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IFN
Kinds of IFN Terms modified by IFN Selected AbstractsHeart 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] Use of in vitro release of interferon-, in the diagnosis of contact allergy to potassium dichromate , a controlled studyCONTACT DERMATITIS, Issue 4 2003A. Trattner The use of in vitro release of interferon-, (IFN-,) in the diagnosis of contact allergy to potassium dichromate was studied in 20 patients who had positive patch tests to chromate and in 30 control subjects (10 patients with contact dermatitis, allergic to other allergens, 10 patients with other dermatologic diseases and 10 healthy subjects). The release of IFN-, in the supernatants of the peripheral blood lymphocytes was significantly higher in the patients with proven allergy to chromate (P = 0·001). Further studies are needed to determine if IFN-, release may serve as an additional diagnostic tool in contact dermatitis. [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] Monitoring cytomegalovirus IE-1 and pp65-specific CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations ,CYTOMETRY, Issue 4 2008Jan W. Gratama Abstract We studied the recovery of CMV-specific CD4+ and CD8+ T-cell immunity in 52 recipients of allogeneic stem cell transplantation (SCT). The proportions of IFN-,-producing CD4+ and CD8+ T cells upon in vitro activation using peptide pools representing the CMV pp65 and IE-1 proteins were assessed at multiple time points post SCT, and correlated with the occurrence of CMV reactivation. In a retrospective analysis, recurrent CMV reactivations occurred in 9 patients and were associated with low pp65-specific CD4+ T-cell and low IE-1-specific CD8+ T-cell reactivities, whereas patients without detectable CMV reactivation (n = 30) or a single reactivation (n = 13) showed a better recovery of these immune responses. CD4+ T-cell responses to IE-1 were infrequent in most patients, whereas CD8+ T-cell responses to pp65 occurred frequently, but did not correlate with protection against (recurrent) reactivation. Prospectively, CMV-specific T-cell responses could be studied prior to 14 reactivation episodes in 8 patients. CD4+ T-cell responses to IE-1 and pp65 were positive in only 1 and 2 episodes, respectively. CD8+ T-cell responses against IE-1 were positive in 4, but against pp65 in 12 episodes, again showing that CD8+ T-cell reactivity against pp65 did not prevent CMV reactivation. Thus, monitoring of particular CMV-specific CD4+ and CD8+ T-cell responses after allogeneic SCT may identify patients at risk for recurrent CMV reactivations. © 2008 Clinical Cytometry Society [source] Inflammatory cytokines augments TGF-,1-induced epithelial-mesenchymal transition in A549 cells by up-regulating T,R-ICYTOSKELETON, Issue 12 2008Xiangde Liu Abstract Epithelial-mesenchymal transition (EMT) is believed to play an important role in fibrosis and tumor invasion. EMT can be induced in vitro cell culture by various stimuli including growth factors and matrix metalloproteinases. In this study, we report that cytomix (a mixture of IL-1,, TNF-, and IFN-,) significantly enhances TGF-,1-induced EMT in A549 cells as evidenced by acquisition of fibroblast-like cell shape, loss of E-cadherin, and reorganization of F-actin. IL-1, or TNF-, alone can also augment TGF-,1-induced EMT. However, a combination of IL-1, and TNF-, or the cytomix is more potent to induce EMT. Cytomix, but not individual cytokine of IL-1,, TNF-, or IFN-,, significantly up-regulates expression of TGF-, receptor type I (T,R-I). Suppression of T,R-I, Smad2 or Smad3 by siRNA partially blocks EMT induction by cytomix plus TGF-,1, indicating cytomix augments TGF-,1-induced EMT through enhancing T,R-I and Smad signaling. These results indicate that inflammatory cytokines together with TGF-,1 may play an important role in the development of fibrosis and tumor progress via the mechanism of epithelial-mesenchymal transition. Cell Motil. Cytoskeleton 2008. © 2008 Wiley-Liss, Inc. [source] Interferon Alfa-2b or Not 2b?DERMATOLOGIC SURGERY, Issue 1 2007Significant Differences Exist in the Decision-Making Process between Melanoma Patients Who Accept or Decline High-Dose Adjuvant Interferon Alfa-2b Treatment BACKGROUND Patients with thick (Breslow >4 mm) primary melanoma and/or regional nodal metastasis have a high risk of tumor recurrence. High-dose adjuvant interferon (IFN) alfa-2b offers ,10% improvement in relapse-free survival and overall survival with significant toxicity. OBJECTIVE The objective was to determine which prognostic factors and patient characteristics are significant in the decision to undergo