheral vein. Results: The mean±SD age of participants was 41.8±12.37 years in the intervention group and 40.4±12.7 years in the control group (p=0.807). The mean±SD panel antibody reaction was 69.9±6.2 in the intervention group and 70.3±13.5 in the control group (p=0.956). There was a significant (p=0.043) difference between panel antibody reaction before and after the intervention (51.6±26.4). Conclusion: Infusion of allograft MSCs, might be an effective therapy for patients with high panel reactive antibodies. [ABSTRACT FROM AUTHOR]

The immunosuppressive effect of antimacrophage serum (AMS) on the primary immune response of mice to sheep red blood cells (SRBC) was studied. AMS, given before a small dose of antigen, abrogated the immune response. Transplantation of normal, galss-adherent macrophages enabled AMS-treated animals to respond to SRBC, while administration of lymph node lymphocytes did not reveres AMS - induced immunosuppression significantly.

Background and Objectives: The exosomes released by mesenchymal stromal cells (MSCs) in classical FBS-containing media have been demonstrated as an alternative, cell-free therapy in various diseases including inflammatory bowel disease (IBD). It has been found that the function of exosomes is affected by culture condition. We previously developed a serum-free, xeno-free and chemically defined medium, and umbilical cord-derived MSCs in this medium retained the immunosuppressive capability., Methods: In this study, we evaluated the immunosuppressive function of exosomes from MSCs (MSC-Exo) in defined medium and their therapeutic effect on treating colitis., Results and Conclusions: In vitro studies indicated that MSC-Exo reduced the concentration of pro-inflammatory cytokines IFN- γ , TNF- α and IL-1 β , and increased the secretion of anti-inflammatory cytokines TGF- β 1 and IL-10, but no significant change of inhibitory effect on peripheral blood mononuclear cells proliferation was shown. In vivo experimental colitis showed that administration of MSC-Exo was able to significantly ameliorate the disease activity index score, weight loss, colon shortening, and the histological colitis score through up-regulation anti-inflammatory responses and down-regulation of inflammatory responses. Moreover, the use of MSC-Exo (200 µ g) led to an improved therapeutic efficacy when compared with MSCs at a dose of 1×10 6 cells. Our findings indicate that the exosomes from MSCs in defined medium possess a certain degree of immunosuppressive effect in vitro and exhibit a therapeutic capability in a mouse model of DSS-induced colitis through suppressing inflammation mechanism.