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Interferon Gamma (interferon + gamma)
Selected Abstracts22-ene-25-oxa-vitamin D: a new vitamin D analogue with profound immunosuppressive capacitiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2005C. Daniel Abstract Background, The biologic role of 1,25-dihydroxyvitamin D3, such as anti-inflammatory functions, reduction of cytokine production by T cells and immunoglobulin production by B cells, is well established. However, its clinical use as an immunosuppressive agent is limited because of the hypercalcemic toxicity occurring after systemic application. The purpose of this study was to investigate the immunmodulatory effects of 22-ene-25-oxa-vitamin D (ZK156979), a novel low calcemic vitamin D analogue. Materials and methods, Human peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated using the Ficoll Hypaque technique, cultured for 24 h and treated with different concentrations of ZK156979 ranging from 10,5 to 10,10 mol L,1 compared with 1,25-dihydroxyvitamin D3[10,5,10,10 mol L,1] following phytohaemagglutinin (PHA) stimulation. Interferon gamma (IFN,), tumour necrosis factor alpha (TNF,), interleukin 1 beta (IL-1,), interleukin 10 (IL-10) and interleukin 4 (IL-4) secretion in supernatants were measured by ELISA. Results, ZK156979 inhibited the PHA-induced Th1-response (IFN, and TNF, levels) and the macrophage-product IL-1, in a concentration-dependent manner (10,10,10,5 mol L,1) with the efficiency on cytokine expression compared with 1,25-dihydroxyvitamin D3 being slightly reduced. In contrast, ZK156979 and 1,25-dihydroxyvitamin D3 both affected the Th2 response, leading to significantly increased IL-10- and IL-4 secretion. Conclusions, ZK156979 is a member of novel vitamin D analogues revealing prominent immunomodulatory and suppressive characteristics with distinctive inhibition of Th1-cytokines whereas the Th2 compartment is augmented, thus providing a considerable therapeutic potential in T-cell -mediated diseases. [source] The Impact of Interferon Gamma Receptor Expression on the Mechanism of Escape From Host Immune Surveillance in Hepatocellular CarcinomaHEPATOLOGY, Issue 3 2000Mitsuo Nagao M.D. Interferon gamma (IFN-,) plays an important role in host defense mechanism and participates in the progression of chronic liver disease. IFN-, exerts its pleiotrophic effects by transcriptional regulation of expression of numerous genes, such as major histocompatibility complex (MHC) class I and Fas, through interaction with IFN-, receptor (IFN-,-R). Although hepatocytes in normal liver express weak or no IFN-,-R, those in acute and chronic liver disease up-regulate its expression. A study using IFN-,-R ,-chain knock-out mice revealed the actions of IFN-, on tumor cells as an extrinsic tumor-suppressor mechanism. However, it is unclear whether or how hepatocellular carcinoma (HCC) blocks the signal transduction of IFN-, to evade host immune surveillance. We examined the expression of IFN-,-R and IFN-,,inducible genes in 44 cases with HCC using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. In noncancerous liver tissues (n = 38), IFN-,-R expression on the cell surface was up-regulated in 27 cases. In IFN-,-R,negative cases (n = 15), tumor size was larger (P = .032), serum ,-fetoprotein (AFP) level was higher (P = .001), intrahepatic and extrahepatic metastasis was more common (P = .044 and .013, respectively), and Ki-67 labeling index (LI) was higher (P = .041), compared with IFN-,-R,positive cases. Accordingly, the evasion mechanism may play an important role in progression, especially metastasis, in HCC. The significant correlation between the status of IFN-,-R and the expression of Fas and MHC implies that the loss of IFN-,-R might contribute to the mechanism of escape from host immune rejection in HCC. [source] Growth factor attenuation of IFN,-mediated hepatocyte apoptosis requires p21waf,1INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 4 2006Christian T. McCullough Summary Interferon gamma (IFN,) is an important mediator of inflammatory liver damage as part of a complex cytokine network. In vitro, IFN, induces hepatocyte apoptosis. We hypothesized that the hepatocyte response to IFN signalling is context-dependent, and that specific growth factors, via phosphatidylinositol 3 kinase (PI(3)K) and protein kinase B/Akt signalling pathways, confer a cytoprotective effect. We established an in vitro model of IFN,-mediated primary hepatocyte injury. We show that epidermal growth factor (EGF) and hepatocyte growth factor (HGF) attenuate the IFN,-induced hepatocyte apoptosis. IRF-1, but not p53, is required for IFN,-mediated apoptosis. The loss of p21waf,1 not only sensitizes the hepatocyte to IFN,-mediated injury but is required for survival factor mediated cytoprotection. We show that the PI(3)K inhibitor, LY294002, partially inhibits the apoptotic response of the hepatocyte to IFN,. In summary, we present evidence that a component of pro-apoptotic IFN, signalling in the primary hepatocyte occurs via the PI(3)K pathway. We show that the hepatocyte response to IFN, is modulated by external survival factors and that this survival signalling requires p21waf,1. [source] Sequence flexibility of the immunodominant HLA A*0201 restricted ppUL83 CD8 T-cell epitope of human cytomegalovirusJOURNAL OF MEDICAL VIROLOGY, Issue 1 2010Jakub Kopycinski Abstract The cytomegalovirus ppUL83 protein contains an immunodominant A*0201 restricted epitope between residues 495 and 503. We investigated the tolerance of this epitope to sequence variation in the context of peptide binding to HLA A*0201 and the ability to induce an Interferon gamma (IFN,) response through engagement with the T-cell receptor (TCR). The majority of mutations investigated resulted in a decrease in the production of IFN, indicating that if such variants occurred in vivo they would not be recognized by CD8 T-cell clones specific for the wild-type epitope. The mechanistic basis for the majority of the mutant peptides was their failure to bind and stabilize class I HLA cell surface expression. However, one peptide with a mutation at the P5 position (methionine to cysteine) resulted in a significant enhanced binding to HLA A*0201 and also an increase in cell surface expression over the wild-type peptide but was unable to engage with the CD8 TCR and trigger IFN, production. This peptide acted as a competitive inhibitor of the wild-type peptide but could not fully inhibit IFN, production by the latter. We subsequently investigated whether mutations of the HLA A*0201 epitope were evident in immunocompromized patients experiencing either rapid exponential or persistent cytomegalovirus replication. J. Med. Virol. 