IFN therapy. METHODS Of 781 patients who underwent sentinel lymph node (SLN) biopsy, 135 of 781 (17.3%) had positive SLN or thick melanomas and were informed of a ,50% risk of recurrence/disease-related mortality and offered IFN. Telephone surveys delineated reasons behind patients' decisions to accept IFN. RESULTS Acceptors, 60 of 135 (45%), decided to take IFN alfa-2b whereas 75 of 135 (55%) declined. Being female (OR, 2.4; 95% CI, 1.17,5.03; p=.017) and positive SLN status (OR, 2.2; 95% CI, 1.01,4.97; p=.048) were strongly associated with patients who chose IFN. Acceptors of IFN were younger, more influenced by physicians, and less affected by depression and side effect profile (p<.05 for all). Decliners were more concerned by strained relationships with family and social life (p<.05). CONCLUSIONS Gender and positive SLN were predictive of high-risk melanoma patients' acceptance of IFN treatment. Physician insight into melanoma patients' therapeutic decision-making process can guide patients through this difficult disease. [source] Cutaneous melanoma: interferon alpha adjuvant therapy for patients at high risk for recurrent diseaseDERMATOLOGIC THERAPY, Issue 1 2006Marko Lens ABSTRACT:, Systemic adjuvant therapy in melanoma patients is the systemic treatment that is administered with the goal of eradicating micrometastatic deposits in patients who are clinically free of disease after surgical removal of the primary melanoma, but with a high risk of systemic recurrence. Interferon-alpha (IFN-,) is one of the most frequently used adjuvant therapies. Several randomized trials evaluated the efficacy of IFN-, in melanoma patients. However, results from conducted trials are controversial. Twelve randomized IFN-, trials are discussed in detail. All trials, including meta-analysis, failed to demonstrate a clear impact of IFN-, therapy on overall survival in melanoma patients. Based on currently available evidence, IFN-, therapy in the adjuvant setting should not be considered standard of care for patients who have melanoma. Results from ongoing studies are awaited. Further research for this therapy is required. [source] IFN-, induces apoptosis in mouse embryonic stem cells, a putative mechanism of its embryotoxicityDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 3 2000Gang-Ming Zou It has been reported that interferon (IFN)-, should inhibit in vitro mouse embryo growth by direct cell toxicity. However, the mechanism involved has not been clearly established. In the present study, this question was addressed using the embryonic stem (ES) cell model. It was found that IFN-, induces a dose-dependent apoptosis in ES cells, as assessed by trypan-blue staining, by Annexin-V labeling and DNA analysis. Moreover, IFN-, treatment cooperates with Fas-mediated apoptosis, a phenomenon that has been recently reported. As Bcl-2 oncoprotein functions as a death repressor molecule in an evolutionarily conserved cell death pathway, its expression was analyzed by flow cytometry. It was demonstrated that Bcl-2 is expressed in ES cells. When compared to untreated ES cells, IFN-,-treated, apoptotic cells expressed a lower Bcl-2 level and a normal level of Fas, whereas surviving cells expressed a normal level of Bcl-2 but a lower Fas expression. Altogether, these data suggest that IFN-, may influence early mouse embryo development by promoting apoptosis, which may constitute a novel mechanism of IFN-, embryotoxicity. [source] Childhood encephalopathy: viruses, immune response, and outcomeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 4 2006Michael Clarke BSc MB ChB FRCPCH This study examined children with an acute encephalopathy illness for evidence of viral infection, disordered blood-brain barrier function, intrathecal immunoglobulin synthesis, and interferon (IFN) production, and related their temporal occurrence to outcome. A prospective study of 22 children (13 males, 9 females; age range 1mo to 13y, median 2y 4mo), recorded clinical details, with serum and cerebrospinal fluid (CSF) analysis near presentation and then on convalescent specimens taken up to day 39 of the neurological illness. Outcome was assessed with standard scales between 18 months and 3 years after presentation. A history consistent with viral infection was given in 17 children but laboratory evidence of viral infection was found in only 7 (7/17). In 18 out of 21 children, an elevated CSF: serum albumin ratio indicative of impairment of the blood,CSF and blood,brain barriers was detected at some stage of the illness. In 14 of the 15 children with a raised immunoglobulin G index, and in 12 of the 14 children where the CSF was positive