Plasma levels of soluble Fas during treatment of chronic hepatitis C patients with interferon alpha.
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Antiviral Agents↗
Biomedical subjects
H Tilg
Publications and source records attributed to H Tilg.
Interferon-alpha (IFN-alpha) enhances cytotoxicity in healthy volunteers and chronic hepatitis C infection mainly by the perforin pathway.
Cell-mediated cytotoxicity is exerted via perforin and Fas ligand (FasL). We have recently shown that IFN-alpha up-regulates FasL expression in T cells isolated from healthy volunteers and augments activation-induced T cell death. Since the Fas/FasL system is implicated in the pathogenesis of hepatic failure and both molecules have been shown to be up-regulated in hepatitis C virus (HCV) infection, we studied whether cytotoxicity via the FasL system is enhanced by IFN-alpha and therefore could contribute to hepatic injury. We investigated FasL and perforin expression in peripheral blood mononuclear cells (PBMC) derived from HCV+ donors by Northern analysis and soluble FasL synthesis by ELISA. Natural killer (NK) cell and cytotoxic T lymphocyte (CTL) cytotoxicity was studied by 51Cr-release assays. IFN-alpha up-regulates FasL mRNA and protein synthesis in mitogen-activated PBMC of HCV+ individuals, as previously found in healthy subjects. Stimulation with IFN-alpha increases perforin mRNA levels in PBMC. In NK cytotoxicity assays, the enhancement of cytotoxicity by IFN-alpha is mainly due to the perforin pathway, while the FasL pathway plays only a minor role. In CTL cytotoxicity experiments neither the FasL nor the perforin pathway is further enhanced by IFN-alpha. Our data suggest that up-regulation of perforin by IFN-alpha results in elevated cytotoxicity, suggesting that IFN-alpha might support elimination of virally infected cells via this pathway. In contrast, the major effect of IFN-alpha on the Fas/FasL system might be the enhanced elimination of activated T cells as a means of finally limiting a T cell response.
Anti-Bacterial Agents↗
Elevated circulating levels of soluble interleukin-1 receptor type II during interleukin-2 immunotherapy.
Interleukin-1 (IL-1) is a critical mediator of inflammation. Two naturally occurring IL-1 antagonists have been described, namely the IL-1 receptor antagonist (IL-1Ra) and the IL-1 receptor type II (IL-1RII). IL-1RII does not transmit a signal upon binding of IL-1, but competes with the signaling of IL-1RI for binding of IL-1. Shedding of IL-1RII yields the soluble IL-1 receptor type II (IL-1sRII) which retains the ability of membrane-bound IL-1RII to bind IL-1beta avidly, but binds IL-1Ra and IL-1alpha with low affinity. In contrast, IL-1sRI retains the ability of membrane-bound IL-1RI to bind IL-1Ra and IL-1alpha with high affinity, but binds IL-1beta poorly. We have previously shown that immunotherapy with IL-2 or IL-6 in cancer patients is associated with a dramatic increase in IL-1Ra plasma levels. In the present study, plasma levels of soluble IL-1 receptors were monitored in healthy individuals and cancer patients. In healthy controls, the mean IL-1sRII level was 4.76 0.16 ng/ml. IL-1sRII levels in cancer patients were comparable to those measured in healthy controls. IL-1sRII levels did not vary during the first 52 hours after initiation of IL-2 therapy, but increased significantly thereafter to reach 9.56 1.16 ng/ml on day 5. In contrast, IL-6 immunotherapy with a 5-day continuous infusion did not trigger an increase in IL-1sRII levels. IL-1sRI levels did not increase during immunotherapy with IL-2 or IL-6. Our results indicate that IL-1sRII, unlike IL-1Ra, remains a modest, natural, anti-inflammatory mechanism triggered by immunotherapy with IL-2, but not with IL-6.