82:94,103, 2010. © 2009 Wiley-Liss, Inc. [source] Interferon gamma (IFN-,) may reverse oral submucous fibrosisJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 1 2001M. F. Haque Abstract: Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity and oropharyngx characterised by fibrosis in the submucosa leading to progressive limitation of the mouth opening. Interferon gamma (IFN-,) is a known anti-fibrotic cytokine. In this study we have investigated: a) the effect of IFN-, on collagen synthesis by arecoline-stimulated OSF fibroblasts in vitro (n=5), b) the effect of intra-lesional IFN-, on the fibrosis of OSF patients (n=29) and c) the immunohistochemical analysis of pre- and post-treatment inflammatory cell infiltrates and cytokine levels in the lesional tissue (n=29). The results show that the increased collagen synthesis in vitro in response to arecoline was inhibited in the presence of IFN-, (0.01,10.0 U/ml) in a dose-related way. In an open uncontrolled study intra-lesional IFN-, treatment showed improvement in the patients mouth opening from an inter-incisal distance before treatment of 21±7 mm, to 30±7 mm immediately after treatment and 30±8 mm 6-months later, giving a net gain of 8±4 mm (42%) (range 4,15 mm). Patients also reported reduced burning dysaesthesia and increased suppleness of the buccal mucosa. The post-treatment immunohistochemistry showed a decreased amount of inflammatory cell infiltrate and an altered level of cytokines compared with the pre-treatment lesional tissue. The effect of IFN-, on collagen synthesis appears to be a key to the treatment of these patients, and intra-lesional injections of the cytokine may have a significant therapeutic effect on OSF. [source] Association of interferon-, +874A polymorphism with the risk of developing cervical cancer in north-Indian populationBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 12 2009R Gangwar Objective, Interferon gamma (IFN -,) is a pro-inflammatory cytokine playing a pivotal role in both innate and adaptive immune responses. A single nucleotide polymorphism located in the first intron of the human IFN-, gene can influence the secretion of cytokine. Therefore, we aimed to investigate the association of IFN-, T/A gene polymorphism with the risk of cervical cancer. Design, Case,control study. Setting, Uttar Pradesh State in India. Sample, Two hundred cases with histologically proven cancer of the cervix and healthy controls (n = 230), age and ethnicity matched were recruited in this study. Methods, Genotyping was performed for bi-allelic +874 (T/A) polymorphism of IFN-, by amplification refractory mutation system method. Main outcome measures, Low producer IFN-, +874 AA genotype was associated with high risk for cervical cancer, which further modulated the increased risk in tobacco users. Results,IFN-, AA genotype which is low producer of IFN-, was associated with increased risk of cervical cancer (OR = 2.43, P = 0.003). Allele A was at 1.54-fold increased risk of cervical cancer (OR=1.54, P = 0.002). The AA genotype showed statistically significant risk with high stage (III + IV) of cervical cancer (OR = 4.99, P = 0.001). In tobacco users, AA genotype showed significantly increased susceptibility to cervical cancer (OR = 5.08, P = 0.010). Conclusion, Variation in IFN-, +874 AA genotype because of ethnicity in north-Indian population may represent an important susceptibility biomarker for cervical cancer risk as well as other diseases and should be explored further. [source] Heart changes in 17-day-old fetuses of diabetic ICR (Institute of Cancer Research) mothers: Improvement with maternal immune stimulationCONGENITAL ANOMALIES, Issue 1 2009Juan Claudio Gutierrez ABSTRACT Maternal diabetes mellitus is associated with increased fetal teratogenesis, including cardiovascular defects. Non-specific maternal immune stimulation with Freund's complete adjuvant (FCA) or interferon gamma (IFN,) has been associated with protection against birth malformations. Using a diabetic mouse model, late-gestation fetal heart and great vessel morphology were analyzed. Four groups of mice were used: non-diabetic females as a control group, hyperglycemic females induced by streptozotocin as a diabetic group, and diabetic females injected either with FCA or IFN,. At day 17 of gestation, females were euthanized and one fetus was arbitrarily selected per litter for fixation and sectioning. Treatment-induced changes in cardiac development were assessed from digital images of serial sections taken at standardized levels in the thorax. One-way parametric and non-parametric ANOVA and ordinal logistic regression were performed to compare the difference among groups (P < 0.05). Maternal hyperglycemia altered morphology of the late-gestation fetal mouse heart by causing ventricular chamber dilation, sectional myocardial reduction, and an increase in transversal aortic area. FCA protected the fetal heart from cavitary dilation in diabetic mothers. FCA and IFN, protected the fetal heart against reduction of myocardial area, and ascending thoracic aorta dilation. Consequences of late gestation heart chamber dilation and myocardial reduction are not yet known. Maternal immune stimulation partially protected against these developmental defects by mechanisms that remain unclear. [source] Monocytes and T lymphocytes contribute to a predominance of interleukin 6 and interleukin 10 in systemic lupus erythematosus,CYTOMETRY, Issue 4 2009Susana Mellor-Pita Abstract Objective To investigate the contribution of T lymphocytes and monocytes to cytokine production in systemic lupus erythematosus (SLE). Methods Forty-five SLE patients and 19 healthy volunteers were included. Serum levels of tumor necrosis factor alpha (TNF,), interferon gamma (IFN,), interleukin (IL)-6, and IL10 were quantified by ELISA. The cytokine production capacities of peripheral blood mononuclear cells were assessed by culturing in vitro with