[Immune dysfunction and cognitive deficit in stress and physiological aging. Part II: New approaches to cognitive disorder prevention and treatment ].

Long-term stress as well as physiological aging result in similar immunological and hormonal disturbances including hypothalamic-pituitary-adrenal) axis depletion, aberrant immune response (regulatory T-cells, Tregs, and T(h17)-lymphocyte accumulation) and decreased dehydroepian-drosterone synthesis both in the brain and in the adrenal glands. Since the main mechanisms of inflammation control, "prompt" (stress hormones) and "delayed" (Tregs), are broken, serum cytokine levels increase and become sufficient for blood-brain-barrier disruption. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Structural and functional alterations of blood-brain-barrier as well as stress- (or age-) induced neuroinflammation promote influx of bone marrow derived dendritic cells and lymphocyte effectors into the brain parenchyma. Thereafter, mass intrusion ofpro-inflammatory mediators and immune cells having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets: 1) reduction of excessive Treg accumulation; 2) supporting hypothalamic-pituitary-adrenal axis and inflammatory reaction attenuation; 3) recovery of dehydroepiandrosterone level; 4) improvement of blood-brain-barrier function.

[Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors].

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.

[Regulatory T-cells: modern approaches to optimization of their numbers].

Regulatory T-cells (Tregs) are important components of the complex adaptive system of the body responsive to environmental challenges. Tregs ensure peripheral tolerance and play an important role in control of inflammatory reactions. Several subsets of Tregs have been described. Naturally occurring CD4+CD25+ Tregs are recognized as a major subset of immune cells responsible for peripheral immune self-tolerance. Another subtype of Tregs is inducible. Such Tregs are generated in the periphery and realize their suppressive potential largely in the form of anti-inflammatory activity. The latter plays an important role in cooperation of three principal anti-inflammatory mechanisms that developed in the course of evolution: macrophages possessed of suppressive activity, Tregs, and stress hormones. Normally, all the three mechanisms of inflammation control are in equilibrium. However, the balance may be disturbed with ageing due to repeated episodes of stress and HPA axis activation. As a result, secretion of stress hormones coupled to antigen overload leads to Treg accumulation. In the course of time activation of the HPA axis is replaced by its inhibition manifested both as a decrease of the baseline cortisol level and a reduction of stress-induced cortisol response. Cortisol present in blood at low concentrations is no longer capable of controlling inflammation and Tregs become a principal mechanism of anti-inflammatory machinery. Superfluous Treg accumulation results in the development of functional somatic syndromes, such as chronic fatigue syndrome, and (in some patients) in the growth of tumours resulting from the suppression of anticancer immunity. On the other hand, the lack of adequate antigen loading in the childhood may delay Treg maturation. Allergy and asthma manifestations may be a consequence of such Treg insufficiency. Thus, both excess and deficiency of Tregs may be at the bottom of morbid conditions. The advances in modern pharmacology open up opportunities for developing new methods to control the Treg level.

[Effect of steroid therapy on the clinical course of bronchial asthma].

Although only some 5% of the asthmatic population develop severe disease, such cases eat up more than half of the spendings for the management of asthma and they are poorly controlled by the currently available therapies. Most of these patients undergo long-term treatment with various steroid formulations that exert selective action in the airways eliminating one cell type and supporting the growth of another. For this reason, inflammation patterns in severe, as opposed to mild, asthma resemble those in COPD, with a high neutrophil count in the sputum, increased oxidative stress, and poor response to corticosteroids. Such differences in asthma pathogenesis may be due to the accumulation of two CD4+ cell subsets (regulatory T cells and Th17 cells) in the lungs. It is believed that the use of alkylating drugs in low (non-cytotoxic) doses selectively inactivating Tregs and Th17 cells is a promising method for the treatment of severe asthma.

[Inflammatory reactions in patients suffering from coronary artery disease with concomitant obesity and type 2 diabetes mellitus].

Of late, inflammatory reactions have been considered to play an important part in the development of atherosclerosis. Acute-phase inflammatory reaction, being initially a protective response directed within the homeostasis system towards lesion repair, may by itself due to various factors favor the development of pathological processes. Considering the role played by inflammation in the development of atherosclerosis, and inflammatory activity in obesity and diabetes mellitus (DM), a range of common and interrelated elements of these processes may be marked out. These are acute phase proteins and cytokines. Insulinoresistance, being the common precursor of obesity and DM, plays the key role in vascular lesion. The use of cytokine activity index seems to be a promising method of revealing patients with high risk of atherosclerosis.

[Dynamics of markers of blood inflammation against the background of antibacterial therapy in children with mucoviscidosis, with the various regimens of intake of pancreatic enzymes]. / Dinamika markerov vospaleniia krovi na fone antibakterial'noi terapii u detei, bol'nykh mukovistsidozom, s razlichnym rezhimom priema pankreaticheskikh fermentov.