Carcinoma, Renal Cell↗
Anti-TNF antibody in Crohn's disease--status of information, comments and recommendations of an international working group.
The chimeric anti-TNF antibody Remicade (Infliximab) has recently been approved for human use by the FDA and is now available on the market. Since there is considerable interest in this kind of treatment among patients with Crohn's disease, an international working group has summarized the presently available information about efficacy, side effects and possible problems of this treatment. Studies show that Remicade is effective in the treatment of active Crohn's disease, maintaining remission and fistulae. The working group does not see Infliximab as a first-line treatment for Crohn's disease. It may be used in active phase recurrent disease, chronic active disease and fistulae if standard treatment was not successful. For the surveillance special attention has to be given to the unknown malignancy rate of Infliximab. Infusion should be performed in an institution, routinely performing intravenous infusions and a two-hour surveillance of the patients should be guaranteed to recognize anaphylactic reactions or acute side effects. There is presently no information indication that the combination with immunosuppressants might increase risks or side effects of this treatment. Due to the limited information available the working group would prefer to use Remicade in studies only and recommends central collection and documentation of all data on efficacy and side effects for the next year.
Antibodies, Monoclonal↗
Interferons and their role In inflammation.
Cytokines are pleiotropic molecules showing a wide variety of biologic functions on various cells and tissues, and several different cytokines exert similar and overlapping functions on certain cells. Interferons (IFNs), among the first cytokines identified, play a crucial role in human disease. The IFN cytokine family consists of type I IFNs (IFN-a and IFN-b) and type II IFN (IFN-g). In the first decades of IFN research, type I IFNs were considered primarily as viral inhibitors, whereas type II IFN, also termed "immune IFN", was generally considered to be uniquely involved in immune reactions. This view has changed considerably in the last years. The importance of type I IFNs in inflammation, immunoregulation and T-cell responses has been identified and has changed dramatically our interpretation of the biological relevance of type I and II IFNs. Recent data suggest that IFN-a is a multifunctional immunomodulatory cytokine with profound effects on the cytokine cascade including several anti-inflammatory properties, whereas IFN-g remains a classical proinflammatory cytokine. These different effects on critical mediators of inflammation may also explain why type I and II IFNs are clinically successful in different diseases. These newly identified immunoregulatory and anti-inflammatory functions of type I IFNs may be of importance in the treatment of diseases such as chronic viral hepatitis or multiple sclerosis and help to explain some of the mechanisms of IFNs.
Adjuvants, Immunologic↗
Differential regulation of interleukin 4 and interleukin 13 production by interferon alpha.
Interferon alpha (IFN-alpha) has proven its clinical usefulness in a variety of diseases of diverse pathogenesis. In addition to direct antiviral effects, recent evidence suggests that its interaction with the cytokine cascade might contribute to its mechanism of action. This study was undertaken to determine whether IFN-alpha influences the synthesis of interleukin 4 (IL-4) and IL-13, two cytokines which share many biological properties on various cells and tissues and which have a profound role in regulating immunological and inflammatory responses. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were stimulated with Concanavalin A (ConA), phorbol myristate acetate (PMA), anti-CD3/CD28 mAbs, either alone or in various combinations, and incubated with increasing concentrations of IFN-alpha. IL-4 and Il-13 mRNA was determined by Northern hybridizations and IL-4 and IL-13 protein synthesis was evaluated by specific enzyme-linked immunosorbent assay (ELISA). IFN-alpha led to a profound decrease of IL-13 mRNA expression after an incubation period of 5 h with ConA alone or in combination with PMA, whereas it showed no regulatory effect on IL-4 mRNA expression. After an incubation period of 24 h, the decrease in IL-13 mRNA expression after addition of IFN-alpha was even more pronounced. At the protein level, IFN-alpha increased IL-4 synthesis dose dependently regardless of the mode of activation. This increase was most pronounced after stimulation with ConA or anti-CD28/PMA. In contrast, IL-13 synthesis was strongly downregulated by IFN-alpha in a dose-dependent manner irrespective of the activating agent. It is concluded that IL-4 and IL-13, although showing similar biological effects, are differentially regulated by IFN-alpha.
