Concentrations Of Interferon-gamma Research Articles

Environmental Enrichment does not Compromise the Immune Response in Mice Chronically Infected withMycobacterium avium

Research on infectious diseases using animal models has been a successful example of translational research. However, because chronic infections are still one of the main causes of death and disability in the world, it is expected that a great number of mice will continue to be used to address this subject. Although increasing awareness regarding animal welfare has led to novel recommendations for animal housing enrichment, studies evaluating the impact of these modifications on the immune response to infection are lacking. The present study shows that validated and recommended simple environmental enrichment does not interfere with the immune response to chronic infection with Mycobacterium avium for up to 20 weeks, as assessed by the bacterial load in the spleen and lung, by the number and activation status of the main cell populations of the immune system and the serum concentration of interferon-gamma. Therefore, enrichment can be encouraged without concern regarding comparability of results among laboratories studying this type of chronic infections.

Antioxidant activity of tryptophan in rats under experimental endotoxic shock

Tryptophan (TRP), the precursor of the scavenger or immunomodulator molecules melatonin (MLT) and picolinic acid, can be found in the diet; and could be an alternative nutritional supplement used to regulate the immune response in the generation of free radicals. In an experimental model, the systemic administration of lipopolysaccharide (LPS), to promote the synthesis of pro-inflammatory cytokines, reactive oxygen species, and antioxidant enzymes, was performed on adult female, pregnant and lactating rats fed with a diet of TRP content (0.5 mg/100 g protein). Lung tissue was evaluated for levels of the products of lipoperoxidation (LPO's), malonaldehyde (MDA) and 4-hydroxy alkenals (4-HDA); nitrites (NO2), glutathione peroxidase (Gpx) enzyme activity, and the serum concentration of interferon-gamma (IFN-γ), which were measured in the following groups: control (CTRL), LPS, MLT, TRP, LPS plus MLT (LPS + MLT), and LPS plus TRP (LPS + TRP). Results showed that the lung tissue levels of MDA and 4-HDA in the LPS + TRP group were significantly lower than in the TRP group. Statistically significant differences were not observed in nitric oxide levels among the groups LPS + MLT and LPS + TRP compared to the group under endotoxic shock (LPS). The Gpx enzyme activity was modified in the LPS + MLT vs the LPS group, but the difference was not statistically significant. The LPS + MLT group showed a smaller serum concentration (98%) of IFN-γ than the LPS group. Statistically significant differences were not observed among the animals of the LPS + TRP and the LPS groups.

Diagnostic Utility of Cytokine Biomarkers in the Evaluation of Acute Knee Pain

The diagnosis of clinically important meniscal tears of the knee remains challenging, and it is unknown why only some injuries become painful. The role of inflammatory cytokines in generating pain following meniscal injury remains unclear. This study aimed to investigate the cytokine profile in patients with acute knee pain believed to be secondary to meniscal damage. This prospective cohort study included thirty-two patients without rheumatoid arthritis who had knee pain for less than six months, with either an acute or insidious onset, and elected to have arthroscopic treatment after nonoperative management had failed. Twenty-three of these patients elected to have the contralateral, nonoperatively treated knee lavaged at the time of arthroscopy. Fifteen asymptomatic control subjects also contributed samples of knee joint fluid, for a total of seventy samples from forty-seven subjects. Lavage of the operatively treated, contralateral, and control knees was performed with the patient under regional anesthesia prior to arthroscopy, if applicable, by the infusion of sterile saline solution into the knee followed by the immediate withdrawal into a syringe. The concentrations of seventeen inflammatory cytokines and chemokines were measured with use of a multiplexed immunoassay panel. Preoperative magnetic resonance imaging findings and cytokine assay results were compared with intraoperative findings. Multivariate analysis of variance detected significantly greater concentrations of interferon gamma (IFN-gamma); interleukins 2, 4, 6, 10, and 13 (IL-2, IL-4, IL-6, IL-10, and IL-13); monocyte chemotactic protein-1 (MCP-1); and macrophage inflammatory protein-1 beta (MIP-1beta) in fluid samples from painful knees than in samples from nonpainful knees. Correlation analysis demonstrated a significant positive correlation between patient-reported pain scores and concentrations of IL-6 (Spearman rho = 0.7), MCP-1 (rho = 0.8), MIP-1beta (rho = 0.6), and IFN-gamma (rho = 0.6). These four cytokines also demonstrated a positive correlation with each other (rho = 0.5 to 0.7). The presence of IFN-gamma, IL-6, MCP-1, or MIP-1beta performed as well as magnetic resonance imaging in the prediction of intraoperative findings. Intra-articular concentrations of four inflammatory cytokines IFN-gamma, IL-6, MCP-1, and MIP-1beta correlated to pain in patients with symptomatic meniscal tears in the knee but were markedly lower in asymptomatic normal knees and in asymptomatic knees with meniscal tears. These cytokines may be involved in the generation of pain following meniscal injury.