PMA+Ionomycin or LPS. The intracellular cytokine expression was measured by flow cytometry in T lymphocytes and monocytes, respectively. The influence of the disease activity (measured as the SLE-disease activity index; SLEDAI) and the treatment the patients were receiving was evaluated. Results Serum IL10, IL6, and TNF, levels were increased in patients (P , 0.01), and a higher spontaneous (without stimuli) intracellular expression of IL10 in CD4+ and CD8+ T lymphocytes (P < 0.05) and of IL6 in monocytes (P = 0.01) were found. After stimulation, patients presented a higher percentage of CD4+ and CD8+ T lymphocytes producing IL4 and IL10 (P , 0.01), and of monocytes producing IL6 (P = 0.04) and IL10 (P = 0.008). The SLEDAI score was positively correlated with the percentage of CD4+IL10+ and CD8+IL10+ T lymphocytes (P < 0.01), and inversely correlated with CD8+TNF,+ (P= 0.02), CD4+IFN,+ (P = 0.04) and CD8+ IFN,+ (P = 0.002) T lymphocytes. Patients receiving high dose prednisone produced higher IL10, but they also were the patients with a more active disease. Conclusion Monocytes and T lymphocytes (CD4+ and CD8+) contribute to an overproduction of IL6 and IL10 in SLE; this correlates with the disease activity but is independent of the treatment the patients are receiving. © 2009 Clinical Cytometry Society [source] A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis,,HEPATOLOGY, Issue 3 2010Silvia Ferri Immunotolerance is maintained by regulatory T cells (Tregs), including CD4+CD25hi, CD8+CD28,, ,,, and CD3+CD56+ [natural killer T (NKT)] cells. CD4+CD25hi cells are impaired in children with autoimmune hepatitis (AIH). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in ,,, CD8+CD28,, NKT, and CD4+CD25hi cells. CD4+CD25hi T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-,) production by CD4+CD25, target cells. Liver forkhead box P3,positive (FOXP3+) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4+CD25hi T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8+CD28, T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, ,, T cells in AIH patients were more numerous versus healthy controls and had an inverted V,1/V,2 ratio and higher IFN-, and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3+ cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and ,, T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010) [source] Neutrophil depletion protects against murine acetaminophen hepatotoxicity,,HEPATOLOGY, Issue 6 2006Zhang-Xu Liu We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-,) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1,deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1,deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1,deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. (HEPATOLOGY 2006;43:1220,1230.) [source] Hepatocytes as cytotoxic effector cells can induce cell death by CD95 ligand-mediated pathway,HEPATOLOGY, Issue 6 2006Clifford S. Guy The liver plays an increasingly recognized role in the host's immune responses. The direct contribution of hepatocytes as effector cells to local immunity, pathogen containment, and liver disease is not determined. This in vitro study examined whether hepatocytes can eliminate other cells via a CD95 ligand (CD95L or FasL)/CD95 (Fas),mediated mechanism and whether this cytotoxic activity can be modulated by cytokines such as interferon gamma (IFN-,) or tumor necrosis factor alpha (TNF-,). We have found that normal woodchuck and human hepatocytes, both cultured and primary freshly isolated, as well as human HepG2 cells, intrinsically transcribe not only CD95 but also CD95L when examined by reverse transcription-polymerase chain reaction (RT-PCR) assays. The functional competence of CD95L, which was detectable in hepatocytes and HepG2 cells by Western blotting, was confirmed in bioassays by induction of apoptosis of CD95-bearing P815 and LS102.9 cell targets and validated by inhibition of the cell killing with CD95 antagonistic antibody or with a general caspase inhibitor. Furthermore, exposure of cultured hepatocytes to IFN-, or their stable transfection with IFN-, cDNA or TNF-, cDNA increased hepatocyte CD95L/CD95,mediated cell killing. In conclusion, hepatocytes express both CD95L and CD95 and they can induce death of other cells by a CD95L-dependent mechanism. IFN-, and, to a lesser extent, TNF-, can enhance hepatocyte CD95L-mediated cytotoxicity. This suggests that the local cytokine environment may modulate the hepatocyte contribution to liver immunity. (HEPATOLOGY 2006;43:1231,1240.) [source] Long-term follow-up after successful interferon therapy of acute hepatitis CHEPATOLOGY, Issue 1 2004Johannes Wiegand Early treatment of acute hepatitis C infection with interferon alfa-2b (IFN-,-2b) prevents chronicity in almost all patients. So far, no data are available on the long-term outcome after interferon (IFN) therapy of acute hepatitis C. The aim of this study was to assess the clinical, virological, and immunological long-term outcome of 31 successfully treated patients with acute hepatitis C infection who were followed for a median of 135 weeks (52-224 weeks) after end of therapy. None of the individuals had clinical evidence of liver disease. Alanine aminotransferase (ALT) levels were normal in all but 1 patient. Serum hepatitis C virus (HCV) RNA was negative throughout follow-up, even when investigated with the highly sensitive transcription-mediated amplification (TMA) assay (cutoff 5-10 IU/mL). In addition, no HCV RNA was detected in peripheral blood mononuclear cells (PBMC) of 15 cases tested. The patients' overall quality-of-life scores as determined by the SF-36 questionnaire did not differ from the German reference control cohort. Ex vivo interferon gamma (IFN-,) ELISPOT analysis detected HCV-specific CD4+ T-helper cell reactivity in only 35% of cases, whereas HCV-specific CD8+ T-cell responses were found in 4 of 5 HLA -A2,positive individuals. Anti-HCV antibody levels decreased significantly during and after therapy in all individuals. In conclusion, early treatment of symptomatic acute hepatitis C with IFN-,-2b leads to a long-term virological, biochemical, and clinical response. Waning of anti-HCV humoral immunity and presence of HCV-specific CD8+ (but not CD4+) T cells highlights the complexity of T-cell and B-cell memory to HCV, which