Gene Expression Regulation↗
IL-6 and arthritis: a detrimental or beneficial mediator?
Acute inflammation is accompanied by changes in the concentrations of several plasma proteins. Cytokines play a crucial role in the regulation of inflammatory events. Inflammatory disorders such as rheumatoid arthritis are characterized by an overproduction of several cytokines including interleukin-6 (IL-6). Recent data suggest that IL-6 and other members of the IL-6-cytokine family have anti-inflammatory and immunosuppressive properties, and therefore may negatively regulate inflammatory processes.
Journal Article↗
Endogenous interleukin 1 receptor antagonist during human bone marrow transplantation: increased levels during graft-versus-host disease, during infectious complications, and after immunoglobulin therapy.
In order to understand in more detail the role of endogenous interleukin 1 receptor antagonist (IL-1ra) during bone marrow transplantation, IL-1ra serum levels of 28 patients undergoing allogeneic (n=25) or autologous (n=3) bone marrow transplantation were measured with a commercially available ELISA. In addition, the impact of intravenous immunoglobulin (IVIG) was evaluated by analyzing IL-1ra serum levels before and 2, 5, and 24 hr after IVIG infusion. IL-1ra measurements revealed a nadir of circulating IL-1ra levels 3-5 days after bone marrow transplantation, with an increase during conditioning and hematological reconstitution. Circulating IL-1ra levels were significantly increased in patients with cytomegalovirus (CMV) disease, CMV reactivation, graft-versus-host disease (GVHD), or fever of unknown origin, when compared with time-matched controls without complications. Highest levels were observed in patients with CMV disease (1922+/-388 pg/ml), followed by patients with CMV reactivation (1575+/-435 pg/ml) and GVHD (1178+/-317 pg/ml). The magnitude of IL-1ra increase in GVHD was related to disease severity. Patients with grade III-IV GVHD developed higher IL-1ra levels than did patients with grade I-II GVHD. Lower but still significantly elevated IL-1ra levels were observed during fever of unknown origin (384+/-87 pg/ml). An increase of IL-1ra serum levels followed the administration of IVIG before transplantation and after hematopoietic reconstitution, but not during aplasia, pointing to the important role of hematopoietic cells in the production of IL-1ra. In conclusion, we show that IL-1ra release is related to conditioning regimen, hematopoietic reconstitution, complications of infectious and alloimmune etiology after bone marrow transplantation, and exogenously administered IVIG.
Adolescent↗
IL-6 and APPs: anti-inflammatory and immunosuppressive mediators.
Acute inflammation is accompanied by changes in the concentrations of acute phase proteins (APPs). While much is known about the cytokines involved in the initiation of inflammation, less is known about the mediators involved in its resolution. Recent data suggest that interleukin 6 (IL-6) and IL-6-regulated APPs are anti-inflammatory and immuno-suppressive, and may negatively regulate the acute phase response.
Acute-Phase Proteins↗
New insights into the mechanisms of interferon alfa: an immunoregulatory and anti-inflammatory cytokine.
Interferon (IFN)-alpha is the most frequently used cytokine in the treatment of diseases of the gastrointestinal tract. This cytokine has emerged as an important regulator of growth and differentiation, affecting cellular communication and immunologic control. The efficacy of IFN-alpha has been shown in many different diseases of viral, malignant, angiogenic, allergic, inflammatory, and fibrotic origin. Cytokines are pleiotropic molecules with a wide variety of biological functions on various cells and tissues, and several different cytokines exert similar and overlapping functions on certain cells. Originally described as an antiviral substance, the role of IFN-alpha as an immunoregulatory molecule has long been ignored. Recent data suggest that IFN-alpha is a multifunctional immunomodulatory cytokine with profound effects on the cytokine cascade including several anti-inflammatory properties. These newly identified immunoregulatory and anti-inflammatory functions may be of importance in the treatment of diseases such as chronic viral hepatitis and help to explain some of the IFN mechanisms.
