OBJECTIVE

To evaluate the clinical significance of preoperative serum levels of interleukin-10 (IL-10) and interleukin-6 (IL-6) in patients with resectable hepatocellular carcinoma (HCC).

BACKGROUND

IL-10 is an immunosuppressive factor and IL-6 is a multifunctional cytokine that plays a role in host defense mechanisms. Both have been reported to be related to the disease prognosis in some human solid tumors. Their role in human HCC has not been investigated.

METHODS

Preoperative serum samples of 67 patients with HCC who underwent potentially curative resection and 27 normal healthy donors were assayed. Levels of IL-10 and IL-6 were determined by enzyme-linked immunosorbent assay. The clinical significance of serum IL-10 and IL-6 was evaluated and compared with conventional clinicopathologic factors.

RESULTS

Levels of IL-10 and IL-6 were significantly higher in patients with HCC than in healthy subjects. There was no correlation between IL-10 and IL-6 levels. Tumor resection resulted in a decrease in IL-10 and IL-6 levels. On univariate analysis, patients with high IL-10 levels had a worse disease-free survival, but IL-6 levels had no correlation with the disease-free survival. Multivariate analysis identified IL-10 levels as a predictor of postresectional outcome, in addition to the well-established clinical risk factors.

CONCLUSIONS

In patients with HCC, the preoperative serum IL-10 level is related to the clinical outcome. IL-10 may play an important role in the progression of HCC.

OBJECTIVE

HSP60-specific T cells contribute to the development of the immune responses in atherosclerosis. This can be dampened by regulatory T cells activated via oral tolerance induction, and we explored the effect of oral tolerance induction to HSP60 and the peptide HSP60 (253 to 268) on atherosclerosis.

RESULTS

HSP60 and HSP60 (253 to 268) were administered orally to LDLr(-/-) mice before induction of atherosclerosis and resulted in a significant 80% reduction in plaque size in the carotid arteries and in a <em>27</em>% reduction in plaque size at the aortic root. Reduction in plaque size correlated with an increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells in several organs and in an increased expression of Foxp3, CD25, and CTLA-4 in atherosclerotic lesions of HSP60-treated mice. The production of <em>interleukin</em> (IL)-10 and transforming growth factor (TGF)-beta by lymph node cells in response to HSP60 was observed after tolerance induction.

CONCLUSIONS

Oral tolerance induction to HSP60 and a small HSP60-peptide leads to an increase in the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells, resulting in a decrease in plaque size as a consequence of increased production of IL-10 and TGF-beta. We conclude that these beneficial results of oral tolerance induction to HSP60 and HSP60 (253 to 268) may provide new therapeutic approaches for the treatment of atherosclerosis.

We determined the cytokine messenger RNA (mRNA) expression pattern of blood mononuclear cells in 29 patients with relapsing-remitting multiple sclerosis every 4 weeks over a period of 12 months. During this period <em>27</em> relapses occurred in 14 patients (48%). Progression of disease activity as assessed by the occurrence of new lesions on nonenhancing T2-weighted magnetic resonance images of the head was detected in 12 (48%) of 25 patients. Using a semiquantitative polymerase chain reaction we demonstrated significant increases in tumor necrosis factor-alpha mRNA expression in peripheral blood mononuclear cells prior to a relapse. In 24 (85%) of <em>27</em> relapses increased tumor necrosis factor-alpha mRNA expression preceded clinical symptoms by 4 weeks. A similar pattern was observed for lymphotoxin mRNA expression. At the same time, transforming growth factor-beta and <em>interleukin</em>-10 mRNA levels declined. Fluctuations in the mRNA expression of tumor necrosis factor-alpha were also observed in 6 patients with stable disease who had active magnetic resonance scans on follow-up. No correlation of disease activity was observed with <em>interleukin</em>-1 beta, -4, or -6, inferferon gamma or endothelin-1 mRNA expression. From these data it can be concluded that variations in cytokine mRNA expression in blood mononuclear cells are correlated with disease activity in relapsing-remitting multiple sclerosis. It may be a valuable parameter to monitor the immunological status of patients in future clinical trials.