The results of the studies show that patients with mucoviscidosis diagnosed for the first time who do not receive any adequate replacement pancreatic therapy should not be prescribed high doses of pancreatic enzymes along with antibacterial therapy when they are hospitalized on account of exacerbation of the bronchopulmonary process. Sharply increased lipid absorption can cause an aggravation of oxidative stress and impair the patient's state instead of improving it. In our opinion, such patients should be prescribed delayed adequate pancreatic therapy with immediate introduction of high doses of antioxidants (vitamins E, A, C, beta-carotene, etc.). There is no doubt that it is necessary to conduct further research into the problem for a greater number of patients.

Spectrum of anti-measles immunoglobulin G subclasses in convalescents after measles.

A simple semiquantitative method for measuring anti-measles IgG subclasses is developed on the basis of commercial diagnostic test system for measurements of anti-measles IgG and a kit of peroxidase-labeled monoclonal antibodies to human IgG subclasses. During the acute phase of the disease specific antibodies are presented mainly by IgG2 antibodies, while in subjects with a history of measles more than 10 years before 2 subgroups were detected, which responded by production of IgG2 or IgG1 subclasses.

alpha1-acid glycoprotein possesses in vitro pro- and antiinflammatory activities.

We studied the effects of alpha1-acid glycoprotein on tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) production and lymphocyte response to phytohemagglutinin in cultured peripheral blood mononuclear leukocytes from 6 healthy donors. We observed 2 opposite responses to alpha1-acid glycoprotein: first, stimulation of TNF-alpha and IL-10 production and inhibition of lymphocyte proliferation, and second, suppression of cytokine production and stimulation of lymphocyte proliferation. In cell cultures isolated from 4 of 6 donors, the TNF-alpha/IL-10 ratio remained unchanged after addition of native alpha1-acid glycoprotein, but some fractions isolated by chromatography on concanavalin A-Sepharose changed this parameter. These changes were most pronounced after treatment with fraction C enriched with molecules with incomplete (biantennary) carbohydrate chains. The mechanisms of alpha1-acid glycoprotein-induced effects on peripheral blood mononuclear leukocytes are discussed.

Effect of semisynthetic analog of alpha(1)-acid glycoprotein on immunomodulatory and antiinflammatory activity of natural glycoprotein.

Pseudo-alpha(1)-acid glycoprotein with carbohydrate chain ratio typical of native form was synthesized by a previously developed original technique of quantitative transfer of alpha(1)-acid glycoprotein carbohydrate chains to other polymeric carrier. Similarly to native glycoprotein, the semisynthetic analog inhibited lymphocyte proliferation and stimulated the production of antiinflammatory cytokines by peripheral blood mononuclear leukocytes. However, it possessed no antioxidant activity and did not inhibit complement activation by the alternative pathway. The role of carbohydrate and protein components of alpha(1)-acid glycoprotein molecule in the realization of its biological effects is discussed.

[Immunologic monitoring of patients with cystic fibrosis: value of different laboratory findings]. / Immunologicheskii monitoring bol'nykh mukovistsidozom, znachenie razlichnykh laboratornykh pokazatelei.

Cystic fibrosis (CF) is a common, serious, and frequently fatal autosomal recessive genetic disorder associated with the poor function of chloride channels. Chronic endobronchial inflammation and bacterial infection are main causes of morbidity and mortality due to CF. The study dealt with a relationship between progression and inflammation markers. Twenty one CF children with acute pulmonary exacerbation were examined. The signs of peripheral blood inflammation (responses of lymphocytes to PHA and their sensitivity to the antiproliferative effect of glucocorticoids) and in situ inflammation markers (sputum elastase activity, IL-8 and TNF-alpha, and protein concentrations in the same sputum specimens). These laboratory findings were used to calculate a "laboratory index" (LI). The clinical status of each patient was evaluated with a "clinical index" (CI), a parameter that includes respiratory secretion cultures, pulmonary function test results, nutritional status, and the presence of disease-related complications. There was a positive linear correlation between LI and CI. The presence of P. aeruginosa was strongly associated with the changes of inflammatory markers. CF patients with prolonged P. aeruginosa infection demonstrated extremely enhanced elastase activity and elevated amounts of sputum IL-8 and TNF-alpha as compared to uninfected subjects. The lung elastase activities, sputum protein contents, and TNF-alpha levels in individuals with short-term colonization were at or below those without P. aeruginosa infection. In patients with or without short-term colonization, the normalization of laboratory parameters was strongly related to evident clinical improvement. At the same time, antibiotic treatment failed to suppress an excessive inflammatory response in the lungs of patients with prolonged P. aeruginosa infection. The importance of individual inflammation markers is discussed in the paper.

[The interaction of peripheral blood leukocytes with alpha1-acid glycoprotein, its carbohydrate chains and neoglycoconjugates]. / Vzaimodeistvie leikotsitov perifericheskoi krovi s alpha1-kislym glikoproteinom, ego uglevodnymi tseliami i neoglikokon"iugatami.