Animals↗
Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes.
In the present study, we investigated the effect of interferon-alpha (IFN-alpha) on the expression of interleukin-10 (IL-10) mRNA and protein synthesis in human monocytes and CD4+ T cells. In mononuclear cells, IFN-alpha induced expression of IL-10 mRNA and further enhanced lipopolysaccharide (LPS)-stimulated IL-10 expression. In purified monocytes, a strong expression of IL-10 mRNA induced by LPS was not further enhanced by IFN-alpha. In highly purified CD4+ T cells, IFN-alpha upregulated IL-10 mRNA upon activation with phytohemagglutinin and phorbol myristate acetate. In purified monocytes, an effect of IFN-alpha on IL-10 protein synthesis was dependent on costimulation with LPS. Maximal stimulation of IL-10 protein by IFN-alpha was seen after prolonged incubation periods of 48 to 96 hours, whereas IFN-gamma reduced IL-10 production in the early incubation period. Similar effects of IFN-alpha were observed in CD4+ T cells activated with CD3 and CD28 monoclonal antibodies. Addition of IFN-alpha caused an increase of IL-10 in culture supernatants of activated T-helper cells of more than 100% after 96 hours of incubation. In contrast, other cytokines, including IFN-gamma and IL-4, had no influence on IL-10 secretion stimulated by CD3 and CD28 in CD4+ T cells. In serum samples of IFN-alpha-treated individuals, we failed to detect an influence of cytokine treatment on IL-10 serum levels, confirming the requirement of additional activating signals for IFN-alpha-mediated effects on IL-10 synthesis. In conclusion, IFN-alpha enhances the late induction of IL-10, which physiologically occurs upon stimulation of monocytes and T cells. Biologically, this effect might enhance the negative-feedback mechanism ascribed to IL-10, which limits inflammatory reactions.
Base Sequence↗
Circulating interleukin-1 receptor antagonist levels in neonates.
UNLABELLED: Circulating interleukin-1 receptor antagonist (IL-1 Ra) levels have been shown to reflect disease activity in certain conditions in adults. We determined circulating IL-1Ra references values for healthy neonates (healthy preterms and term infants with mild disease only) on days 2 (n = 17) and 4 of life (n = 23). Mean gestational age was 35 +/- 2.6 weeks. On the 2nd day of life IL1-Ra levels were 0.78 ng/ml (0.49/2.65), on day 4 0.38 ng/ml (0.20/0.48) (median, 25th/75th percentile, P = 0.01). The values were not influenced by gender. In neonates with severe illness (septicaemia, asphyxia, neonatal respiratory distress syndrome), who received invasive intensive care, circulating IL-1Ra levels were significantly higher than in the reference group of healthy newborns. On the 2nd day of life (14.72 ng/ml (4.38/18.67) versus 0.78 ng/ml (0.49/2.65), P < 0.0001; on day 4 of life, 3.38 ng/ml (0.80/11.99) versus 0.38 ng/ml (0.20/0.48), P < 0.005 (values are median; 25th/75th percentile, Mann-Whitney U-Wilcoxon Rank Sum W Test, two-tailed P). CONCLUSION: Compared to healthy individuals beyond the neonatal period, Il-1Ra concentrations are physiologically elevated within the first days of life and decline to low levels within days. In contrast, IL-1Ra levels are strikingly elevated in sick neonates.
Biomarkers↗
CD4 monoclonal antibody VIT4 in human alloimmune response in vitro and in vivo.