A novel cytokine <em>interleukin</em>-<em>27</em> (IL-<em>27</em>), composed of p28 and Epstein-Barr virus-induced gene 3 (EBI3), is produced from activated dendritic cells and is involved in an early phase of T-helper type I differentiation. We examined whether Colon 26 murine colon carcinoma cells that were retrovirally transduced with the p28-linked EBI3 gene (Colon 26/IL-<em>27</em>) could produce antitumor effects in inoculated mice. Although proliferation in vitro of Colon 26/IL-<em>27</em> cells was not different from that of parent cells, syngeneic BALB/c mice rejected Colon 26/IL-<em>27</em> tumors inoculated and subsequently acquired tumor-specific protective immunity. In contrast, mice inoculated with Colon 26 cells transduced with either the p28 or EBI3 gene developed tumors and survival of the mice remained the same as that of the mice inoculated with parent cells. Syngeneic nude mice developed Colon 26/IL-<em>27</em> tumors, but the growth was retarded compared to that of parent tumors. Depletion of natural killer cells from nude mice with anti-asialo GM(1) antibody diminished the growth retardation of Colon 26/IL-<em>27</em> tumors. Survival of severe combined immunodeficient mice that received subcutaneous inoculation of Colon 26/IL-<em>27</em> cells was not different from that of the immunodeficient mice inoculated with parent cells. Interferon-gamma was produced from CD4(+) and CD8(+) T, and natural killer cells of the mice that rejected Colon 26/IL-<em>27</em> tumors and cytotoxic activity against Colon 26 cells were also detected from the mice. These data collectively suggest that expressed IL-<em>27</em> in tumors produces T cell-dependent and-independent antitumor effects and is a possible therapeutic strategy for cancer.

To determine if 6 weeks of supplementation with vitamins E and C could alleviate exercise-induced lipid peroxidation and inflammation, we studied 22 runners during a 50 km ultramarathon. Subjects were randomly assigned to one of two groups: (1) placebos (PL) or (2) antioxidants (AO: 1000 mg vitamin C and 300 mg RRR-alpha-tocopheryl acetate). Blood samples were obtained prior to supplementation (baseline), after 3 weeks of supplementation, 1 h pre-, mid-, and postrace, 2 h postrace and for 6 days postrace. Plasma levels of alpha-tocopherol (alpha-TOH), ascorbic acid (AA), uric acid (UA), F2-isoprostanes (F2-IsoPs), tumor necrosis factor alpha (TNF-alpha), <em>interleukin</em>-6 (IL-6), and C-reactive protein (CRP) were measured. With supplementation, plasma alpha-TOH and AA increased in the AO but not the PL group. Although F2-IsoP levels were similar between groups at baseline, 28 +/- 2 (PL) and <em>27</em> +/- 3 pg/ml (AO), F2-IsoPs increased during the run only in the PL group (41 +/- 3 pg/ml). In PL women, F2-IsoPs were elevated postrace (p <.01), but returned to prerace concentrations by 2 h postrace. In PL men, F2-IsoP concentrations were higher postrace, 2 h postrace, and 1, 2, 3, 4, and 6 days postrace (PL vs. AO group, each p <.03). Markers of inflammation were increased dramatically in response to the run regardless of treatment group. Thus, AO supplementation prevented endurance exercise-induced lipid peroxidation but had no effect on inflammatory markers.

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD.

METHODS

We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278.

RESULTS

We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related.

CONCLUSIONS

Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia.

BACKGROUND

MedImmune.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified <em>27</em> genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and <em>interleukin</em> in multiple autoimmune diseases.

A lambda cDNA library was prepared from polyadenylated RNA isolated from quiescent human diploid FS-4 fibroblasts stimulated with tumor necrosis factor for 3 h. Differential screening was used to isolate cDNA sequences that are stimulated by tumor necrosis factor. Eight distinct tumor necrosis factor-stimulated gene sequences (designated TSG-1, -6, -8, -12, -14, -21, -<em>27</em>, and -37) were partially sequenced and compared with known sequences from GenBank. TSG-1 was identical to the gene for <em>interleukin</em>-8. TSG-8 corresponded to the gene for monocyte chemotactic and activating factor. TSG-21 and -<em>27</em> were identical to the genes for collagenase and stromelysin, respectively. The other four sequences showed no homologies with known genes. Patterns of induction of mRNAs corresponding to the eight cloned cDNAs by various cytokines, growth factors, and activators of second messenger pathways were analyzed in FS-4 cells.