Effects of chronic exposure to DDT and TCDD on disease activity in murine systemic lupus erythematosus

Oestrogens contribute to the female preponderance of autoimmune diseases such as systemic lupus erythematosus (SLE). Environmental xenoestrogens superimposed upon endogenous pituitary-gonadal axis may affect the development of autoimmunity. This study examined the effects of chronic exposure to xenoestrogens -- o,p'-dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on disease activity in the New Zealand Black/New Zealand White F1 hybrid (B/W) mouse model of SLE. Intact female mice had repeatedly received injections of DDT, TCDD or control vehicle since 6 weeks of age. Weight change, albuminuria, mortality, relevant immunological and histological parameters were assessed. DDT exposure markedly increased the incidence of albuminuria and reduced uterine weight but had no measured effects on immunity or mortality in this study. TCDD-exposed mice had significantly lower incidence of albuminuria, serum anti-DNA antibody and total IgG levels, and mortality compared to controls. Also, TCDD group had significantly lower thymic and splenic weights, decreased percentages of CD4(+)CD8(+) thymocytes and splenic CD4(+) T cells, increased percentage of splenic B220(+)sIgM(+) B cells and higher serum interferon gamma concentration. Taken together, DDT exposure appeared to accelerate the development of albuminuria in lupus-prone mice. TCDD was immunosuppressive to murine SLE. Xenoestrogens may have compound- and tissue-specific effects that require further elucidation in future work.

CIAP-1 Controls Innate Immunity to C. pneumoniae Pulmonary Infection

The resistance of epithelial cells infected with Chlamydophila pneumoniae for apoptosis has been attributed to the induced expression and increased stability of anti-apoptotic proteins called inhibitor of apoptosis proteins (IAPs). The significance of cellular inhibitor of apoptosis protein-1 (cIAP-1) in C. pneumoniae pulmonary infection and innate immune response was investigated in cIAP-1 knockout (KO) mice using a novel non-invasive intra-tracheal infection method. In contrast to wildtype, cIAP-1 knockout mice failed to clear the infection from their lungs. Wildtype mice responded to infection with a strong inflammatory response in the lung. In contrast, the recruitment of macrophages was reduced in cIAP-1 KO mice compared to wildtype mice. The concentration of Interferon gamma (IFN-γ) was increased whereas that of Tumor Necrosis Factor (TNF-α) was reduced in the lungs of infected cIAP-1 KO mice compared to infected wildtype mice. Ex vivo experiments on mouse peritoneal macrophages and splenocytes revealed that cIAP-1 is required for innate immune responses of these cells. Our findings thus suggest a new immunoregulatory role of cIAP-1 in the course of bacterial infection.

Enhancement of Human γ-Interferon Production in Recombinant E. coli Using Batch Cultivation

