HPA axis exhaustion and regulatory T cell accumulation in patients with a functional somatic syndrome: recent view on the problem of Gulf War veterans.

The authors proceeded from the assumption that physical and mental symptoms of functional somatic syndromes (including those observed in Gulf War veterans) are based on both underactivity of hypothalamic-pituitary-adrenal (HPA) axis and excessive accumulation of regulatory T cells (Tregs). Permanent psychogenic stress coupled with high antigen loading leads to gradual depletion of HPA axis, which is manifested by the reduction of stress-induced cortisol response. Under stress hormone deficiency, Tregs begin to play a principal role in anti-inflammatory mechanisms and each new pro-inflammatory stimulus increases their number. Superfluous accumulation of active Tregs results in malfunction of Th1 cells in the brain that leads to the appearance of neurodegeneration foci, which seems to be an anatomic substance for various cognitive and psychological symptoms. New approaches to the treatment of such conditions are also discussed.

Preventive and therapeutic effects of alpha-acid glycoprotein in mice infected with B. anthracis.

We studied the effects of alpha1-acid glycoprotein preparations on the survival rate of BALB/c mice infected with the lethal dose of B. anthracis STI-1. Apart from native alpha1-acid glycoprotein from donor blood, we studied 3 glycoforms differing in the affinity for concanavalin A and structure of carbohydrate chains. The protective effect of alpha1-acid glycoprotein preparations did not depend on its dose and was observed 3 months after treatment (0.3 mg per mouse). The protective effect was revealed in mice receiving alpha1-acid glycoprotein preparations 2 h before infection and 24 h after inoculation of the bacterial culture. In the latter case the survival rate of animals was much higher compared to that observed in preventive administration of alpha1-acid glycoprotein. The protective effect practically did not depend on the time of treatment with glycoforms. Pretreatment with alpha1-acid glycoprotein preparations significantly decreased plasma interferon-gamma concentration. Administration of the test preparations 24 h after infection decreased the concentration of tumor necrosis factor-alpha.

Tumor necrosis factor-alpha/interleukin-10 balance in normal and cystic fibrosis children.

BACKGROUND: The balance between tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) is important for immune homeostasis maintenance. Exuberant production of TNF-alpha contributes to overwhelming inflammatory response and tissue damage. But, commonly, increase in TNF-alpha is counterbalanced by simultaneous synthesis of an anti-inflammatory cytokine IL-10, which suppresses production of many activating and regulatory mediators. AIMS: In the present study, the relationships between TNF-alpha and IL-10 in the plasma of healthy school-children and cystic fibrosis (CF) patients have been investigated. METHODS: Blood samples were obtained from 12 CF patients with chronic pulmonary disease and 18 healthy schoolchildren vaccinated with live attenuated rubella vaccine. IL-10 and TNF-alpha were determined in the plasma samples using commercially available enzyme-linked immunosorbent assay kits. RESULTS: Before vaccination, most healthy children (13 of 18) demonstrated superiority of pro-inflammatory TNF-alpha over anti-inflammatory IL-10 (TNF-alpha/IL-10 > 1). In these subjects, a significant positive linear association between the cytokine values has been found. Vaccine challenge resulted in a marked reduction of TNF-alpha/IL-10 ratios. In addition, a disappearance of correlation between the cytokine values was observed. Such disturbance was related to exuberant elevation of the IL-10 levels after inoculation. On the contrary, in CF individuals, plasma cytokine values remained in strong linear association independently of TNF-alpha or IL-10 predominance. No spikes in the plasma levels of IL-10 in CF patients during a 6-month observation period have been revealed. CONCLUSIONS: There were no fundamental differences between CF and healthy children in the regulation of TNF-alpha and IL-10 secretion. Thus, immune quiescence seemed to be associated with the predominance of TNF-alpha, whereas immune disturbance was characterized by IL-10 superiority. The only abnormality that was found in CF patients consisted of their inability to produce unlimitedly IL-10 in response to antigen stimuli.

Improvement of nutrient absorption may enhance systemic oxidative stress in cystic fibrosis patients.

BACKGROUND: The life expectancy of patients with cystic fibrosis (CF) is largely dependent on the pulmonary disease severity and progress. Malnutrition may be an important complicating factor in active and chronic lung disease. AIMS: The focus of this study was to investigate several inflammatory markers in pancreatic-insufficient CF patients with different enzyme treatment regimens. METHODS: CF patients with pancreatic insufficiency were examined at a time of symptomatic exacerbation of their lung disease. Group A (n = 11) regularly received microspheric enzymes. Group B (n = 8) were treated with enzymes during the hospitalization period only and demonstrated the presence of malnutrition. Inflammatory markers in the sputa (neutrophil elastase activity, interleukin-8 and tumour necrosis factor-alpha levels) and in the peripheral blood (plasma malondialdehyde (MDA), lymphocyte response to PHA, and the cell sensitivity to steroid suppression) have been investigated. RESULTS: During acute lung exacerbation, group B demonstrated reduced levels of lymphocyte proliferation. This parameter was normalized after combined antibiotic and pancreatic enzyme therapy. Simultaneously, plasma MDA in group B markedly increased following treatment. For this group, a significant positive linear association between values of plasma MDA and lymphocyte proliferation has been observed. For group A, neither the same correlation nor changes in MDA levels and lymphocyte proliferation have been found. CONCLUSIONS: Our data indicate that acute lung exacerbation in malnourished CF patients may be associated with alteration in T-lymphocyte activity. Adequate therapy normalizes lymphocyte function but results in systemic oxidative stress.