OBJECTIVE

The mechanisms underlying neurological deterioration in patients with lacunar infarction are not completely understood. In this study, we sought to investigate the role of proinflammatory molecules in the early worsening and outcome of acute lacunar stroke.

METHODS

We performed a secondary analysis of 113 consecutive patients with lacunar infarction included within the first 24 hours of the onset of symptoms in a previous study aimed at investigating clinical and biochemical factors of early neurological deterioration (END). END was defined as a fall of>> or =1 points in the motor items of Canadian Stroke Scale between inclusion and 48 hours. Poor outcome at 3 months was considered death or Barthel Index <85. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and intercellular adhesion molecule-1 (ICAM-1) were determined by enzyme-linked immunoabsorbent assay in blood samples obtained on admission.

RESULTS

END was recorded in 27 patients (23.9%); poor outcome was noted in 26 (23%). Median (quartiles) concentrations in plasma of TNF-alpha [16.5 pg/mL (13.7 and 21.2 pg/mL) versus 7.5 pg/mL (6.2 and 9.0 pg/mL)], IL-6 [28.8 pg/mL (22.5 and 35.7 pg/mL) versus 11.5 pg/mL (8.5 and 16.2 pg/mL)], and ICAM-1 [285 pg/mL (219 and 315 pg/mL) versus 158 pg/mL (137 and 187 pg/mL)] were significantly higher in patients who had END than in those with nonprogressing strokes (P< 0.001). Significant differences were also observed between patients with poor and good outcome at 3 months. Logistic regression analysis after adjustment for potential confounders showed that TNF-alpha >14 pg/mL and ICAM-1 >208 pg/mL were independently associated with both END (OR, 511; 95% CI, 17 to 4937; P<0.001; and OR, 315; 95% CI, 17 to 5748; P< 0.001, respectively) and poor outcome at 3 months (OR, 3.0; 95% CI, 1.0 to 8.5; P=0.042; and OR, 4.2; 95% CI, 1.3 to 13.6; P<0.015, respectively).

CONCLUSIONS

High concentrations of inflammatory markers in blood are associated with END and poor functional outcome in lacunar infarctions. These findings suggest that inflammation contributes to brain injury in lacunar stroke.

BACKGROUND

Type 1 regulatory T (Tr1) cells, characterized by the secretion of high levels of the anti-inflammatory cytokine interleukin-10 (IL-10), play an important role in the regulation of autoimmune diseases and transplantation. However, effective strategies that specifically induce Tr1 cells in vivo are limited. Furthermore, the pathways controlling the induction of these cells in vivo are not well understood.

RESULTS

Here we report that nasal administration of anti-CD3 antibody induces suppressive Tr1 cells in mice. The in vivo induction of Tr1 cells by nasal anti-CD3 is dependent on IL-27 produced by upper airway resident dendritic cells (DCs), and is controlled by the transcription factors aryl hydrocarbon receptor (AHR) and c-Maf. Subsequently, IL-21 acts in an autocrine fashion to expand and maintain the Tr1 cells induced in vivo by nasally administered anti-CD3.

CONCLUSIONS

Our findings identify a unique approach to generate Tr1 cells in vivo and provide insights into the mechanisms by which these cells are induced.

The early use of fresh frozen plasma as a resuscitative agent after hemorrhagic shock has been associated with improved survival, but the mechanism of protection is unknown. Hemorrhagic shock causes endothelial cell dysfunction and we hypothesized that fresh frozen plasma would restore endothelial integrity and reduce syndecan-1 shedding after hemorrhagic shock. A prospective, observational study in severely injured patients in hemorrhagic shock demonstrated significantly elevated levels of syndecan-1 (554±93 ng/ml) after injury, which decreased with resuscitation (187±36 ng/ml) but was elevated compared to normal donors (<em>27</em>±1 ng/ml). Three pro-inflammatory cytokines, interferon-γ, fractalkine, and <em>interleukin</em>-1β, negatively correlated while one anti-inflammatory cytokine, IL-10, positively correlated with shed syndecan-1. These cytokines all play an important role in maintaining endothelial integrity. An in vitro model of endothelial injury then specifically examined endothelial permeability after treatment with fresh frozen plasma orlactated Ringers. Shock or endothelial injury disrupted junctional integrity and increased permeability, which was improved with fresh frozen plasma, but not lactated Ringers. Changes in endothelial cell permeability correlated with syndecan-1 shedding. These data suggest that plasma based resuscitation preserved endothelial syndecan-1 and maintained endothelial integrity, and may help to explain the protective effects of fresh frozen plasma after hemorrhagic shock.