Development of inexpensive and simple culture media and appropriate induction conditions are always favorable for industry. In this research, chemical composition and stoichiometric data for gamma-interferon production and recombinant Escherichia coli growth were used in order to achieve a simple medium and favorable induction conditions. To achieve this goal, the effects of medium composition and induction conditions on the production of gamma-interferon were investigated in batch culture of E. coli BL21 (DE3) [pET3a-ifngamma]. These conditions were considered as suitable conditions for the production of gamma-interferon: 2.5x M9 medium, supplemented with a mixture of amino acids (milligram per liter), including glutamic acid 215, aspartic acid 250, lysine 160, and phenylalanine 90, and induction at late-log phase (OD(600) = 4.5). Under these conditions, dry cell weight of 6 +/- 0.2 g/l and gamma-interferon concentration of 2.15 +/- 0.1 g/l were obtained. Later, without changing the concentration ratio of amino acids and glucose, the effect of increase in the primary glucose concentration on productivity of gamma-interferon was investigated. It was found that 25 g/l glucose will result in maximum attainable biomass and recombinant human gamma-interferon. At improved conditions, a dry cell weight of 14 +/- 0.2 g/l, concentration and overall productivity of gamma-interferon 4.2 +/- 0.1 g/l and 420 +/- 10 mg/l h, respectively, were obtained.

Circulating Levels of Interferon-γ in Course of Hepatitis C Virus-Related Arthritis

The aim was to weigh the serum concentrations of interferon gamma (IFN-gamma), a cytokine that enhances Th1-cell differentiation and suppresses collagen synthesis and angiogenesis, in two apparently distinct diseases, hepatitis C virus-related arthritis (HCVrA) and rheumatoid arthritis (RA), which share some overlapping immunological features. In this study, IFN-gamma serum levels were assayed by an ELISA method in 21 HCVrA patients and in 16 with RA. Very low IFN-gamma serum levels were found in five out of 21 patients with HCVrA and only in three out of 16 RA patients. Median value (range) resulted decrease in both HCVrA and RA groups, that is, 0.29 (0.04-1.49) versus 0.20 (0.05-1.18) IU/mL, P = 0.58. No correlation was evidenced with hepatic and arthritic involvements, nor between IFN-gamma serum levels and viral replication and moreover with the positivity of antinuclear antibody, rheumatoid factor, and anti-cyclic citrullinated peptides antibodies. These results show that IFN-gamma behavior appears similar in HCVrA and RA groups reinforcing the lack of significant differences between HCVrA and RA patients. Low circulating levels could be explained with the fact that IFN-gamma is not an isolate cytokine, but a piece of composite system regulated in a complex fashion, with many different factors contributing.

Synthesis and Immunomodulation of Human Lymphocyte Proliferation and Cytokine (Interferon‐γ) Production of Four Novel Malonitrilamides

Leflunomide is an immunomodulator drug with applications in the management of arthritis rheumatoid. In this study, four novel analogs (4a-d) of A771726, the active metabolite of leflunomide were synthesized and examined in vitro for their immunomodulation activity by examining human lymphocyte proliferation and determination of the cytokine interferon-gamma concentrations in human lymphocyte cell culture. For this purpose, 5 x 10(4) human lymphocyte cells were incubated at 37 degrees C in 5% CO(2) with phytohemagglutinin and one of the analogs (concentrations 1-100 mM), negative controls or cyclosporine (0.1 mM). Effects of the compounds on lymphocyte proliferation and interferon-gamma production were determined by MTT assay and enzyme-linked immunosorbent assay, respectively. Our results showed that all four compounds dose-dependently suppressed lymphocyte proliferation. Moreover, these compounds at some concentrations reduced interferon-gamma production which is an indicator of the immune response. Generally, the most potent analog was 4b with an amide linkage (X=NH) and the weakest analog was 4a with an ester linkage (X=O). Compound 4a has little similarity with the leflunomide active metabolite which has an amide linkage. In this study, four novel compounds were synthesized that showed considerable immunosuppressive effects that deserve further investigations.

Systemic Cytokine Response Profiles Associated With Respiratory Virus-Induced Acute Otitis Media