for oligoclonal bands, this was preceded by, or was observed at the same time as, an abnormal albumin ratio. Sixteen children (16/18) had elevated IFN-, levels in serum, or CSF, or in both. We conclude that these findings indicate an initial disruption of the blood-brain barrier followed by intrathecal antibody production by activated lymphocytes, clonally restricted to a few antigens. This is the first in vivo study to show this as an important pathogenetic mechanism of encephalitis in children. Poor outcome was associated with young age, a deteriorating electroencephalogram pattern from grade 1 to grade 2, and the degree of blood-brain barrier impairment, particularly when prolonged, but not with Glasgow Coma Scale score. The persistence of IFN-, was associated with a good prognosis. [source] Psychopathological changes and quality of life in hepatitis C virus-infected, opioid-dependent patients during maintenance therapyADDICTION, Issue 4 2009Arne Schäfer ABSTRACT Aims To examine among maintenance patients (methadone or buprenorphine) with and without hepatitis C virus (HCV) infection (i) the frequency of psychopathological symptoms at baseline and 1-year follow-up; (ii) the association between antiviral interferon (IFN) treatment and psychopathological symptoms; and (iii) to explore whether IFN therapy has an effect on 1-year outcome of maintenance treatment. Design Naturalistic prospective longitudinal cohort design. Setting A total of 223 substitution centres in Germany. Participants A nationally representative sample of 2414 maintenance patients, namely 800 without and 1614 with HCV infection, of whom 122 received IFN therapy. Measures HCV infection (HCV+/HCV - ), IFN (IFN+/IFN - ) treatment status and clinical measures. Diagnostic status and severity (rated by clinician), psychopathology (BSI,Brief Symptom Inventory) and quality of life (EQ-5D,EuroQol Group questionnaire). Findings HCV+ patients revealed indications for a moderately increased psychopathological burden and poorer quality of life at baseline and follow-up compared to HCV - patients. HCV+ patients showed a marked deterioration over time only in the BSI subscale somatization (P = 0.002), and the frequency of sleep disorders almost doubled over time (12.8% at baseline; 24.1% at follow-up; P < 0.01). IFN treatment, received by 10% of HCV+ patients, did not impair efficacy or tolerability of maintenance therapy and was associated overall with neither increased psychopathological burden nor reduced quality of life. Conclusions Findings suggest no increased risk among HCV+ patients on maintenance therapy for depressive or other psychopathological syndromes. In our patient sample, IFN treatment was not associated with increased psychopathological burden, reduced quality of life or poorer tolerability and efficacy of maintenance treatment. [source] Production of biologically active equine interleukin 12 through expression of p35, p40 and single chain IL-12 in mammalian and baculovirus expression systemsEQUINE VETERINARY JOURNAL, Issue 7 2001E. L. J. McMONAGLE Summary Interleukin-12 (IL-12) is a key cytokine in the development of cell-mediated immune responses. Bioactive IL-12 is a heterodimeric cytokine composed of disulphide linked p35 and p40 subunits. The aim of this study was to verify biologically activity of the products expressed from equine interleukin-12 (IL-12) p35 and p40 cDNAs and to establish whether equine IL-12 could be expressed as a p35/p40 fusion polypeptide, as has been reported for IL-12a of several mammalian species. We report production of equine IL-12 through expression of p35 and p40 subunits in mammalian and insect cells and of a p35:p40 fusion polypeptide in mammalian cells. Conditioned medium recovered from cultures transiently transfected with constructs encoding equine p35 and p40 subunits or single chain IL-12 enhanced IFN-, production in cells derived from equine lymph nodes. Preincubation of IFN-, inducing preparations with anti-p40 monoclonal antibody resulted in a significant decrease in IFN-, induction capacity. Medium recovered from p35 and p40-expressing baculovirus infected cultures enhanced target cell IFN-, production and proliferation. Experimental studies in mice and other animals have revealed a therapeutic benefit of IL-12 in cancer, inflammatory and infectious disease and an adjuvant effect in prophylactic regimes. Production of a bioactive species-specific IL-12 is a first step towards an investigation of its potential application in equine species. [source] Cytomegalovirus hyperimmunoglobulin: mechanisms in allo-immune response in vitroEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2007K. Hoetzenecker