In the present report the immunosuppressive effects of the murine anti-human CD4 monoclonal antibody (mAb) VIT4 on human alloimmune response in vitro were analyzed. Moreover, the antibody was tested for its activity to prolong allograft survival in seven patients with steroid-refractory allograft rejection. VIT4 inhibited the proliferative response to alloantigens in the mixed lymphocyte reaction (MLR) in a dose-dependent manner. At concentrations of 1 and 10 micrograms/ml VIT4 blocked MLR by 55 +/- 11% and 77 +/- 1%, respectively. Also alloantigen-specific proliferation of in vitro- generated memory T cells was dose-dependently reduced to 23 +/- 1% at a VIT4 concentration of 100 micrograms/ml. Furthermore, at the same dose level VIT4 blocked proliferation of antigen-specific short-term alloreactive CD4+ cell lines and significantly inhibited the in vitro generation of cytotoxic T lymphocytes (CTL). In a pilot study VIT4 (5 mg/d i.v.) was administered to 7 patients with steroid-refractory allograft rejection for 14 days. In 4 of 7 patients graft function transiently improved and graft survival in all patients was prolonged to a mean of 694 days (range 128-2163) from the beginning of the VIT4 treatment. In the light of our in vitro results and the preliminary clinical data, further clinical trials using higher antibody doses are greatly warranted to assess the efficacy of anti-CD4 mAb VIT4 in the treatment of allograft rejection.
Animals↗
Interferon-alpha and its effects on the cytokine cascade: a pro- and anti-inflammatory cytokine.
Interferon-alpha (IFN alpha) has emerged as an important regulator of growth and differentiation, affecting cellular communication and signal transduction pathways as well as immunological control. The efficacy of IFN alpha has been demonstrated in many different diseases of viral, malignant, angiogenic, allergic, inflammatory, and fibrotic origin. Cytokines are pleiotropic and redundant molecules showing a wide variety of biologic functions on various tissues and cells, and several different cytokines exert similar and overlapping functions on certain cells. Data gained in the last years support this view also for IFN alpha. Initially thought to have mainly immunomodulating and proinflammatory effects, recent data suggest that IFN alpha has several anti-inflammatory properties. These newly identified anti-inflammatory and immunosuppressive functions may help to explain some of the IFN mechanisms.
Animals↗
Interferon-alpha induces circulating tumor necrosis factor receptor p55 in humans.
In the present studies we investigated the effect of interferon-alpha (IFN alpha) on the release of the soluble (extracellular) form of the tumor necrosis factor p55 receptor (TNFsRp55), because TNFsRp55 is a natural antagonist of tumor necrosis factor (TNF)-induced inflammation and also might be part of the antiinflammatory properties of IFN alpha. Plasma levels of TNFsRp55 were measured by a specific radioimmunoassay in five healthy volunteers and in five patients with chronic hepatitis C treated with IFN alpha. Levels showed a significant increase after a single injection of 5.0 million U IFN alpha in both healthy and hepatitis patient groups. Peak values (3.5 to 4.5 ng/mL) were observed within 12 hours of beginning treatment. Thereafter, levels promptly declined, reaching baseline values within 24 hours. TNF alpha and C-reactive protein (CRP) levels were below the detection limit in the same plasma samples. In addition, IFN alpha suppressed significantly interleukin (IL)-1 alpha-induced TNF alpha protein synthesis by human peripheral blood mononuclear cells. These results suggest that the antiinflammatory properties of IFN alpha may be, in part, also due to the induction and/or release of TNF soluble receptors and the suppression of TNF alpha synthesis.
C-Reactive Protein↗
Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy.