Acute otitis media (AOM) results from a complex interplay between the infectious agents and host immune responses. Cytokines play a major role in the pathogenesis of AOM, but there are few studies on the systemic cytokine response during AOM. Sera were collected from 145 children (median age = 13.5 months) at the time of diagnosis of AOM. Concentrations of 17 cytokines (IL-1beta, -2, -4, -5, -6, -7, -8, -10, -12, -13, -17, granulocyte-colony stimulating factor (G-CSF), granulocyte-monocyte-colony stimulating factor, interferon-gamma, MCP-1, MIP-1beta, TNF-alpha) were determined and correlated with viral etiology and clinical outcome. The statistical analysis was conducted using bioinformatics software. Cluster patterns of concentrations of cytokines were examined by unsupervised hierarchical clustering algorithms. Four major cluster groups were identified, one of the groups was significantly enriched for cases of respiratory syncytial virus (RSV)-induced AOM as compared with other viruses. Specifically, RSV-induced AOM had significantly higher concentrations of G-CSF, MCP-1, IL-10, IL-6, interferon-gamma, and IL-8 (P < 0.05). Using a decision tree classifier, higher G-CSF concentrations produced 87.6% accuracy to predict RSV-induced AOM. Overall, higher IL-13 concentrations produced 84.2% accuracy to predict early clinical failure of antibiotic treatment. Children with AOM have a unique pattern of systemic cytokine response that relates to virus etiology and clinical outcome. Based on G-CSF and IL-13 measurements, it is possible to accurately classify RSV-induced AOM and early treatment failure, respectively; these observations will need to be validated in an independent population.

Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants.

The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days. For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21. Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1beta, 6, 8, and 10 and interferon gamma and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor beta. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude. The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.

Vaccenic acid favourably alters immune function in obese JCR:LA- cp rats

Vaccenic acid (VA) is a ruminant-derived trans-fat and precursor of conjugated linoleic acid (CLA). The objective of the present study was to explore the effects of VA on immune function in a model of the metabolic syndrome, JCR:LA-cp rats. Lean (2:1 mix of +/cp and +/+) and obese (cp/cp) rats, aged 8 weeks, were fed a control (0% VA) or a VA diet (1.5% (w/w) VA) for 3 weeks (twenty rats per group). Splenocytes and mesenteric lymph node (MLN) immune cell phenotypes (flow cytometry), ex vivo cytokine production (ELISA) and phospholipid fatty acid concentrations were measured. Obese rats had higher proportions of splenic macrophages, total T-cells, helper T-cells (total and percentage CD25+), cytotoxic T-cells (total and percentage CD25+) and produced higher concentrations of IL-6 to concanavalin A (ConA) compared with lean rats. Obese rats had lower proportions of MLN T-cells, new T-cells (CD3+CD90+) and cytotoxic T-cells, but higher proportions of helper cells that were CD45RC+, CD25+ and CD4lo, and produced higher concentrations of IL-2, IL-10, interferon gamma and TNFalpha in response to ConA compared with lean rats. VA was higher in plasma phospholipids and both VA and CLA (cis-9, trans-11) were higher in MLN phospholipids compared with control-fed rats. Lean VA-fed rats had lower proportions of MLN and splenocyte CD45RC+ helper cells, and helper T-cells. Splenocytes from VA-fed rats produced 16-23% less IL-2, IL-10 and TNFalpha compared with controls. VA normalised production of MLN IL-2 and TNFalpha in obese rats to levels similar to those seen in lean rats. These results indicate that dietary VA favourably alters the pro-inflammatory tendency of mesenteric lymphocytes from JCR:LA-cp rats.

Orientia tsutsugamushiBacteremia and Cytokine Levels in Vietnamese Scrub Typhus Patients

Scrub typhus, caused by the intracellular bacterium Orientia tsutsugamushi, is a major cause of febrile illness in the Asia/Pacific region. Here, we implemented a novel real-time PCR and determined the relation of DNA target gene concentration with serum cytokine levels. The limit of detection of the novel real-time PCR was 1,062 DNA copies per ml of EDTA whole blood. Specificity was excellent as determined on a panel of blood- and skin-borne bacteria, including Rickettsia spp. as well as healthy Vietnamese blood donors. Bacterial DNA concentrations after 9 to 12 days from symptoms onset were significantly higher than in earlier or later periods (P<0.05). Significantly higher concentrations of gamma interferon (IFN-gamma) and interleukin-10 (IL-10) occurred during the acute phase of disease (<10 days from onset) as opposed to the convalescent phase (P<0.05). No significant differences were observed between the acute and the convalescent phases for tumor necrosis factor alpha (TNF-alpha) and IL-1beta concentrations. Regression analysis of DNA concentrations and cytokine levels identified a significant positive relationship for IL-10 (P<0.0182) but not for IFN-gamma, TNF-alpha, and IL-1beta. In conclusion, proinflammatory cytokines and IL-10 were differentially related to human bacteremia. They may thus be induced by different constituents of O. tsutsugamushi. As a future prospect in a clinical diagnostic laboratory, quantitative real-time PCR may serve as a reliable tool to monitor therapy and to detect treatment failure.