Abstract Background Cytomegalovirus hyperimmunoglobulin (CMVIg) containing drugs are routinely administered in cardiac transplantation for prophylaxis against CMV disease. Yet little is known about their influence on transplant relevant immune functions. The aim of this study was to evaluate the effect of CMVIg on cellular immunity in in vitro experiments and to define their role in tolerance inducing mechanisms. Materials and methods/results CMVIg reduces proliferation in mixed lymphocyte reactions and anti-CD3 blastogenesis assays and is related to decreased production of immune modulating cytokines interleukin (IL)-2, interferonr (IFN,), IL-10. This antiproliferative effect is associated with a cell-cycle arrest in the G0/G1 phase and induction of apoptosis in CD8+ and natural killer cells. Co-incubation with CMVIg causes down-regulation of cell bound immunoglobulin and Fc,RIII surface expression on natural killer cells and leads to attenuation of antibody dependent cellular cytotoxicity effector functions. Conclusions We conclude that CMVIg induces immunological features on leukocytes in vitro that are known to be related to tolerance induction. Our observations extend the current concept of CMVIg as passive CMV prophylaxis to a therapeutic drug compound capable of reducing allogeneic immune response. [source] 22-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] Interferon-, in healthy subjects: selective modulation of inflammatory mediatorsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2001J. De Metz Background It is suggested that interferon-, (IFN-,), like other cytokines, is a mediator in the host inflammatory response, which could be of importance in the pathophysiology of sepsis. The role of IFN-, in human host inflammatory responses, however, has not been studied. Design In a placebo-controlled trial we studied the acute effects of IFN-, administration on host inflammatory mediators in healthy men: i.e. the cytokine/chemokine cascade system, acute-phase proteins, activation markers of the innate cellular immunity and coagulation/fibrinolysis parameters. Results IFN-, increased plasma levels of interleukin-6 (IL-6), IL-8 and IFN-,-inducible protein-10 (IP-10) (P < 0·05), but did not affect plasma levels of other cytokines (IL-4, IL-10, tumour necrosis factor-,, IL-12p40/p70). Plasma concentrations of C-reactive protein and secretory phospholipase A2 both increased (P < 0·05). Plasma levels of the leucocyte activation marker elastase-,1,antitrypsin complexes increased after IFN-, administration (P < 0·05), IFN-, increased the percentage of high-affinity Fc,-receptor (Fc,RI) -positive neutrophils (P < 0·05), but did not affect the mean fluorescence intensity of Fc,RI on neutrophils. Procoagulant and profibrinolytic effects of IFN-, were evidenced by increased plasma levels of prothrombin fragment F1 + F2, tissue-plasminogen activator and plasmin-,2,antiplasmin complexes (P < 0·05). Conclusion We conclude that IFN-, selectively affects host inflammatory mediators in humans. [source] Interferon-, +874A/T and interleukin-4 intron3 VNTR gene polymorphisms in Chinese patients with idiopathic thrombocytopenic purpuraEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2007Xiaoli Chen Abstract Objectives:, The polarization of Th1/Th2 towards Th1 contributes to the pathogenesis of idiopathic thrombocytopenic purpura (ITP). Cytokines may play crucial roles in the pathogenesis of ITP. The purpose of this study was to investigate whether the interferon (IFN)-, +874(A/T) and interleukin-4 (IL-4) variable number of tandem repeats (VNTR) in intron3 polymorphisms may be responsible in part for genetic susceptibility to ITP. Methods:, Genotyping of IFN-, +874A/T and IL-4 intron3 VNTR was performed in 196 patients with ITP and 128 healthy individuals by polymerase chain reaction sequence-specific primers and direct PCR respectively. Results:, There was no association between IFN-, +874A/T and IL-4 intron3 VNTR polymorphism and ITP risk when all patients, as a group, were analyzed. When the patients were subdivided into two groups: childhood ITP and adult ITP, no statistical differences were found in the genotype and allele frequencies of IFN-, +874A/T and IL-4 intron3 VNTR between the two groups and the controls. Similar results were observed between acute childhood ITP, chronic childhood ITP, acute adult ITP or chronic adult ITP and the controls. Conclusion:, These polymorphisms were distributed similarly between the patients with ITP and the controls, demonstrating that these two candidate gene polymorphisms are not attributed to ITP