OBJECTIVE

To compare the conjunctival epithelial cell expressions of inflammatory cytokines in normal subjects and in glaucoma patients treated over the long term.

METHODS

Case-control study.

METHODS

A total of 69 glaucoma patients treated over the long term and 15 normal subjects with no ocular abnormality or topical treatment.

METHODS

Amongst the 69 glaucoma patients, <em>27</em> were treated with preserved beta-blockers, 24 with unpreserved 0.5% timolol, and the other 18 patients with an association of>> or =2 preserved drugs. All patients were treated for more than 1 year with the same treatment, with no significant differences between groups for mean ages and durations of treatment at the time of the study. Impression cytology specimens were taken and processed for immunofluorescence techniques. Conjunctival cell expressions of HLA DR, as a standard for inflammatory level, and the <em>interleukins</em> IL-6, IL-8, and IL-10 were obtained and quantified using flow cytometry.

METHODS

Immune markers and proinflammatory cytokines in impression cytology specimens.

RESULTS

We found a significantly increased expression of all immunoinflammatory markers and mediators in the conjunctival epithelium of glaucoma patients compared with normal eyes. Human leukocyte antigen DR was significantly higher in the 2 groups receiving preserved drugs than in the unpreserved timolol group. The 3 interleukins were similarly overexpressed in all glaucoma groups, with no significant between-groups differences except for the expression level of IL-8, which was significantly higher in the multitreatment group than in the preservative-free one.

CONCLUSIONS

The present study confirms the increased expression of immunoinflammatory markers by the conjunctival epithelium of glaucoma patients treated over the long term. The development of nontoxic preservatives or preservative-free solutions is therefore of great interest.

The <em>interleukin</em> (IL)-6 family cytokines is a group of cytokines consisting of IL-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC), and IL-<em>27</em>. They are grouped into one family because the receptor complex of each cytokine contains two (IL-6 and IL-11) or one molecule (all others cytokines) of the signaling receptor subunit gp130. IL-6 family cytokines have overlapping but also distinct biologic activities and are involved among others in the regulation of the hepatic acute phase reaction, in B-cell stimulation, in the regulation of the balance between regulatory and effector T cells, in metabolic regulation, and in many neural functions. Blockade of IL-6 family cytokines has been shown to be beneficial in autoimmune diseases, but bacterial infections and metabolic side effects have been observed. Recent advances in cytokine blockade might help to minimize such side effects during therapeutic blockade.

During inflammation, inducible nitric oxide synthase (iNOS) is induced to generate the important mediator nitric oxide (NO). <em>Interleukin</em> 1beta (IL-1beta) induces iNOS messenger RNA (mRNA), iNOS protein, and NO in rat hepatocytes. We found that the stability of iNOS mRNA changed during the induction and that the antisense (AS) strand corresponding to the 3'-untranslated region (3'UTR) of iNOS mRNA was transcribed from the iNOS gene. Expression levels of the iNOS AS transcript correlated with those of iNOS mRNA. The 1.5-kilobase region 3'-flanking to iNOS gene exon <em>27</em> was involved in IL-1beta induction. Knockdown experiments suggest that sense oligonucleotides to iNOS mRNA significantly reduced iNOS mRNA levels in the hepatocytes by blocking the interaction between iNOS mRNA and the AS transcript. Overexpression of iNOS AS transcript stabilized the reporter luciferase mRNA through the fused iNOS mRNA 3'UTR. These results together with the data in a yeast RNA-hybrid assay suggested that the iNOS AS transcript interacted with iNOS mRNA and stabilized iNOS mRNA. The iNOS mRNA colocalized with the AU-rich element-binding protein HuR, a human homolog of embryonic lethal-abnormal visual protein, and heterogeneous nuclear ribonucleoprotein L (hnRNP L) in the cytoplasm of rat hepatocytes. Interaction assays further revealed that the iNOS AS transcript interacted with HuR, which interacted with hnRNP L, suggesting that iNOS mRNA, the AS transcript, and the RNA-binding proteins may mutually interact.