Effects of dietary uridine 5'-monophosphate on immune responses in newborn calves

When compared with normal milk, bovine colostrum contains a large amount of uridine 5'-monophosphate (UMP) and its derivatives. In the present study, we carried out 2 experiments to determine the effects of dietary UMP (2 g/d) on the immune status of newborn calves. In Exp. 1, newborn Holstein bull calves were fed milk replacer alone (control group) or milk replacer supplemented with UMP (UMP group) from d 4 to 10 after birth. The increase in interferon-gamma concentration by peripheral blood mononuclear cells (PBMC) on d 24 tended to be greater in the UMP group than in the control group (P = 0.06). The IgA concentration of the ileal mucosa was greater in the UMP group than in the control group (P < 0.05), although there was no difference between groups in the jejunal mucosa. In Exp. 2, newborn Holstein bull calves were fed milk replacer alone (control group) or milk replacer supplemented with UMP (UMP group) from d 4 to 56 after birth. The proliferation of PBMC was greater in the UMP group than in the control group on d 14, 28, and 42 (P < 0.01). The increase in interferon-gamma concentration by PBMC was greater in the UMP group than in the control group on d 28 and 42 (P < 0.05). From these results, we concluded that dietary UMP affected the immune responses of newborn calves.

Pretreatment with the Gram-positive bacterial cell wall molecule peptidoglycan improves bacterial clearance and decreases inflammation and mortality in mice challenged with Staphylococcus aureus

To determine whether tolerance and enhancement of innate immune function can be induced by the Gram-positive cell wall component peptidoglycan. Controlled, in vivo laboratory study. Male mice, 8-12 wks (C57BL6/J; C3H/HeJ; B6.129-Tlr2/J). Mice were given intraperitoneal injections of 1 mg peptidoglycan on two consecutive days. Mice were then challenged with an intravenous injection of live Staphylococcus aureus (1 x 10 colony-forming units) 2 days after the second pretreatment. Mice pretreated with peptidoglycan had diminished plasma concentrations of tumor necrosis factor-alpha and interferon-gamma in response to the bacterial challenge when compared with untreated controls. Plasma interleukin-10 after bacterial challenge was higher in peptidoglycan-pretreated mice than in controls. Clearance of bacteria after the staphylococcal challenge was improved in mice pretreated with peptidoglycan, and mortality in response to a subsequent Staphylococcus challenge was significantly attenuated. Peptidoglycan pretreatment of mice lacking intact toll-like receptor-4 signaling (C3H/HeJ) or toll-like receptor-2 signaling (toll-like receptor-2 knockouts) had similar effects on plasma cytokine balance, bacterial clearance, and mortality. Exposure to peptidoglycan significantly attenuated inflammation and enhanced bacterial clearance after a subsequent challenge with S. aureus. These results show that exposure to Gram-positive bacterial cell wall components can induce tolerance and enhance innate immune function and neither toll-like receptor-2 nor toll-like receptor-4 are necessary for this phenomenon. Further, although the altered cytokine balance is similar to that seen in septic patients, induced tolerance differs importantly from the clinical scenario of sepsis in that bacterial clearance and survival are improved compared with normal control animals.