susceptibility. [source] Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpuraEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2000Chie Yoshimura Abstract: We investigated the levels of various cytokines and soluble factors in ITP patients, in order to determine the influence of these factors on the pathogenesis of ITP. We found increases in IL-2, IL-6, IFN-,, and M-CSF levels in ITP patients compared with those in healthy individuals. On lymphocyte phenotype analysis, we found no clear difference in total T cell population (CD2+ CD19, cells) or cytotoxic T cell frequency (CD8+ CD11b, cells) between these two groups. The frequency of helper/inducer T cells (CD4+ CD8, cells) was decreased in ITP patients. There was a significant increase in activated T cells (CD3+ HLA-DR+ cells) in ITP patients. Furthermore, frequencies of NK cells of potent activity (CD16+ CD56+ cells) were significantly elevated in ITP patients. Seventeen of the 54 ITP patients (31.5%) had elevated levels of sFas, and 11 of the 54 patients (20.4%) of sFasL. In addition, a significant increase of sFasL was observed in sFas-positive ITP patients, and in these patients the sFasL level was correlated with that of sFas (r=0.687, p<0.01). We found significant increases in IL-2 and sIL-2R levels in sFas-positive ITP patients. For other factors examined, however, there were no differences in level between sFas-positive and-negative ITP patients. Percentages of activated T cells (CD3+ and HLA-DR+ cells) and NK cells (CD16+ and CD56+ cells) were significantly higher in sFas-positive ITP patients than in sFas-negative ITP patients. These findings suggests that the pathogenesis of ITP includes alteration of the Fas/FasL pathway. [source] Alpha2beta1 integrin is the major collagen-binding integrin expressed on human Th17 cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Marc Boisvert Abstract Growing evidence indicates that collagen-binding integrins are important costimulatory molecules of effector T cells. In this study, we demonstrate that the major collagen-binding integrin expressed by human Th17 cells is alpha2beta1 (,2,1) or VLA-2, also known as the receptor for collagen I on T cells. Our results show that human naïve CD4+ T cells cultured under Th17 polarization conditions preferentially upregulate ,2,1 integrin rather than ,1,1 integrin, which is the receptor for collagen IV on T cells. Double staining analysis for integrin receptors and intracellular IL-17 showed that ,2 integrin but not ,1 integrin is associated with Th17 cells. Cell adhesion experiments demonstrated that Th17 cells attach to collagen I and collagen II using ,2,1 integrin but did not attach to collagen IV. Functional studies revealed that collagens I and II but not collagen IV costimulate the production of IL-17A, IL-17F and IFN-, by human Th17 cells activated with anti-CD3. These results identify ,2,1 integrin as the major collagen receptor expressed on human Th17 cells and suggest that it can be an important costimulatory molecule of Th17 cell responses. [source] Targeting of LcrV virulence protein from Yersinia pestis to dendritic cells protects mice against pneumonic plagueEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Yoonkyung Do Abstract To help design needed new vaccines for pneumonic plague, we targeted the Yersinia pestis LcrV protein directly to CD8,+ DEC-205+ or CD8,, DCIR2+ DC along with a clinically feasible adjuvant, poly IC. By studying Y. pestis in mice, we could evaluate the capacity of this targeting approach to protect against a human pathogen. The DEC-targeted LcrV induced polarized Th1 immunity, whereas DCIR2-targeted LcrV induced fewer CD4+ T cells secreting IFN-,, but higher IL-4, IL-5, IL-10, and IL-13 production. DCIR-2 targeting elicited higher anti-LcrV Ab titers than DEC targeting, which were comparable to a protein vaccine given in alhydrogel adjuvant, but the latter did not induce detectable T-cell immunity. When DEC- and DCIR2-targeted and F1-V+ alhydrogel-vaccinated mice were challenged 6,wk after vaccination with the virulent CO92 Y. pestis, the protection level and Ab titers induced by DCIR2 targeting were similar to those induced by F1-V protein with alhydrogel vaccination. Therefore, LcrV targeting to DC elicits combined humoral and cellular immunity, and for the first time with this approach, also induces protection in a mouse model for a human pathogen. [source] Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4+ T-cell proliferation and IFN-, production in response to myelin basic protein and myelin oligodendrocyte glycoproteinEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Christopher T. Harp Abstract Recent evidence