might be significantly altered by IFN treatment. (HEPATOLOGY 2004;40:98,107.) [source] Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosisHEPATOLOGY, Issue 2 2001Monica G. Chiaramonte In several allergic, autoimmune, and infectious diseases, fibrosis is a major cause of morbidity and mortality. Here, using a model of infection-induced liver fibrosis, we show that interleukin (IL)-13 is required at all stages of Schistosomiasis mansoni infection to induce fibrosis. IL-4 production was preserved in IL-13,deficient mice, yet failed to significantly contribute to the fibrotic response in either acute or chronic infection. Significant fibrosis develops in all infected mice, although the magnitude of the response varies widely in inbred mice. C3H/HeN, BALB/c, and C57BL/6 mice develop high, intermediate, and low levels of fibrosis, respectively. Despite these differences, IL-13 antagonism resulted in a marked amelioration of fibrosis in all strains. The fibrotic mechanism in the high- and low-responder strains was unrelated to their tissue eosinophil or mast cell responses, but did correlate with their patterns of IL-13, IL-10, and interferon gamma (IFN-,) mRNA expression. Indeed, severe fibrosis correlated with a high IL-13 and low IFN-,/IL-10 mRNA response. Because fibrotic diseases are typically progressive disorders, an important issue was to determine whether IL-13 inactivation might be used to treat an established and ongoing fibrotic disease. Here, IL-13 antagonism was highly efficacious, even after fibrosis and the Th2 cytokine response were firmly established. These studies demonstrate the central role played by IL-13 in fibrogenesis and suggest that therapeutic approaches aimed at disrupting the IL-13 pathway will be highly effective at preventing fibrotic disease caused by chronic Th2-mediated inflammatory reactions. [source] Cold liver ischemia-reperfusion injury critically depends on liver T cells and is improved by donor pretreatment with interleukin 10 in miceHEPATOLOGY, Issue 6 2000Olivier Le Moine M.D. Kupffer cells are thought to mediate most of the deleterious effects of liver ischemia-reperfusion injury. The role of liver T cells and the impact of resident cell deactivation by interleukin 10 (IL-10) have never been addressed. Using a model of ex vivo liver cold ischemia and reperfusion, we assessed liver injury, tumor necrosis factor (TNF) and interferon gamma (IFN-,) release from livers of balb/c mice, nude mice, nude mice reconstituted with T cells, and gadolinium balb/c pretreated mice. The anti-inflammatory cytokine IL-10 was then used to define the best strategy of administration potentially able to modulate ischemia-reperfusion injury. For this purpose IL-10 was administered to the donor before liver harvesting, in the preservation medium during cold ischemia or during reperfusion. TNF and IFN-, were released time dependently and paralleled liver injury after reperfusion of cold preserved livers. Reperfused livers from nude or gadolinium pretreated mice disclosed a dramatic decrease in TNF and IFN-, release. Tissue injury was reduced by 51% in the absence of T cells and by 88% when Kupffer cells were deactivated. This effect was reverted by T-cell transfer to nude mice. Only donor pretreatment with IL-10 or IL-10 infusion during reperfusion led to a significant decrease in liver injury, TNF, and IFN-, release (,66% or ,41%, ,95% or ,94%, and ,70% or ,70%, respectively). In conclusion, liver resident T cells are critically involved in cold ischemia-reperfusion injury and pretreatment of the donor with IL-10 decreases liver injury and the release of T-cell, and macrophage-dependent cytokines. [source] A psychoneuroimmunological review on cytokines involved in antidepressant treatment responseHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 3 2010Debbie G. A. Janssen Abstract Objectives The literature exploring the role that cytokine functioning plays in the pathogenesis and treatment of depressive illness is reviewed. The review focuses on the influence of antidepressants on cytokines, and on how treatment response might be affected by genetic variants of cytokines. Method The authors systematically reviewed the scientific literature on the subject over the last 20 years, searching PubMed, PsychInfo, and Cochrane databases. Results Antidepressants modulate cytokine functioning, and these mechanisms appear to directly influence treatment outcome in depression. Antidepressants appear to normalize serum levels of major inflammatory cytokines, including interleukin (IL)-1,, IL-6, tumor necrosis factor alpha (TNF- ,), and interferon gamma (IFN- ,). Antidepressants are postulated to modulate cytokine functioning through their effects on intracellular cyclic adenosyl monophosphate (cAMP), serotonin metabolism, the hypothalamo-pituitary-adrenocortical (HPA) axis or through a direct action on neurogenesis. Preliminary research shows that cytokine genotypes and functioning may be able to help predict antidepressant treatment response. Conclusions Current literature demonstrates an association between antidepressant action and cytokine functioning in major depression. Improved understanding of the specific pharmacologic and pharmacogenetic mechanisms is needed. Such knowledge may serve to enhance our understanding of depression, leading to promising new directions in the pathology, nosology, and treatment of depression. Copyright © 2010 John Wiley & Sons, Ltd. [source] Fontolizumab in moderate to severe Crohn's disease: A phase 2, randomized, double-blind, placebo-controlled, multiple-dose studyINFLAMMATORY BOWEL DISEASES, Issue 2 2010Walter Reinisch MD Abstract Background: The safety and efficacy of fontolizumab, a humanized anti-interferon gamma antibody, was investigated in patients with Crohn's disease (CD). Elevated gut mucosal levels of interferon gamma, a key cytokine involved in the inflammatory process of CD, are associated with disease symptoms. Methods: A total of 201 patients with Crohn's Disease Activity Index (CDAI) scores between 250 and 450 were randomized to receive an initial intravenous dose of 1.0 or 4.0 mg/kg fontolizumab or placebo, followed by up to 3 subcutaneous doses of 0.1 or 1.0 mg/kg fontolizumab or placebo every 4 weeks. Clinical response at day 29, the primary efficacy endpoint, was defined as a