CONCLUSIONS

The natural AS transcript of the iNOS gene interacts with iNOS mRNA and may play an important role in the stability of iNOS mRNA. This RNA-RNA interaction may be a new therapeutic target for NO-mediating inflammatory diseases.

OBJECTIVE

We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma.

METHODS

Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN-alpha-2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN-alpha-2a and IV vinblastine.

RESULTS

Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P =.0248). Both arm A (median overall survival, 25 months; P =.0440) and arm B (median overall survival, 27 months; P =.0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN-alpha-2a-based therapies were moderately or well tolerated.

CONCLUSIONS

Our results established the safety and improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF-alpha-2a-based outpatient immunochemotherapies, compared with sc-INF-alpha-2a/IV vinblastine.

<em>Interleukin</em> (IL-) <em>27</em> is a helical cytokine of the greater IL-6/IL-12 family with a broad range of pro- and anti-inflammatory properties. It can skew T helper cell development, suppress T cell proliferation, stimulate cytotoxic T cell activity, induce isotype switching in B cells, and has diverse effects on innate immune cells. In vivo, its most important role appears to be that of immune regulation, as mice with defects in IL-<em>27</em> or its receptor display enhanced immune responses in a range of infectious and noninfectious situations. In this review, we discuss the body of knowledge on IL-<em>27</em> and its potential therapeutic utility.

In a study aimed at correlating cytokine levels in synovial fluid with the pathology of rheumatoid arthritis (RA), tumour necrosis factor alpha, <em>interleukin</em> 1 beta and interferon gamma were immunoassayed in <em>27</em> patients with RA, 16 patients with other arthritides, 23 with osteoarthritis, 13 patients with trauma, and 18 patients at necropsy without inflammatory disease and not known to have had joint disease (median <em>27</em> hours after death). The results for <em>interleukin</em> 1 beta clearly show higher cytokine levels in patients with RA and other arthritides than in patients with osteoarthritis, trauma, or the patients at necropsy. Interferon gamma levels in patients with osteoarthritis and the patients at necropsy, however, were significantly greater than in patients with RA, and tumour necrosis factor alpha levels were also greater in the patients at necropsy compared with patients with RA. This study also correlated histomorphological patterns of synovitis and indicators of local inflammatory activity with synovial fluid cytokine levels, showing, for example, a positive association of <em>interleukin</em> 1 beta titre and a negative association of interferon gamma titre with ulcerogranulomatous synovitis (itself associated with RA). Taken together, these results extend and strengthen data suggesting a possible part played by increased synovial fluid levels of <em>interleukin</em> 1 beta in joint destruction in RA, but provide no evidence for increases in levels of tumour necrosis factor alpha or interferon gamma affecting the disease pathology.

Our understanding of the role of <em>interleukin</em> (IL)-12 in controlling tuberculosis has expanded because of increased interest in other members of the IL-12 family of cytokines. Recent data show that IL-12, IL-23 and IL-<em>27</em> have specific roles in the initiation, expansion and control of the cellular response to tuberculosis. Specifically, IL-12, and to a lesser degree IL-23, generates protective cellular responses and promotes survival, whereas IL-<em>27</em> moderates the inflammatory response and is required for long-term survival. Paradoxically, IL-<em>27</em> also limits bacterial control, suggesting that a balance between bacterial killing and tissue damage is required for survival. Understanding the balance between IL-12, IL-23 and IL-<em>27</em> is crucial to the development of immune intervention in tuberculosis.

BACKGROUND

Adherence to the Mediterranean diet (MD) is associated with reduced morbidity and mortality due to cardiovascular disease. However, how the MD exerts its effects is not fully known.

OBJECTIVE

To assess the 12-month effects of two enhanced MDs compared to a low-fat diet on inflammatory biomarkers related to atherosclerosis and plaque vulnerability in a subcohort of the PREDIMED (Prevención con Dieta Mediterránea) study.

METHODS

A total of 164 participants at high risk for cardiovascular disease were randomized into three diet groups: MD supplemented with 50mL/d of extra virgin olive oil (MD+EVOO) or 30 g/d of nuts (MD+Nuts) and a low-fat diet. Changes in classical cardiovascular risk factors, inflammatory biomarkers of atherosclerosis and plaque vulnerability were measured after 12 months of intervention.