suggests that B- and T-cell interactions may be paramount in relapsing-remitting MS (RRMS) disease pathogenesis. We hypothesized that memory B-cell pools from RRMS patients may specifically harbor a subset of potent neuro-APC that support neuro-Ag reactive T-cell proliferation and cytokine secretion. To test this hypothesis, we compared CD80 and HLA-DR expression, IL-10 and lymphotoxin-, secretion, neuro-Ag binding capacity, and neuro-Ag presentation by memory B cells from RRMS patients to naïve B cells from RRMS patients and to memory and naïve B cells from healthy donors (HD). We identified memory B cells from some RRMS patients that elicited CD4+ T-cell proliferation and IFN-, secretion in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Notwithstanding the fact that the phenotypic parameters that promote efficient Ag presentation were observed to be similar between RRMS and HD memory B cells, a corresponding capability to elicit CD4+ T-cell proliferation in response to myelin basic protein and myelin oligodendrocyte glycoprotein was not observed in HD memory B cells. Our results demonstrate for the first time that the memory B-cell pool in RRMS harbors neuro-Ag specific B cells that can activate T cells. [source] Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Jean-Marie Ramirez Abstract Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-,, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4+ T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4+ T cells to produce IL-22 without IL-17 and IFN-,. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161+ Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4+ T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. [source] Innate, antigen-independent role for T cells in the activation of the immune system by Propionibacterium acnesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Sandrine Tchaptchet Abstract Propionibacterium acnes is a human commensal but also an opportunistic pathogen. In mice, P. acnes exerts strong immunomodulatory activities, including formation of intrahepatic granulomas and induction of LPS hypersensitivity. These activities are dependent on P. acnes recognition via TLR9 and subsequent IL-12-mediated IFN-, production. We show that P. acnes elicits IL-12p40 and p35 mRNA expression in macrophages, and IFN-, mRNA in liver CD4+ T cells and NK cells. After priming with P. acnes, CD4+ T cells serve as the major IFN-, mRNA source. In the absence of CD4+ T cells, CD8+ T cells (regardless of antigenic specificity) or NK cells can produce sufficient IFN-, to induce the P. acnes -driven immune effects. Moreover, in the absence of ,,T cells, ,,T cells also enable the development of strongly enhanced TNF-, and IFN-, responses to LPS and intrahepatic granuloma formation. Thus, under microbial pressure, different T-cell types, independent of their antigen specificity, exert NK-cell-like functions, which contribute decisively to the activation of the innate immune system. [source] Tumor expression of CD200 inhibits IL-10 production by tumor-associated myeloid cells and prevents tumor immune evasion of CTL therapyEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Lixin Wang Abstract CD200 is a cell-surface glycoprotein that functions through interaction with the CD200 receptor on myeloid lineage cells to regulate myeloid cell functions. Expression of CD200 has been implicated in multiple types of human cancer; however, the impact of tumor expression of CD200 on tumor immunity remains poorly understood. To evaluate this issue, we generated CD200-positive mouse plasmacytoma J558 and mastocytoma P815 cells. We found that established CD200-positive tumors were often completely rejected by adoptively transferred CTL without tumor recurrence; in contrast, CD200-negative tumors were initially rejected by adoptively transferred CTL but the majority of tumors recurred. Tumor expression of CD200 significantly inhibited suppressive activity and IL-10 production by tumor-associated myeloid cells (TAMC), and as a result, more CTL accumulated in the tumor and exhibited a greater capacity to produce IFN-, in CD200-positive tumors than in CD200-negative tumors. Neutralization of IL-10 significantly inhibited the suppressor activity of TAMC, and IL-10-deficiency allowed TAMC to kill cancer cells and their antigenic variants, which prevented tumor recurrence during CTL therapy. Thus, tumor expression of CD200 prevents tumor recurrence via inhibiting IL-10 production by TAMC. [source] Highly avid, oligoclonal, early-differentiated antigen-specific CD8+ T cells in chronic HIV-2 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Aleksandra