decrease in the CDAI of at least 100 points from baseline levels. Results: Of 201 patients, 135 (67%) completed the study. Day 29 response rates were similar in all treatment groups (31%,38%). At subsequent timepoints a significantly greater proportion of patients in the 1.0 mg/kg intravenous / 1.0 mg/kg subcutaneous fontolizumab group had clinical response and significantly greater improvement in the CDAI score compared with patients who received placebo. All fontolizumab groups had significant improvement in C-reactive protein levels. The overall frequency of adverse events was similar in all groups (58%,75%); most events were related to exacerbation of CD. There was a low frequency (5.2%) of neutralizing antibodies to fontolizumab. Conclusions: Although a strong clinical response to fontolizumab was not observed, significant decreases in C-reactive protein levels suggest a biological effect. Fontolizumab was well tolerated, and further studies to assess its efficacy are warranted. Inflamm Bowel Dis 2009 [source] Predominant T helper type 2-inflammatory responses promote murine colon cancersINTERNATIONAL JOURNAL OF CANCER, Issue 9 2006Emi Osawa Abstract Colon cancer is one of the most serious complications of inflammatory bowel diseases, especially ulcerative colitis (UC). Previous studies have shown that characteristic immunological event during inflammation in UC is the expression of T helper-type 2 (Th2) cell-derived cytokines. In this study, we investigated the influence of a predominant Th2-type cytokine response in colitis on carcinogen-induced colon tumors. Wild type (WT), interferon gamma (IFN-,) gene deficient (,/,) [Th2 dominant] or interleukin (IL)-4,/, [Th1-dominant] mice of BALB/c background were used in this study. To compare tumor formation, mice were given the carcinogen azoxymethane (AOM) and intrarectal administration of trinitrobenzene sulfonic acid (TNBS), to induce colitis. Thirty-three weeks after initial treatment, the total colon was examined. When IFN-,,/, mice were treated with AOM and TNBS, significantly higher number of tumors were seen (8.4 ± 1.7) than in WT (3.3 ± 2.9) or IL-4,/, (3.1 ± 3.4) mice, which received identical treatments. A separate set of experiment, using less doses of AOM and TNBS also showed the higher frequency of tumor formation in IFN-,,/, mice than in IL-4,/, mice. Histologically, the tumors were well- or moderately-differentiated adenocarcinomas. No invasion into the submucosal or serosal layers of the intestine was seen. In immunohistological staining, some tumors in IFN-,,/, mice showed distinct nuclear expression of ,-catenin, in contrast to the strong membrane staining seen in tumors of IL-4,/, mice. In conclusion, colonic inflammation associated with Th2-donimant cytokine responses enhanced the formation of malignant neoplasms. © 2005 Wiley-Liss, Inc. [source] Suppression of the TIG3 tumor suppressor gene in human ovarian carcinomas is mediated via mitogen-activated kinase-dependent and -independent mechanismsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Kristina Lotz Abstract The TIG3 gene is a retinoic acid inducible class II tumor suppressor gene downregulated in several human tumors and malignant cell lines. Diminished TIG3 expression correlates with decreased differentiation whereas forced expression of TIG3 suppresses oncogenic signaling pathways and subsequently induces differentiation or apoptosis in tumor cells. Analysis of TIG3 mRNA expression in a large set of cDNA pools derived from matched tumor and normal human tissues showed a significant downregulation of TIG3 in 29% of the cDNA samples obtained from ovarian carcinomas. Using in situ hybridization, we demonstrated expression of TIG3 in the epithelial lining of 7 normal ovaries but loss of TIG3 expression in 15/19 of human ovarian carcinoma tissues. In SKOV-3, CAOV-3 and ES-2 ovarian carcinoma cell lines, downregulation of TIG3 mRNA was reversible and dependent on an activated MEK-ERK signaling pathway. Re-expression of TIG3 mRNA in these cells upon specific interference with the MEK-pathway was correlated with growth inhibition of the cells. In OVCAR-3 and A27/80 ovarian carcinoma cells, TIG3 suppression is MEK-ERK independent, but expression could be reconstituted upon interferon gamma (IFN,) induction. Overexpression of TIG3 in A27/80 ovarian carcinoma cells significantly impaired cell growth and despite increased mRNA levels, TIG3 protein was hardly detectable. These results suggest that TIG3 is negatively regulated by an activated MEK-ERK signaling pathway. Further mechanisms must interfere with TIG3 expression that are independent of MEK and partially include interferon-responsive components. © 2005 Wiley-Liss, Inc. [source] Longitudinal evaluation of GCF IFN-, levels and periodontal status in HIV+ patientsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 11 2003T. Alpagot Abstract Background/Aim: Loss of periodontal support and related tooth loss is a common finding among HIV+ patients. The etiology of this destruction may be an increase in the levels of pro-inflammatory cytokines and subsequent increase in periodontal disease activity. The purpose of this study was to investigate the associations between gingival crevicular fluid interferon gamma (GCF IFN- ,) and clinical measures of periodontal disease in HIV+ individuals. We monitored GCF IFN- , and periodontal status of selected sites in 33 HIV+ subjects over a 6-month period. Method: Clinical measurements including gingival index, plaque index, bleeding on probing, probing depth, attachment loss (AL), and GCF samples were taken from four lower incisors and the upper right posterior sextant of each patient at baseline and 6-month visits by means of sterile paper strips. GCF levels of IFN- , were determined by sandwich ELISA assays. A progressing site was defined as a site that had 2 mm or more AL during the 6-month study period. Results: Twenty-five of the 264 examination sites showed 2 mm or more clinical AL during the 6-month study period. Significantly higher GCF levels of IFN- , were found at progressing sites than in nonprogressing sites (p<0.001). GCF levels of IFN- , were highly correlated with clinical measurements taken at baseline and 6-month visits (0.001 Nitric oxide synthase type-II is synthesized by human gingival tissue and cultured human