RESULTS

Compared to participants in the low-fat diet group, those receiving MD+EVOO and MD+Nuts showed a higher decrease in systolic (6mmHg) and diastolic (3mmHg) blood pressure (P = 0.02; both), as well as a reduction of 10% and 8% in LDL-cholesterol (P = 0.04), respectively. Patients in the MD+Nuts group showed a significant reduction of 34% in CD40 expression on monocyte surface compared to low-fat diet patients (P = 0.03). In addition, inflammatory biomarkers related to plaque instability such as C-reactive protein and <em>interleukin</em>-6 were reduced by 45% and 35% and 95% and 90% in the MD+EVOO and MD+Nuts groups, respectively (P<0.05; all) compared to the low-fat diet group. Likewise, sICAM and P-selectin were also reduced by 50% and <em>27</em>%, respectively in the MD+EVOO group (P = 0.04) and P-selectin by 19% in MD+Nuts group (P = 0.04) compared to the low-fat diet group.

CONCLUSIONS

Adherence to the MD is associated with an increase in serum markers of atheroma plaque stability which may explain, at least in part, the protective role of MD against ischemic heart disease.

BACKGROUND

www.controlled-trials.com ISRCTN35739639.

OBJECTIVE

The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD).

METHODS

This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations.

RESULTS

Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, <em>27</em> patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. <em>Interleukin</em> 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients.

CONCLUSIONS

MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.

BACKGROUND

Fatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS), but the putative role of proinflammatory cytokines remains to be elucidated.

METHODS

Thirty-seven patients (<em>27</em> women, 10 men) with relapsing remitting (n = 29) and secondary progressive (n = 8) MS, aged 41.0 +/- 10.2 years, were studied. Fatigue was assessed by Krupp's Fatigue Severity Scale (FSS). Cytokine mRNA expression for interferon (IFN)-gamma tumor necrosis factor (TNF)-alpha and <em>interleukin</em> (IL)-10 were measured by real time RT PCR. Autonomic function was evaluated by standard tests for parasympathetic and sympathetic function, as well as by serum levels of norepinephrine and epinephrine.

RESULTS

Median levels of TNF-alpha mRNA expression were significantly higher in MS patients with (FSS>> or = 4.0 and>> or = 5.0, n = 26 and n = 14, respectively) than in those without fatigue (FSS < 4.0, n = 11). No differences were seen for IFN-gamma and IL-10 mRNA expression. Cytokine levels were not correlated to autonomic tests or to serum catecholamine levels.

CONCLUSIONS

These results suggest that TNF-alpha, as a principal proinflammatory mediator, is associated with MS-related fatigue. This is in support of a pathogenic role of the MS-related inflammatory process in the development of fatigue.

OBJECTIVE

From in vitro studies using cultures of orbital fibroblasts, it has become clear that cytokines play an important role in the orbital inflammation in Graves' ophthalmopathy (GO). Orbital fibroblasts seem to be the key target cells of the autoimmune attack, and they are able to express the TSH receptor (TSH-R). In vivo data on the presence of cytokines in orbital tissues are sparse, and mostly limited to samples obtained from patients with endstage, inactive GO; the same holds true for the presence of the TSH-R. The aim of the present study was to determine whether the cytokine profile and TSH-R expression differ in the active vs. the inactive stage of GO.

METHODS

Orbital fat/connective tissue was obtained from six patients with active, untreated GO undergoing emergency orbital decompression, and from 11 patients with inactive GO subjected to rehabilitative decompressive surgery. The mRNA levels of various cytokines and the TSH-R were assessed by real-time polymerase chain reaction (PCR) using the LightCycler. Data are expressed as ratios (unknown mRNA/beta-actin mRNA).