Leligdowicz Abstract HIV-1-specific CD8+ T cells are present in most HIV-1-infected people and play an important role in controlling viral replication, but the characteristics of an effective HIV-specific T-cell response are largely unknown. The majority of HIV-2-infected people behave as long-term non-progressors while those who progress to AIDS do so in a manner indistinguishable from HIV-1. A detailed study of HIV-2 infection may identify protective immune responses. Robust gag p26-specific T-cell responses are elicited during HIV-2 infection and correlate with control of viremia. In this study, we analyzed features of an HLA-B*3501-restricted T-cell response to HIV-2 p26 that may contribute to virus control. In contrast to HIV-1, HIV-2-specific T cells are at an early stage of differentiation (CD27+CD28+), a finding that relates directly to CD4+ T-cell levels and inversely to immune activation. The cells demonstrate IFN-, secretion, oligoclonal T-cell receptor V, gene segment usage, exceptional avidity and secretion of pro-inflammatory cytokines. Despite the potentially strong selection pressure imposed on the virus by these cells, there was no evidence of HIV-2 sequence evolution. We propose that in chronic HIV-2 infection, the maintenance of early-differentiated, highly avid CD8+ T cells could account for the non-progressive course of disease. Such responses may be desirable from an HIV vaccine. [source] Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memoryEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Yufei Wang Abstract Evidence is presented that thermal or oxidizing stress-activated DC interact with CD4+ T cells to induce and maintain a TCR-independent homeostatic memory circuit. Stress-activated DC expressed endogenous intra-cellular and cell surface HSP70. The NF-,B signalling pathway was activated and led to the expression of membrane-associated IL-15 molecules. These interacted with the IL-15 receptor complex on CD4+ T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-, production. CD40 ligand on CD4+ T cells in turn re-activated CD40 molecules on DC, inducing DC maturation and IL-15 expression thereby maintaining the feedback circuit. The proliferating CD4+ T cells were characterized as CD45RA, CD62L+ central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC-class-II-TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC-class II antibodies. These findings suggest that stress can activate a DC-CD4+ T-cell interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory. [source] Natural killer cells become tolerogenic after interaction with apoptotic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Wai Po Chong Abstract NK cells are effectors in innate immunity and also participate in immunoregulation through the release of TGF-,1 and lysis of activated/autoreactive T cells. Apoptotic cells (AC) have been shown to induce tolerogenic properties in innate immune cells, including macrophages and dendritic cells, but not NK cells. In this study, we demonstrated that after interaction with AC, NK cells released TGF-,1, which in turn suppressed the production of IFN-, by NK cells upon IL-12 and IgG activation. We further identified phosphatidylserine as a potential target on AC for the NK cells, as phosphatidylserine could stimulate NK cells to release TGF-,1, which in turn suppressed CD4+ T-cell proliferation and activation. Moreover, AC-treated NK cells displayed cytotoxicity against autologous-activated CD4+ T cells by upregulating NKp46. This lysis occurred in part through the NKp46-vimentin pathway, as activated CD4+ T cells expressed vimentin on the cell surface and blocking of vimentin or NKp46, but not other NK-cell receptors, significantly suppressed the NK-cell cytotoxicity. We report here a novel interaction between NK cells and AC, resulting in the tolerogenic properties of NK cells required for immune contraction. [source] Altered effector functions of virus-specific and virus cross-reactive CD8+ T cells in mice immunized with related flavivirusesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010Derek W. Trobaugh Abstract Memory cross-reactive CD8+ T-cell responses may induce protection or immunopathology upon secondary viral challenge. To elucidate the potential role of T cells in sequential flavivirus infection, we characterized cross-reactive CD4+ and CD8+ T-cell responses between attenuated and pathogenic Japanese encephalitis virus (JEV) and pathogenic West Nile virus (WNV). A previously reported WNV NS4b CD8+ T-cell epitope and its JEV variant elicited CD8+ T-cell responses in both JEV- and WNV-infected mice. The peptide variant