gingival fibroblastsJOURNAL OF PERIODONTAL RESEARCH, Issue 4 2000H. K. Kendall Nitric oxide is known to be an important inflammatory mediator, and is implicated in the pathophysiology of a range of inflammatory disorders. The aim of this study was to determine the localization and distribution of endothelial NOS (NOSII) in human gingival tissue, and to ascertain if human gingival fibroblasts express NOS-II when stimulated with interferon gamma (IFN-,) and bacterial lipopolysaccharide (LPS). The distribution of NOS-II in inflamed and non-inflamed specimens of human gingivae was studied using a monoclonal antibody against nitric oxide synthase II. Cultures of fibroblasts derived from healthy human gingivae were used for the cell culture experiments. The results from immunohistochemical staining of the tissues indicated an upregulation of NOS-II expression in inflamed compared to non-inflamed gingival tissue. Fibroblasts and inflammatory cells within the inflamed connective tissue were positively stained for NOS-II. In addition, basal keratinocytes also stained strongly for NOS-II, in both healthy and inflamed tissue sections. When cultured human gingival fibroblasts were stimulated by INF-, and Porphyromonas gingivalis LPS, NOS-II was more strongly expressed than when the cells were exposed to LPS or IFN-, alone. These data suggest that, as for other inflammatory diseases, NO plays a role in the pathophysiology of periodontitis. [source] Preparation of a monolithic column for weak cation exchange chromatography and its application in the separation of biopolymersJOURNAL OF SEPARATION SCIENCE, JSS, Issue 1 2006Yinmao Wei Abstract A procedure for the preparation of a monolithic column for weak cation exchange chromatography was presented. The structure of the monolithic column was evaluated by mercury intrusion. The hydrodynamic and chromatographic properties of the monolithic column , such as back pressures at different flow rates, effects of pH on protein retention, dynamic loading capacity, recovery, and stability , were determined under conditions typical for ion-exchange chromatography. The prepared monolithic column might be used in a relatively broad pH range from 4.0 to 12.0 and exhibited an excellent separation to five proteins at the flow rates of both 1.0 and 8.0 mL/min, respectively. In addition, the prepared column was first used in the purification and simultaneous renaturation of recombinant human interferon gamma (rhIFN-,) in the extract solution with 7.0 mol/L guanidine hydrochloride. The purity and specific bioactivity of the purified rhIFN-, in only one chromatographic step were obtained to be 93% and 7.8×107 IU/mg, respectively. [source] The immunological basis of psoriasisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2003C E M Griffiths ABSTRACT Evidence that psoriasis is an immune-mediated disorder comes from laboratory studies, clinical observation, and use of targeted therapies. Immunohistochemical studies have shown that the majority of T cells in psoriatic plaques are CD45RO+ memory-effector T cells that migrate into skin in recognition of an as yet undetermined antigen. There is also a predominance of Th1 cytokines, namely interferon gamma, in psoriatic plaques, in contrast to the predominance of Th2 cytokines found in atopic dermatitis. The efficacy of therapeutic agents that target T cells, such as anti-CD4+ monoclonal antibodies, cyclosporin, and interleukin-2 fusion toxin, has provided further substantial evidence that psoriasis is a T-cell-mediated disease. New T-cell targeted approaches and cytokine modulation are advancing basic science in providing an understanding of the evidence for the importance of the immune process in the biology of psoriasis. [source] Quantitative Analysis of Inflammatory and Immune Responses in Dogs with Gastritis and Their Relationship to Helicobacter spp.JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2005Infection The present study sought to quantitatively examine mucosal inflammatory and immune responses in dogs with gastritis and the relationship of these responses to infection with Helicobacter. Gastric biopsies from 30 dogs were evaluated for B- and T-lymphocytes, neutrophils, eosinophils, macrophages, and mast cells. Mucosal atrophy, fibrosis, cellularity, and severity of gastritis were graded qualitatively. Messenger-RNA (mRNA) for actin, interleukin-1, (IL-1,), IL-4, IL-8, and IL-10, transforming growth factor beta (TGF-,), and interferon gamma (IFN-,) was quantified by polymerase chain reaction (PCR). The presence of Helicobacter spp. was determined by urease activity, histology, PCR, and enzyme-linked immunosorbent assay. mRNA for IL-1,, IL-8, IL-10, TGF-,, and IFN-, was detected in most dogs. IL-4 mRNA was detected in only 1 dog. Correlations were observed for IL-1, versus IL-8 and IL-10; IL-8 versus IL-10, IFN-,, and TGF-,; and IL-10 versus IFN-,. Mucosal pathology was related to cytokine mRNA expression (neutrophils to IL-8 and IFN-,, macrophages and lymphocytes to IFN-,, and fibrosis to IL-1,). Gastritis was categorized as lymphoplasmacytic in all dogs, and its histologic severity correlated with atrophy, infiltration with lymphocytes and macrophages, and expression of IL-10 and IFN-,. Of the dogs examined, 76.7% were infected with Helicobacter spp. Infection was associated with increased expression of TGF-, and fibrosis. Circulating anti- Helicobacter immunoglobulin G titers were higher in uninfected than infected dogs. We conclude that lymphoplasmacytic gastritis in dogs is characterized by concurrent activation of proinflammatory and immunomodulatory cytokines, with increased mRNA expression related to mucosal pathology. No significant associations between Helicobacter infection and proinflammatory cytokine expression, severity of gastritis, or differences in the pathogenicity of different Helicobacter spp. were found. [source] Early immunological monitoring after pediatric liver transplantation: Cytokine immune deviation and graft acceptance in 40 recipientsLIVER TRANSPLANTATION, Issue 3 2007Jérémie Gras Cytokine deviation may be a factor contributing to graft acceptance. We analyze, in the context of liver transplantation, circulating cytokine levels and their mRNA precursors in liver biopsy samples to study a putative correlation with early immunologic