RESULTS

Active GO patients had much higher TSH-R expression than inactive patients: 4/0-24 (median value/range) vs. 0/0-9, P = 0.01. TSH-R expression was related to the Clinical Activity Score (r = 0.595, P = 0.015). Patients with active GO compared to those with inactive GO had higher mRNA levels of the proinflammatory cytokines <em>interleukin</em>-1beta (IL-1beta) (445/153-877 vs. 0/0-455, P = 0.001), IL-6 (1583/968-18825 vs. 559/0-7181, P = 0.01), IL-8 (1422/38-7579 vs. 32/0-1081, P = 0.046) and IL-10 (145/58-318 vs. <em>27</em>/0-189, P = 0.002). In active GO there also existed a trend towards a predominance of T helper 1 (Th1)-derived cytokines as evident from higher IL-2 (37/0-158 vs. 0/0-68, P = 0.043), interferon-gamma (IFN-gamma) (20/0-79 vs. 0/0-16, P = 0.12) and IL-12 (2.3/0-14.8 vs. 0/0-1.6, P = 0.10) mRNAs. IL-1 receptor agonist (IL-1RA), IL-2 receptor (IL-2R), IL-3, IL-4, IL-5, IL-13, IL-18 and tumour necrosis factor-alpha (TNF-alpha) mRNAs were similar in both groups.

CONCLUSIONS

These data show that at the mRNA level, TSH-R expression is largely present only during the active stages of GO. The active phase is characterized by the presence of proinflammatory and Th1-derived cytokines, whereas other cytokines, among them Th2-derived cytokines, do not seem to be linked to a specific stage of GO.

OBJECTIVE

Cross-sectional studies suggest that clinical insomnia is associated with immune downregulation. However, there is a definite need for experimental studies on this question. The goal of this randomized controlled study was to assess the effect of an 8-week cognitive-behavioral therapy (CBT) for chronic insomnia on immune functioning of breast cancer survivors. Previous analyses of this study showed that CBT was associated with improved sleep and quality of life, and reduced psychological distress.

METHODS

Fifty-seven women with chronic insomnia secondary to breast cancer were randomly assigned to CBT (n = <em>27</em>) or to a waiting-list control condition (WLC; n = 30). Peripheral-blood samples were taken at baseline and post-treatment (and postwaiting for WLC patients), as well as at 3-, 6-, and 12-month follow-up for immune measures, including enumeration of blood cell counts (ie, WBCs, monocytes, lymphocytes, CD3+, CD4+, CD8+, and CD16+/CD56+) and cytokine production (ie, <em>interleukin</em>-1-beta [IL-1beta] and interferon gamma [IFN-gamma]).

RESULTS

Patients treated with CBT had higher secretion of IFN-gamma and lower increase of lymphocytes at post-treatment compared with control patients. Pooled data from both treated groups indicated significantly increased levels of IFN-gamma and IL-1beta from pre- to post-treatment. In addition, significant changes in WBCs, lymphocytes, and IFN-gamma were found at follow-up compared with post-treatment.

CONCLUSIONS

This study provides some support to the hypothesis of a causal relationship between clinical insomnia and immune functioning. Future studies are needed to investigate the clinical impact of such immune alterations.

BACKGROUND

Operative injury to the body from all procedures causes a stereotypical cascade of neuroendocrine, cytokine, myeloid, and acute phase responses. This response has been examined commonly by the use of cortisol, interleukin-6 (IL-6), white cell count, and C-reactive protein (CRP). We aimed to determine which markers of the systemic inflammatory response were useful in determining the magnitude of injury after elective operations.

METHODS

A systematic review of the literature was performed using surgery, endocrine response, systemic inflammatory response, cortisol, IL-6, white cell count, and CRP. For each analyte the studies were grouped according to whether the operative injury was considered to be minor, moderate, or major and then by the operative procedure.

RESULTS

A total of 164 studies were included involving 14,362 patients. The IL-6 and CRP responses clearly were associated with the magnitude of operative injury and the invasiveness of the operative procedure. For example, the peak CRP response increased from 52 mg/L with cholecystectomy to 123 mg/L with colorectal cancer resection, 145 mg/L with hip replacement, 163 mg/L after abdominal aortic aneurysm repair, and 189 mg/L after open cardiac surgery. There also appeared to be a difference between minimally invasive/laparoscopic and open procedures such as cholecystectomy (27 vs 80 mg/L), colorectal cancer resection (97 vs 133 mg/L), and aortic aneurysm repair (132 vs 180 mg/L).

CONCLUSIONS

Peak IL-6 and CRP concentrations consistently were associated with the magnitude of operative injury and operative procedure. These markers may be useful in the objective assessment of which components of Enhanced Recovery after Surgery are likely to improve patient outcome and to assess the possible impact of operative injury on immune function.