Effect of melatonin on human nighttime endotoxaemia: randomized, double-blinded, cross-over study.

BACKGROUND: Endotoxaemia is widely used as an experimental model to study sepsis under controlled conditions. Nighttime endotoxaemia induces a more pronounced inflammatory stress response compared to daytime. Previously, we have shown that melatonin has antioxidative and anti-inflammatory effects in inflammatory response to daytime endotoxaemia. Herein, we examined the effect of melatonin in response to human nighttime endotoxaemia. PATIENTS AND METHODS: Twelve healthy male volunteers were enrolled in a randomized, placebo-controlled, double-blinded cross-over trial. Subjects were induced by lipopolysaccharide (LPS) endotoxin 0.3 ng/kg body weight intravenously at 24:00. One hour prior to induction of endotoxaemia, an 8-h infusion of melatonin 100 mg or placebo was initiated. Blood samples were drawn before and 2, 4, 6 and 8 h after induction of endotoxaemia and plasma was tested for pro-inflammatory markers (tumor necrosis factor alpha, TNF-α, interleukin-1ß, IL-1ß, interleukin-1, IL-6, and YKL-40), anti-inflammatory markers (interleukin-1 receptor antagonist, IL-1Ra, interleukin-10, IL-10, soluble tumor necrosis factor receptors I and II, sTNF-RI and sTNF-RII), marker for oxidative damage (malondialdehyde (MDA)) and antioxidative enzyme (ascorbic acid (AA) and dehydroascorbic acid (DHA)). RESULTS: Compared to placebo, melatonin did not reduce plasma levels of any of pro- and anti-inflammatory markers and it also failed to influence levels of AA, DHA and MDA. CONCLUSION: Melatonin has no beneficial effect on inflammation and oxidative damage induced by nighttime endotoxaemia in contrast to daytime endotoxaemia.

Anti-TNF-α biotherapies: perspectives for evidence-based personalized medicine.

This article discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with genetically engineered anti-TNF-α immunoglobulin constructs. Arguments why therapeutic decision-making should not rely on clinical outcome alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulating levels of functional anti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individual patients and provide more effective and economical long-term therapies with minimal risk of side effects. Large-scale immunopharmacological knowledge of how patients 'handle' TNF-α biopharmaceuticals would also help industry develop more effective and safer TNF-α inhibitors.

Potential use of rapamycin in HIV infection.

The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti-HIV properties both in vitro and in vivo that qualifies it as a potential new anti-HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV-1 replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV-1 infection in human peripheral blood leucocytes-SCID reconstituted mice. In addition, a prospective nonrandomized trial of HIV patient series receiving RAPA monotherapy after liver transplantation indicated significantly better control of HIV and hepatitis C virus (HCV) replication among patients taking RAPA monotherapy. Taken together, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV-1 infection.

Cell saver for on-pump coronary operations reduces systemic inflammatory markers: a randomized trial.

BACKGROUND: This study investigated whether intraoperative use of a cell saver reduces the systemic inflammatory response after coronary operations using cardiopulmonary bypass (CPB). METHODS: The study randomized 29 patients, 15 to cell saving of pericardial suction blood and residual blood in the CPB circuit after perfusion (cell saver group) vs 14 who received direct retransfusion of the suction blood and the CPB circuit blood (control group). Outcome measures were plasma concentrations of the inflammatory markers interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-alpha, soluble tumor necrosis factor receptors I and II, and procalcitonin at 6, 24, and 72 hours postoperatively. RESULTS: At 6 hours postoperatively, the cell saver group displayed significantly reduced plasma levels of IL-6 and IL-8 (p < 0.05). A reduction in IL-10 was also found (p = 0.05), along with nonsignificant reductions in the remaining markers. At 24 and 72 hours, significant differences between groups no longer existed. In the cell saver group, the suction blood and CPB circuit blood were cleared for tumor necrosis factor receptors (p < 0.005), and IL-6, IL-8, IL-10, and procalcitonin were significantly reduced (p < 0.05). Median intraoperative blood loss was 250 mL in the cell saver group vs 475 mL (p < 0.02). Immediately postoperatively the hemoglobin level was higher in the cell saver group (p < 0.03). Transfusion requirements were similar. CONCLUSIONS: The cell saver reduced the systemic levels of the proinflammatory markers IL-6 and IL-8 at 6 hours after CPB. The role of the anti-inflammatory molecules IL-10 and soluble tumor necrosis factor receptors is undefined in this setting.

Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis.