The interaction of human peripheral blood leukocytes with alpha 1-acid glycoprotein (AGP), its glycoforms as well as neoglyco-conjugates representing carbohydrate chains of AGP or its fragments was studied by flow cytometry. It was shown that the main target cells for AGP as well as for conjugates of its carbohydrate chains with polyacrylamide (PAA) are monocytes and polymorphonuclear leukocytes but not lymphocytes. The interaction of AGP with monocytes and granulocytes are mediated by its carbohydrate chains: the binding of AGP with cells was inhibited by AGP, AGP oligosaccharides as well as conjugates of oligosaccharides and its fragments with PAA. The data obtained show the existence of monocyte (and granulocyte) receptors which interact with complex type sialooligosaccharides of AGP.

[Conjugates and carbohydrate chains of alpha 1-acid glycoprotein with polyacrylamide maintain the immunomodulating activity of native glycoprotein]. / Kon''iugaty uglevodnykh tsepei alpha1-kislogo glikoproteina s poliakrilamidom sokhraniuiut immunomoduliruiushchuiu aktivnost' prirodnogo glikoproteina.

Translocation of carbohydrate glycoprotein N-chains onto soluble polyacrylamide was proposed as a method for studying the biological role of carbohydrate chains. N-linked carbohydrate chains of alpha 1-acid glycoprotein (AGP) were aminated at the reducing GlcNAc moiety and covalently attached to polyacrylamide (PAA). Thus "pseudo-AGP" was obtained where peptide core was replaced with PAA. The synthetic model mimics AGP by M(r) and carbohydrate content as well as the ratio of tetra-, tri- and diantennary and mono-, di-, tri- and tetrasialo chains. It was shown that the conjugate inhibits proliferation of lymphocytes like the parent AGP. Therefore, the property of AGP to inhibit the lymphocyte proliferation is attributed to its carbohydrate chains, whereas peptide core serves as carrier providing polyvalent interaction of multiple carbohydrate chains with cell.

[The effect of low doses of dexamethasone on interleukin-2 production by human peripheral blood lymphocytes]. / Vliianie nizkikh doz deksametazona na produktsiiu interleikina-2 limfotsitami perifericheskoi krovi cheloveka.

Dose-dependent modifying of mitogen-induced interleukin-2 (IL-2) release by human peripheral blood lymphocytes (PBL) treated with dexamethasone (Dx) was demonstrated. In four independent experiments with PBL of 10 human subjects the effect of Dx administration on IL-2 release in serum-free culture medium could vary from appreciable enhancing to complete suppression. The enhancing effect was observed distinctly with PBL of 7 individuals. A transition from stimulation to suppression of IL-2 production by Dx was essentially observed in the dose range of 10(-9) to 10(-8) M. Thus the glucocorticoid hormones can both increase and decrease the production of L-2 which occupies a central position in the cascade of events involved in the immune response. Mechanisms of IL-2 release modification by Dx are discussed.

[Comparative study of mechanisms of antiproliferative action of low concentrations of mafosfamide and cyclosporin A]. / Sravnitel'noe izuchenie mekhanizmov antiproliferativnogo deistviia nizkikh kontsentratsii mafosfamida i tsiklosporina a.

Exact mechanisms of Mf and CsA effect have been investigated in BALB/c, DBA/2, CC57BR, and C57BL/6 mice. Different sensitivity of spleen cells of mice of different strains to Mf and CsA antiproliferative effect has been demonstrated. These interstrain variations have not been related with an inhibition of interleukin-2 (IL-2) release but, perhaps depended on the IL-2 receptor (IL-2R) expression differences. The p75 chain of IL-2R as a possible target for Mf, has been discussed.

[Antiprolifirative effect of chlorbutin and sensitivity of patients with glomerulonephritis to this drug]. / Antiproliferativnoe deistvie khlorbutina i chuvstvitel'nost' bol'nykh glomerulonefritom k terapii etim preparatom.

Children suffering from different forms of glomerulonephritis were examined for the sensitivity of peripheral blood lymphocytes to the antiproliferative action of chlorambucil in vitro. All the patients were given chlorambucil treatment in accordance with a 4-component scheme. As a result, in 15 patients (group I), a complete clinicolaboratory remission was attained. In 8 patients, (group II), the treatment results were estimated as a partial remission and in 8 patients (group III), the treatment turned out ineffective. In 14 patients of group I, the sensitivity of peripheral blood lymphocytes to the antiproliferative action of chlorambucil was viewed as high whereas in 7 patients of group III as low. Peripheral blood lymphocytes from group II patients had a low sensitivity to chlorambucil. The prognostic value of the laboratory test suggested is under discussion.

[Sensitivity of human lymphocytes to antiproliferative effects of glucocorticoids and effectiveness of reception]. / Chuvstvitel'nost' limfotsitov cheloveka k antiproliferativnomu deistviiu gliukokortikoidov i éffektivnost' retseptsii.

The relation between the type of lymphocyte dexamethasone sensitivity in vitro of 9 healthy donors and their corticosteroid receptor characteristics was tested. It was found that in the high sensitivity group the effectiveness of corticosteroid reception (ratio of quantity of glucocorticoid receptors and constant of dissociation (Bm/Kd) was significantly higher than in the group of low sensitivity. Thus, genetically related parameters of binding of glucocorticoid hormones to its receptors play a great role in lymphocyte glucocorticoid sensitivity of inhibition of mitogen stimulation.