Stimulatory and protective effects of alkylating agents applied in ultra-low concentrations.

Alkylating drugs belonging to the nitrogen mustard family are known as cytostatic and immunosuppressive agents. Ultra-low doses of these drugs may demonstrate pharmacological effects unlike this category of drugs. In the case of a gradual dose decrease, the number of targets for alkylation is also reduced and the drug switches from cytostatic to cell growth modifier. We postulate that application of ultra-low doses of alkylating drugs may result in a beneficial effect in the therapy of diseases associated with chronic inflammation of the mucosa, especially with the signs of epithelial atrophy.

Inflammatory markers in cystic fibrosis patients with lung Pseudomonas aeruginosa infection.

Chronic endobronchial inflammation and bacterial infection are the main causes of morbidity and mortality in cystic fibrosis (CF), an autosomal recessive genetic disorder associated with improper function of chloride channels. Inflammation in CF lung is greatly amplified after Pseudomonas aeruginosa infection. In this study the relationship between P. aeruginosa status and inflammatory markers has been investigated. Seventeen CF children in acute lung exacerbation were examined. CF patients without P. aeruginosa infection were characterized by elevated activity of sputum elastase, reduced response of peripheral blood lymphocytes to PHA and significant resistance to the antiproliferative action of glucocorticoids. These parameters were normalized after antibiotic treatment. The patients with prolonged P. aeruginosa infection demonstrated extremely high levels of elastase activity and elevated amounts of sputum IL-8 and TNF-alpha. Although antibiotic treatment resulted in clinical improvement, it failed to suppress excessive immune response in the lung. The data indicate that CF patients with prolonged P. aeruginosa need the modified treatment, which should include immunomodulating drugs and protease inhibitors as well as antibacterial therapy.

Immunomodulating activities of a natural alpha1-acid glycoprotein and its carbohydrate chains attached to the protein-free polymer.

Immunomodulating effects of a neoglycoconjugate created on the basis of alpha1-acid glycoprotein (AGP) carbohydrate chains and synthetic protein-free carrier have been investigated. It was demonstrated that this pseudo-AGP suppressed PHA- or anti-CD3 antibody-induced lymphocyte proliferation in a dose-dependent manner. Pseudo-AGP revealed a similar antiproliferative effect as the natural AGP samples. Stimulation of the LPS-induced proinflammatory cytokine production by mononuclear cells treated with both natural and pseudo-AGP has been also demonstrated. These data show that carbohydrate chains of AGP play a crucial role in the studied biological effect realization.

Changes in TNF and IL-6 production after diphtheria toxoid vaccination: drug modulation of the cytokine levels.

The effect of vaccination with diphtheria toxoid (AD-M) on TNF and IL-6 production has been studied in humans. In the present study it was demonstrated that immunization with AD-M resulted in changes of in vitro TNF and IL-6 production by peripheral blood mononuclear cells. TNF release was suppressed but IL-6 production was stimulated. On the other hand, serum levels of TNF were markedly increased over a period of 3 weeks. It was also demonstrated that the postvaccinal cytokine production disturbances may be corrected by pretreatment with a new synthetic hexapeptid (Imunofan((R))). It is possible that the imunofan treatment could prevent some postvaccinal complications.

Immunosuppressive action of cyclophosphamide in mice: contribution of some factors to determination of strain differences.

Mechanisms of strain differences in susceptibility to cyclophosphamide (CP) has been investigated with BALB/c, DBA/2, CC57BR, and C57BL/6 mice. It was shown that the final immunosuppressive effects of CP is a result of a combination of such factors as the level of CP alkylating metabolites in the bloodstream and the sensitivity of the target cells to antiproliferative action of these metabolites. The importance of the immune status peculiarities has been discussed.

Inhibition of phytohemagglutinin-induced lymphocyte proliferation by dexamethasone: mechanisms of individual susceptibility.

Direct positive correlation has been shown between the level of stimulation of peripheral blood lymphocytes and of the inhibition degree of PHA stimulation by dexamethasone. On the basis of this correlation we subdivided all the examined individuals into three groups of susceptibility: resistant, sensitive, and intermediate. The studies carried out in these groups showed that the reception effectiveness of glucocorticoids (GC) was much higher in the sensitive group than in the group of resistant individuals. In this group interleukin 2 (IL-2) production was relatively high; in the intermediate group this parameter was lower, and in the group of sensitive individuals the mean indices of IL-2 production were the lowest. However, this latter group unlike the two others was heterogeneous and may be divided into two subgroups: high and low IL-2 producers. HLA antigens B7 and DR2 were also shown to be associated with a decrease in sensitivity to GC inhibition of PHA-induced lymphocyte proliferation. Our results indicate that the method we used is adequate enough for dividing individuals into sensitivity groups.

Pharmacokinetics of alkylating metabolites of cyclophosphamide in different strains of mice.

Determination of the amount of alkylating (NBP) metabolites of cyclophosphamide (CP) in blood serum of BALB/c and DBA/2 mice has revealed that the shape of the curve describing the accumulation of NBP-metabolites, depends on the administered drug dose and animals' genotype. The experimental data obtained made it possible to suggest an improved pharmacokinetic model which takes into account a possible switching in of factors conditioning non-linear changes in the intensity of the accumulation processes in blood and elimination of CP alkylating metabolites from blood. The effect of different CP alkylating metabolite kinetics in BALB/c and DBA/2 mice on a different sensitivity of these mice to the immunodepressive action of CP in vivo, has been discussed.