The objective of this study was to investigate the in vivo production of interleukin 10 (IL-10) in cancer patients undergoing immunotherapy with IL-1 alpha, IL-2 or IL-6 and to study the effect of the same cytokines on the in vitro synthesis of IL-10 by human monocytes and macrophages. In the IL-1 alpha clinical trial, patients received 0.03 g/kg of IL-1 alpha as a 30 minute infusion daily for 5 consecutive days. In these patients, plasma IL-10 levels rose rapidly and peaked within 1 h (121 +/- 16 pg/mL; n = 4) after the first IL-1 alpha infusion. Thereafter, the levels rapidly declined to baseline within 8 h. The peak plasma IL-10 levels measured on days 3 and 5 of therapy were somewhat less pronounced than those on day 1. IL-2 immunotherapy was also associated with the induction of circulating IL-10. These patients were treated with high-dose (6 x 10(5) IU/kg) IL-2 every 8 h for 5 consecutive days. IL-10 was detectable in these patients within 2-4 h after the first IL-2 infusion (105 +/- 12 pg/mL). In contrast to the transient bursts of IL-10 detected in patients treated with IL-1 alpha, IL-10 levels progressively increased throughout the treatment course in the IL-2-treated patients reaching peak levels on day 5 (240 +/- 22 pg/mL; n = 10). IL-6 immunotherapy with a 5-day continuous infusion was not associated with detectable levels of circulating IL-10. Peripheral blood mononuclear cells and in vitro-derived macrophages synthesized similar amounts of IL-10 after stimulation with IL-1 alpha or IL-2, but were unresponsive to IL-6. These results suggest that the proinflammatory cytokines IL-1 alpha and IL-2 induce the anti-inflammatory cytokine IL-10 in vitro and in vivo, whereas Il-6 is not able to stimulate IL-10 synthesis.
Humans↗
Serum neopterin concentrations in chronic liver disease.
Neopterin is produced by macrophages after stimulation with interferon gamma or lipopolysaccharide. Its production is increased in many infectious, autoimmune, and malignant diseases. The aim of this study was to examine whether, on the basis of neopterin as a marker, liver diseases could be classified according to aetiology and stage of disease. A cohort of 264 patients with chronic liver diseases (viral, metabolic, autoimmune, toxic) and 150 normal controls were studied; 136 of the patients had cirrhosis. Increased serum neopterin concentrations were found in 41% of all patients (controls 6.0 (2.2) nmol/l), with patients in the cirrhotic stage of disease showing higher neopterin values (mean (SD) 15.7 (23.6) nmol/ml) than those in the non-cirrhotic stage (9.9 (5.5)). There were no statistically significant differences in the serum neopterin concentrations that could be considered characteristic for different stages of disease classified according to the Child criteria. Such differences in concentrations of neopterin that were found in patients with liver diseases grouped according to underlying causes were only marginal. Serum neopterin concentrations were found to be significantly lower than in any other disease group only in patients with Wilson's disease. The results suggest that activated macrophages participate in the development of chronic liver disease. Measurement of serum neopterin does not offer a reliable method for differentiating between various aetiologies of chronic liver diseases and does not help to predict severity of cirrhosis.
Biopterins↗
[Gas gangrene as a manifestation of endogenous Clostridium septicum infection].
Endogenous, nontraumatic clostridial myonecrosis has a frequent association with colon carcinoma, leukemia, diabetes mellitus, and drug-induced immunosuppression. We present two cases of Clostridium septicum myonecrosis. An 18-year-old girl developed severe abdominal pain on day 7 after hospitalization for cytostatic treatment of acute lymphoblastic leukemia. Blood cultures yielded Clostridium septicum and histopathological exam of muscle tissue showed extended myonecrosis. Eventually the patient recovered with antibiotics and surgical therapy. A 72-year-old diabetic woman was treated as an outpatient with an intramuscular injection of steroidal antiphlogistics for "acute lumbar disc disease". The next morning persistence of hip pain and discoloration of the right thigh caused hospitalization under the suspected diagnosis "fracture of the neck of the femur". Clostridium septicum was cultured from intraoperatively taken swabs. At autopsy, in addition to the gangrene, there was an adenocarcinoma of the cecum, which had not been diagnosed during life.
Adolescent↗