The effects of CO2 on cytokine concentrations in endotoxin-stimulated human whole blood

Hypercapnia is known to modulate inflammation in lungs. However, the effect of hypocapnia and hypercapnia on blood cytokine production during sepsis is not well understood. We hypothesized that CO2 modulates ex vivo inflammatory cytokine production during endotoxin stimulation. To test this hypothesis, we measured the production of pro- and anti-inflammatory cytokines in endotoxin-stimulated human whole blood cultures under hypercapnic, normocapnic, and hypocapnic conditions. Prospective randomized study. Basic research laboratory. Ten male and 10 female volunteers. Venous blood samples, taken from volunteers were cultured at 37 degrees C, under hypocapnic (2% CO2), normocapnic (5% CO2), and hypercapnic (7% CO2) conditions, with and without endotoxin stimulation. After 24 hrs of incubation, each culture's supernatant was analyzed for tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-10, and interferon-gamma concentrations by enzyme-linked immunosorbent assay. Data were analyzed using nonparametric repeated measures of analysis of variance followed by Dunn's multiple comparisons test. Analysis of variance with Bonferroni correction was used to compare gender differences in cytokine concentrations. The Pearson test was used to estimate correlation between hydrogen ion and individual cytokine concentrations. Concentrations of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta and of the anti-inflammatory cytokine interleukin-10 under hypercapnic condition were significantly decreased (p < 0.05, 0.01, and 0.001, respectively) for both genders when compared with either normocapnic or hypocapnic conditions. Concentrations of tumor necrosis factor-alpha and interleukin-1beta were significantly higher in men. In women, concentrations of interleukin-6 were significantly decreased under hypercapnic condition when compared with hypocapnic condition. An inverse relationship was found between hydrogen ion concentration and concentrations of tumor necrosis factor-alpha and interleukin-10. Our results are consistent with the hypothesis that CO2 can affect the production of pro- and anti-inflammatory cytokines after ex vivo stimulation with endotoxin.

Human defensins and cytokines in vaginal lavage fluid of women with bacterial vaginosis

Objective To measure the concentrations of interferon gamma (IFN-γ), interleukin (IL)-2, IL-4, IL-5, human β-defensin 2 (HBD-2), and human defensin 5 (HD-5) in the vaginal lavage fluid (VLF) of healthy women and women with bacterial vaginosis (BV). Methods VLF samples were obtained from 73 women with BV, 15 women with intermediate vaginal flora, 33 healthy women with vaginal pH greater than or equal to 4.5, and a control group of 39 healthy women with vaginal pH less than 4.5. The concentrations of IFN-γ, IL-2, IL-4, IL-5, HBD-2, and HD-5 were measured using enzyme-linked immunosorbent assay kits. Results Concentrations of HBD-2 and HD-5 in the VLF of women with BV were significantly higher than in the control group ( P < 0.05). IL-4 concentration was significantly lower in the VLF of women with BV than in the control group ( P < 0.05). Conclusions HBD-2 and HD-5 may be involved in defending against invasion by BV-related microorganisms and the decrease in IL-4 concentration may increase susceptibility to BV.

Mycobacteria-induced autoantibody production is associated with susceptibility to infection but not with host propensity to develop autoimmune disease.

Mycobacteria cause increase in autoantibody production in the host during the first weeks of infection. The level of the autoantibody enhancement varies widely in different hosts, suggesting that it depends on features of the host make-up. We have investigated the participation of two characteristics of the host in the modulation of mycobacteria-induced autoantibody production: (i) the host being genetically determined to later develop spontaneous autoimmune disease; (ii) the host being susceptible/resistant to mycobacterial infection. Mycobacterium avium infection was studied in 3-month-old mice that are prone (NZB and C57B1/6-lpr/lpr strains) or not (NZW and C.D2 strains) to develop, when older, autoimmune disease; these murine strains are either naturally susceptible (C57B1/6-lpr/lpr and NZW) or resistant (NZB and C.D2) to mycobacteria. Mycobacterium avium infection was produced by i.p. injection of 3 x 10(7) viable bacilli. At days 15 and 30 of the infection, we determined the following parameters: (i) number of cells producing natural autoantibodies (splenic cells showing surface antibodies against bromelain-treated mouse (BrM) erythrocytes); (ii) suppression of the primary response to T cell-dependent antigen (i.e. to sheep erythrocytes); (iii) immunoglobulin classes and IgG isotypes; (iv) titres of anti-dsDNA antibodies; and (v) serum concentrations of interferon-gamma (IFN-gamma). We found that the highest elevations in natural autoantibodies were associated with hosts being naturally susceptible to mycobacteria, but not with the host being genetically determined to later develop autoimmune disease. The rise in autoantibodies was predominantly of the IgM type, being associated with suppression of the T cell response and accompanied by increase in serum IFN-gamma. Mycobacteria failed to induce any significant enhancement in pathogenic anti-dsDNA antibodies. Our data suggest that the finding of a high level of autoantibodies during the early phase of mycobacterial infection reflects host susceptibility of the infectious agent, and that it is not related with its propensity to later develop autoimmune disorders.

Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A4 to promote the resolution of allergic airway inflammation

Interleukin 23 (IL-23) is integral to the pathogenesis of chronic inflammation. The resolution of acute inflammation is an active process mediated by specific signals and mediators such as resolvin E1 (RvE1). Here we provide evidence that RvE1, in nanogram quantities, promoted the resolution of inflammatory airway responses in part by directly suppressing the production of IL-23 and IL-6 in the lung. Also contributing to the pro-resolution effects of RvE1 treatment were higher concentrations of interferon-gamma in the lungs of RvE1-treated mice. Our findings indicate a pivotal function for IL-23 and IL-6, which promote the survival and differentiation of IL-17-producing T helper cells, in maintaining inflammation and also identify an RvE1-initiated resolution program for allergic airway responses.

Clinical and Virological Characteristics of 15 Patients with Chronic Active Epstein‐Barr Virus Infection Treated with Hematopoietic Stem Cell Transplantation

Chronic active Epstein-Barr virus (EBV) infection is characterized by recurrent infectious mononucleosis-like symptoms, and infected patients have high viral loads in their peripheral blood. Standard therapy for the disease has not yet been established. Recently, hematopoietic stem cell transplantation (HSCT) has been introduced and has the potential to become a standard treatment, although guidelines for HSCT to treat chronic active EBV infection have not yet been proposed. Fifteen patients were retrospectively analyzed, both clinically and virologically, to investigate the factors associated with prognosis of chronic active EBV infection treated with HSCT. After HSCT, 7 patients died after survival periods that ranged from 1 to 16 months (mean duration of survival after HSCT, 5 months). Three patients were considered to have died of transplantation-related complications. The duration between infection onset and diagnosis was significantly longer in patients who died than in those who survived. Five of the 7 patients who died experienced > or =3 life-threatening complications. The plasma concentrations of interferon-gamma, interleukin-10, thrombomodulin, and soluble E-selectin did not differ significantly between the groups of patients. With regard to sequence variations in the EBV latent membrane protein 1 gene, no specific patterns were found in the patients who died. Importantly, the plasma EBV load at diagnosis was significantly higher in patients who died than in living patients. Moreover, plasma viral load was shown to be an important factor to monitor during follow-up for patients after HSCT. The number of life-threatening complications and plasma viral load are indicative of the stage of disease progression and may be useful factors for predicting the outcome of HSCT.

Inhibition of Interleukin-12 Production by Trypanosoma brucei in Rat Macrophages

The immune response of a host infected with Trypanosoma brucei is modulated by trypomastigotes. We examined the changes in cytokine production in T. brucei gambiense (Wellcome strain; WS) infected rats and the influence on production of interleukin (IL)-12 by macrophages. The blood concentration of interferon-gamma, tumor necrosis factor-alpha, and IL-10 increased beginning the second day after infection. However, an increase in IL-12p40 was not observed until 4 days after infection. When spleen macrophages and Kupffer cells harvested from uninfected rats and HS-P cells (a rat macrophagelike cell line) were cocultured with WS, IL-12p40 production did not change. When HS-P cells were cultured with WS, transport of nuclear factor-kappaB into the nucleus increased. Levels of macrophage colony-stimulating factor (M-CSF) and granulocyte macrophage colony-stimulating factor mRNA in the spleens and livers of WS-infected rats were high in comparison with uninfected rats, suggesting that the WS promotes macrophage proliferation. The level of IL-12p40 mRNA in HS-P cells cocultured with WS increased in response to transfection with a small interfering RNA against M-CSF or addition of anti-M-CSF antibody. These results suggest that the WS inhibits IL-12p40 mRNA production by promoting production of macrophage colony-stimulating factor by macrophages.