outcome. Forty primary pediatric liver recipients were submitted to a prospective immune monitoring protocol, including 8 of 40 patients with an early, biopsy-proven acute rejection episode. The 32 patients with graft acceptance showed markedly increased interleukin (IL)-10 blood levels at 2 hours after reperfusion on days 1 and 4 after transplantation as compared with baseline, whereas patients with graft rejection only exhibited increased IL-10 levels at 2 hours. A good correlation was observed between IL-10 peripheral levels and levels ascertained by IL-10 reverse transcriptase,polymerase chain reaction at 2 hours and on day 7. Patients with graft acceptance also showed a decrease in interferon gamma (IFN-,) at 1 and 2 hours after reperfusion on days 1, 4, 7, 14, and 28 after transplantation. One patient with graft tolerance who had subsequent immunosuppression withdrawal after posttransplantation lymphoproliferative disease showed a similar intraoperative IL-10 pattern, whereas posttransplantation tumor necrosis factor alpha and IFN-, levels greatly decreased. The occurrence of cytokine immune deviation may therefore be related to early graft acceptance in children who receive liver transplants. Liver Transpl 13:426,433, 2007. © 2007 AASLD. [source] Vaccination against hepatitis B in liver transplant recipients: Pilot analysis of cellular immune response shows evidence of HBsAg-specific regulatory T cellsLIVER TRANSPLANTATION, Issue 3 2007Tanja Bauer After liver transplantation for hepatitis-B-related diseases, patients currently receive lifelong treatment with hepatitis B immunoglobulin to prevent endogenous reinfection with hepatitis B virus (HBV). Active immunization with hepatitis B vaccine would be a preferable alternative; however, most attempts to immunize these patients with standard vaccine have failed. A recent study with a new adjuvanted hepatitis B vaccine was exceptionally successful, leading to a high-titered long-lasting antibody response in 80% of all vaccinees. To identify the immunological mechanisms behind these unexpected results, the successfully vaccinated participants were tested for hepatitis B surface antigen (HBsAg)-specific T and B cells, and their cellular responses to revaccination with conventional vaccine were studied. HBsAg-specific CD4+ T lymphocytes could be detected in 13 of 16 patients after immunization with the new vaccine. Unexpectedly, these T cells produced almost exclusively interleukin (IL)-10 and had a CD4+/CD25+ phenotype. They were functionally active, suppressing cytokine secretion in HBsAg-specific (Th1) cells, thus representing antigen-specific regulatory T cells (TReg). Following a booster dose with conventional vaccine 22-31 months after completion of the initial vaccination series, the T-cell pattern in the revaccinated individuals changed substantially: 7 days after revaccination 9 of 11 individuals showed a switch to a Th1-type immune response with HBsAg-specific T cells secreting IL-2, interferon gamma and tumor necrosis factor alpha as observed in healthy controls. Four weeks after the booster, 4 patients still showed a Th1-type cytokine pattern, whereas in 5 patients only IL-10-secreting cells were detectable. After 1 year, in 3 of 4 revaccinated individuals only IL-10-secreting cells could be found, whereas the specific T cells of the fourth patient still showed a Th1-type of response. HBsAg-specific TReg cells could be demonstrated in HBV-positive liver transplant recipients successfully immunized with a new adjuvanted vaccine. Revaccination led to immediate disappearance of the these cells and the appearance of HBsAg-specific T cells with a Th1-type cytokine profile, which in most cases were replaced by the IL-10-secreting regulatory cells during the following months. The specific induction of TReg cells could contribute to the poor response of liver transplant recipients to conventional vaccine. In conclusion,, for successful vaccination of these patients, a vaccine with a strong inhibitory effect on TReg cells would be desirable. Liver Transpl 13:434,442, 2007. © 2007 AASLD. [source] Microbial exposure, interferon gamma gene demethylation in naïve T-cells, and the risk of allergic diseaseALLERGY, Issue 3 2009P. J. Vuillermin The period of immune programming during early life presents a critical window of opportunity for the prevention of allergic diseases. There is mounting evidence that inappropriate immune programming may involve disruption of specific epigenetic modifications (switches) at immune-related genes. This novel area of research has great potential, as epigenetic changes are known to be sensitive to environmental factors and may therefore provide a mechanistic link for the observed association between specific environmental cues, faulty immune development, and the risk of allergic disease. In addition, the dynamic and potentially reversible nature of epigenetic modifications offers potentially novel targets for therapeutic and/or preventative interventions. We review the evidence that (1) failure to up-regulate the interferon gamma (IFN,) response during infancy is an important determinant of the risk of allergic disease, (2) expression of the IFN, gene in naïve T-cells is regulated by epigenetic mechanisms, and (3) failure to up-regulate IFN, gene expression of naïve T-cells associated with low early life microbial exposure. Taken together, these lines of evidence suggest that low microbial exposure during early life increases the risk of allergic disease by reducing demethylation (activation) of the IFN, gene of naive T-cells. [source] A previous infection with Toxoplasma gondii does not protect against a challenge with Neospora caninum in pregnant sheepPARASITE IMMUNOLOGY, Issue 3 2001E.A. Innes Sheep immunized with Toxoplasma gondii (Toxovax®) prior to pregnancy were tested for their ability to withstand a challenge at 90 days gestation with 107 Neospora caninum (NC1) tachyzoites. The antibody responses in sheep following immunization with T. gondi were specific for T. gondii whereas peripheral blood mononuclear cells responded to both T. gondii and caninum antigen in vitro. This suggested that there was induction of crossreactive immune recognition in the sheep, at least at the cellular level. Following challenge of sheep at mid-gestation with N caninum, no febrile