homologous to the immunizing virus induced greater cytokine secretion and activated higher frequencies of epitope-specific CD8+ T cells. However, there was a virus-dependent, peptide variant-independent pattern of cytokine secretion; the IFN,+ -to-IFN,+TNF,+ CD8+ T-cell ratio was greater in JEV- than in WNV-infected mice. Despite similarities in viral burden for pathogenic WNV and JEV viruses, CD8+ T cells from pathogenic JEV-immunized mice exhibited functional and phenotypic profiles similar to those seen for the attenuated JEV strain. Patterns of killer cell lectin-like receptor G1 (KLRG1) and CD127 expression differed by virus type, with a rapid expansion and contraction of short-lived effector cells in JEV infection and persistence of high levels of short-lived effector cells in WNV infection. Such cross-reactive T-cell responses to primary infection may affect the outcomes of sequential flavivirus infections. [source] Unexpected roles for DEAD-box protein 3 in viral RNA sensing pathwaysEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Orla Mulhern Abstract Detection of viral nucleic acid within infected cells is essential to an effective anti-viral response. The retinoic acid-inducible gene-I-like receptors (RLR) form part of the virus detection repertoire and are critically important in sensing viral RNA in the cytoplasm. Efforts continue to define the signalling components downstream of RLR that are required to induce type I IFN (IFN-, and promoter stimulator-1) after viral infection. One surprising finding was that the Asp-Glu-Ala-Asp box helicase DEAD/H Box 3 (DDX3), known for some time to have a number of roles in cellular RNA regulation in the nucleus, has a role in the RLR cytoplasmic signalling pathway involved in promoter stimulator-1 induction. In this issue of the European Journal of Immunology, an article reports an additional distinct positive role for DDX3 in the RLR RNA sensing pathway. This further emphasises the importance of DDX3 in anti-viral immunity, and is consistent with the idea that viruses target DDX3 for immune evasion. [source] Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010William F. Carson Abstract Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4+ T-cell responses remains unclear. In the present study, CD4+ T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4+CD62L+ T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4+CD62L+ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the TH1 or TH2 lineage. Repressive histone methylation marks were also evident at promoter regions for the TH1 cytokine IFN-, and the TH2 transcription factor GATA-3 in naïve CD4+ T cells from CLP mice. These results provide evidence that CD4+ T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription. [source] In vitro -induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sitesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Marko Janke Abstract Recently, IL-17 produced by Th17 cells was described as pro-inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL-17 leads to amelioration of collagen-induced arthritis. IL-17 induction in naïve CD4+ T cells depends on IL-6 and TGF-, and is enhanced by IL-23. The in vivo inflammatory potential of in vitro -primed Th17 cells however, remains unclear. Here, we show that, although IL-17 neutralisation results in amelioration of murine OVA-induced arthritis, in vitro -primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re-isolated Th17 cells acquired IFN-, expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL-6, TGF-, and IL-23 might not provide sufficient signals to induce "fully qualified" Th17 cells. [source] Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparumEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010Linda J. Wammes Abstract Chronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum -parasitized RBC in Indonesian schoolchildren. Geohelminth-infected children's in vitro T-cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD4+CD25hiFOXP3+ T cells was similar regardless of infection status, the suppressive activity differed between geohelminth-infected and geohelminth-uninfected groups: Ag-specific proliferative responses increased upon CD4+CD25hi T-cell depletion in geohelminth-infected subjects only. In addition, IFN-, production in response to both BCG and parasitized RBC was increased after removal of CD4+CD25hi T cells. These data demonstrate that geohelminth-associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth-induced immune modulation may have important consequences for co-endemic infections and vaccine trials. [source] | ||||||||||||||||||||||||||||||||||||||||