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Pukhalsky A.,Research Center for Medical Genetics | Shmarina G.,Research Center for Medical Genetics | Alioshkin V.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology
OMICS A Journal of Integrative Biology | Year: 2012

Surplus accumulation of regulatory T cells (Tregs) is known to be at the bottom of many morbid conditions, among them being neuropsychiatric diseases. In particular, Tregs may inhibit Th1 cells, including brain autoimmune lymphocytes, controlling the local microglial response and brain tissue homeostasis. The present study was undertaken in an attempt to suggest a novel approach for the treatment of maladaptation to mental stress associated with excessive Treg accumulation. Recently it was shown that alkylating drugs (ADs), such as melphalan and cyclophosphamide (Cy) in the dose 100-fold lower than cytostatic one are capable to disturb signal transduction by IL-2R. In this study we demonstrated that IL-2R is not a unique receptor, which may be blocked with ADs. Similar effect has been shown for two other surface receptors: TNFR and Fas. Molecular mechanisms of the receptor blockage were investigated on the model of TNF signaling. Study of NF-κB activity in nuclear extracts showed that alkylating agents act at the level of surface receptor or of the receptor platform. It was also shown that ADs administration in ultralow doses results in selective elimination of Tregs. In this study we used a new laboratory model of Treg accumulation in mice. Such Treg accumulation was associated with cognitive and behavioral abnormalities, which may be prevented by Cy administration. © Copyright 2012, Mary Ann Liebert, Inc. Source

Pukhalsky A.L.,Research Center for Medical Genetics | Shmarina G.V.,Research Center for Medical Genetics | Alioshkin V.A.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology
Vestnik Rossiiskoi Akademii Meditsinskikh Nauk | Year: 2011

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 selftol-erance. 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. Source

Toptygina A.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology | Alioshkin V.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology
Archives of Physiology and Biochemistry | Year: 2012

60 children aged 1-2 years old (32 boys and 28 girls) were vaccinated with Priorix. Vaccinated children included healthy control (19 children, group 1), and children with immunological disturbances such as episodes of respiratory infection. From the latter group, 20 children did not receive (group 2), and 21 children received 0.15 mg/kg of Polyoxidonium simultaneously with the vaccine (group 3).On days 7 and 30 after vaccination, CD-markers on lymphocytes and concentration of specific antibodies, as well as levels of 11 cytokines in serum were evaluated by flow cytometry, ELISA, and multiplex techniques respectively. It was found that injection of Polyoxidonium skewed T helper differentiation to Th2 type. Antibody responses were significantly higher in children with preferable Th2 responses. Children from group 3 possessed higher titers of specific IgG-antibodies. Our study shows that Polyoxidonium could smooth out the immune reaction on vaccination. It is important for children with some immunological disturbances. © 2012 Informa UK, Ltd. Source

Pukhalsky A.L.,Research Center for Medical Genetics | Shmarina G.V.,Research Center for Medical Genetics | Kapustin I.V.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology | Stukalov S.V.,Research Center for Medical Genetics | And 2 more authors.
Cell and Tissue Biology | Year: 2011

The relationship between the levels of 70 kDa family heat shock protein (Hsp) synthesis and lymphocyte sensitivity to stressors was investigated. Lymphocyte cultivation in mitogen deprived culture medium and/or the cell treatment with alkylating agents have been used as a stress challenge. Model experiments with two inbred murine strains genetically contrasting by the sensitivity to alkylating agents demonstrated that the basic level of Hsp synthesis depends on genotype. The quantity Hsp70 mRNA, as well as intracellular level of the proteins, in BALB/c was significantly higher than those in C57BL/6 mice. The mice, which were characterized by higher Hsp levels, demonstrated higher resistance to alkylating agent action. The induction of surplus amount of Hsp by heat shock increased the cell resistance to an alkylating agent melphalan. Lymphocyte isolated from high Hsp producers BALB/c mice were more resistant to apoptotic signals induced by mitogen deprivation. © 2011 Pleiades Publishing, Ltd. Source

Pukhalsky A.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology | Shmarina G.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology | Alioshkin V.,Gn Gabrichevsky Institute Of Epidemiology And Microbiology
Advances in Neuroimmune Biology | Year: 2012

The brain and immune system being the two 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, which is separated from the rest of the body by blood-brain-barrier (BBB), produces the cytokines by itself and the latter along with other neurotransmitters regulate various brain functions including cognition, memory, and neuronal differentiation. 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. Long-term stress as well as physiological aging result in hormonal disturbance, first of all in the form of HPA axis depletion and dehydroepiandrosterone (DHEA) decrease. Thus, the changes observed in stressed subject form a picture typical of the aging brain. The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. Clinical and experimental studies confirm efficiency of such choice although in some instances we can say only about indirect evidences. © 2012-IOS Press and the authors. All rights reserved. Source

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