responses were recorded in the group of sheep which had previously received Toxovax® while significant febrile responses were recorded in the group of sheep which received N challenge alone. Antibody responses to N developed in all sheep following challenge and antibody responses to T,gondii were boosted in the group of sheep which had previously been immunized with Toxovax®. No antibodies to were observed in the sheep which received the challenge alone. Peripheral blood mononuclear cells from both groups of sheep responded to T.gondii N.caninum antigen invitro and interferon gamma was present in the cell-free supernatant from activated cells. However despite evidence of the induction of crossreactive immunity between T.gondii N.caninum this was not sufficient to prevent foetal death. The group of sheep which had received Toxovax® prior to pregnancy and the group of sheep which only received the N.caninum challenge experienced 100% foetal death compared with 0% in the unchallenged control group. Vaccination prior to pregnancy with Toxovax® did protect against foetal death following oral challenge at 90 days with 2000 oocysts which caused 100% foetal death in a control challenge group. [source] ORIGINAL ARTICLE: The Role of Cytokine Expression in Different Subgroups of Subfertile MenAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2009Srividya Seshadri Problem, The aim of this study was to evaluate the levels of seminal plasma cytokines interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 11 (IL-11), interleukin 12 (IL-12), tumour necrosis factor alpha (TNF-,) and interferon gamma (IFN-,) in male subfertility. Method of study, A total of 73 male partners of an infertile couple attending a regional andrology unit were recruited into this prospective study and subdivided into the various groups based on semen analysis. Concentrations of cytokines such as IL-6, IL-8, IL-10, IL-11, IL-12, TNF-, and IFN-, in the seminal plasma were determined using enzyme linked immunosorbent assay (ELISA). Results, Significant higher concentrations (P < 0.05) of IL-6 in the mild and severe oligospermic group, IL-8 and IL-10 in the asthenospermic group and IL-6, IL-10, TNF-, and IFN-, in the obstructed azoospermic group were determined. IL-10 concentrations correlated significantly with other cytokines in the obstructed azoospermic group and the asthenospermic group. Conclusion, Our study confirms that cytokines rarely act in isolation, but rather in a network of other cytokines and may affect sperm function directly or indirectly. The presence of increased levels of cytokines in the obstructed azoospermic group suggests that the cytokines may not originate from the testis. [source] Antibody and T-cell responses specific for the androgen receptor in patients with prostate cancerTHE PROSTATE, Issue 16 2007Brian M. Olson Abstract BACKGROUND The androgen receptor (AR) is a steroid hormone receptor that is an essential regulator of prostate development, and the primary molecular target for the treatment of metastatic prostate cancer. In this report, we evaluated whether patients with prostate cancer have pre-existing immune responses specific for the AR as evidence that the AR also might be pursued as an immunological target antigen. METHODS The detection of auto-antibodies specific for the AR in patient sera was evaluated by ELISA and Western blotting. Peripheral blood mononuclear cells were analyzed for the presence of AR-specific T-cells, as measured by T-cell proliferation, interferon gamma (IFN,) and interleukin-10 secretion. RESULTS We found that a significantly higher frequency of prostate cancer patients have AR LBD-specific antibody responses than do healthy male volunteers [18/105 cancer patients (17.1%) vs. 0/41 healthy volunteers, P,=,0.0049], and that these responses were present regardless of the patients' disease stage [8/46 organ-confined prostate cancer patients (17.4%), 3/22 metastatic androgen-dependent patients (13.6%), and 7/37 metastatic, androgen-independent patients (18.9%)]. These antibodies were pre-dominantly of the IgG isotype, and furthermore of the IgG2 sub-isotype. In addition, we found that patients with antibody responses also had concurrent antigen-specific CD4+ and CD8+ T-cell proliferation and IFN, secretion when compared to patients without antibody responses. CONCLUSIONS These data demonstrate that some patients with prostate cancer have pre-existing humoral and cellular immune responses specific for the AR, suggesting that tolerance against the AR is not absolute and that the AR may be a potential immunotherapeutic target antigen. Prostate 67: 1729,1739, 2007. © 2007 Wiley-Liss, Inc. [source] Alternative Macrophage Activation-Associated Transcripts in T-Cell-Mediated Rejection of Mouse Kidney AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010K. S. Famulski Macrophages display two activation states that are considered mutually exclusive: classical macrophage activation (CMA), inducible by IFNG, and alternative macrophage activation (AMA), inducible by IL4 and IL13. CMA is prominent in allograft rejection and AMA is associated with tissue remodeling after injury. We studied expression of AMA markers in mouse kidney allografts and in kidneys with acute tubular necrosis (ATN). In rejecting allografts, unlike interferon gamma (IFNG) effects and T-cell infiltration that developed rapidly and plateaued by day 7, AMA transcripts (Arg1, Mrc1, Mmp12 and Ear1) rose progressively as tubulitis and parenchymal deterioration developed at days 21 and 42, despite persistent IFNG effects. AMA in allografts was associated with transcripts for AMA inducers IL4, IL13 and inhibin A, but also occurred when hosts lacked IL4/IL13 receptors, suggesting a role for inhibin A. Kidneys with ATN injured by ischemia/reperfusion also had increased expression of AMA markers and inhibin A. Thus kidneys undergoing T-cell-mediated rejection progressively acquire macrophages with alternative activation phenotype despite strong local IFNG effects, independent of IL4 and IL13. Although the mechanisms and causal relationships remain to be determined, high AMA transcript levels in rejecting allografts are strongly associated with and may be a consequence of parenchymal deterioration similar to ATN. [source]
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