The effect of consumption of Immulina, a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis, on adaptive immune responses was investigated by evaluation of changes in leukocyte responsiveness to two foreign recall antigens, Candida albicans (CA) and tetanus toxoid (TT), in vitro. Consumption of Immulina by 11 healthy male volunteers caused an immediate, but temporary, increase of CA-induced CD4+ T-helper (Th) cell proliferation (P < .02). TT-induced Th cell proliferation was increased in individuals over 50 years of age (P < .05) and correlated with age (P < .02). Consumption for 8 days enhanced the CA-induced B cell proliferation (P < .02), but after 56 days a diminution was seen (P < .03). The CA-elicited production of the Th1 cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and interferon (IFN)-gamma was increased after Immunlina administration for 3 days (P < .001, < .03, and < .007, respectively), and increased IL-2 production persisted after 56 days (P < .004). The TNF-alpha, IFN-gamma, and IL-6 responses to TT were enhanced after 8 and 14 days (P < .002-.05), while IL-5 responses increased significantly within 3 days (P < .04) and fell below baseline levels after 14 days (P < .008). Conversely, consumption for 3 days inhibited the IL-4 responses to both CA and TT (P < .008 and P < .03, respectively). No effects on IL-10 responses were observed. Upon addition to normal mononuclear cells in vitro, Immulina elicited strong TNF-alpha, IL-1beta, and IL-6 responses, indicating that it acts by inducing a pro-inflammatory state. Taken together, the data suggest that Immulina causes an age-dependent, temporary enhancement of adaptive immune responses.

Prevention of carrageenan-induced pleurisy in mice by anti-CD30 ligand monoclonal antibody.

CD30 ligand (CD30L) and its receptor CD30 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies that play a major role in inflammation and immune regulation. To gain insight into the in vivo role of CD30L/CD30 in inflammatory diseases, we have used carrageenan (CAR)-induced pleurisy in mice, a preclinical model of airway inflammation where type 1 proinflammatory cytokines such as interleukin (IL)-1 and TNF-alpha play a key pathogenic role. The data show that prophylactic treatment with anti-CD30L mAb markedly reduces both laboratory and histological signs of CAR-induced pleurisy. These data suggest involvement of CD30-mediated signals in acute immunoinflammatory pathways induced by CAR.

Blood cell gene expression profiling in rheumatoid arthritis. Discriminative genes and effect of rheumatoid factor.

UNLABELLED: To study the pathogenic importance of the rheumatoid factor (RF) in rheumatoid arthritis (RA) and to identify genes differentially expressed in patients and healthy individuals, total RNA was isolated from peripheral blood mononuclear cells (PBMC) from eight RF-positive and six RF-negative RA patients, and seven healthy controls. Gene expression of about 10,000 genes were examined using oligonucleotide-based DNA chip microarrays. The analyses showed no significant differences in PBMC expression patterns from RF-positive and RF-negative patients. However, comparisons of gene expression patterns from all fourteen RA patients and healthy controls identified a subset of discriminative genes. These results were validated by real time reverse transcription polymerase chain reaction (RT-PCR) on another group of RA patients and healthy controls. This confirmed that the following genes had a significantly higher expression in RA patients than in healthy controls: CD14 antigen, defensin alpha-1 and alpha-3 (DEFA), fatty-acid-Coenzyme A ligase, long-chain 2 (FACL), ribonuclease 2 (RNASE2), S100 calcium-binding protein A8 and A12 (S100A8 and S100A12). In contrast, the expression of MHC class II, DQ beta1 (HLA-DQB1) was significantly reduced in RA patients compared to healthy controls. CONCLUSIONS: With the analytical procedure employed, we did not find any indication that RF-positive and RF-negative RA are two fundamentally different diseases. Most of the genes discriminative between RA patients and healthy individuals are known to be involved in immunoinflammatory responses, especially those related to altered phagocytic functions.

Vaccination for birch pollen allergy. Induction of affinity-matured or blocking IgG antibodies does not account for the reduced binding of IgE to Bet v 1.

Specific allergy vaccination (SAV) is associated with increased levels of allergen specific IgG in serum. It is not clear, however, to what extent qualitative changes in allergen binding to IgG may be induced as well. We therefore analyzed the binding of the major allergen in pollen of birch (Betula verrucosa) (Bet v 1), the major allergen in birch pollen, to serum IgG and IgE, separately and in competition. Sera from six birch pollen-allergic patients were obtained before and after 5 years of SAV, and binding was assessed with 125I-Bet v 1. Before SAV, IgG bound more than eight times the amount of Bet v 1 compared with IgE, and together they accounted for more than 85% of the serum binding capacity. While SAV induced minimal changes in IgE binding, the IgG binding capacities increased 6-32 times. In contrast, the binding avidities (K(d) 28-40pM) changed less than 20%, pre- and post-SAV IgG provided similar inhibition of Bet v 1 binding to IgE at equimolar levels, and cross inhibition studies between IgG and IgE showed low inter-individual differences. Following SAV, all sera reduced Bet v 1 binding to CD23(+) cells, correlating with reduced binding of Bet v 1 to IgE (P<0.001). These results show that high avidity IgG of low inter-individual difference in Bet v 1 binding quality is the dominant binding factor of Bet v 1 in sera of birch pollen-allergic patients, and that SAV-induced inhibition of binding of Bet v 1 to IgE can be explained mainly or solely by increased amounts of IgG.