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Maghazachi A.A.,Institute of Basic Medical science
Current Topics in Microbiology and Immunology | Year: 2010

Natural killer (NK) cells represent a major subpopulation of lymphocytes. These cells have effector functions as they recognize and kill transformed cells as well as microbially infected cells. In addition, alloreactive NK cells have been successfully used to treat patients with acute myeloid leukemia and other hematological malignancies. NK cells are also endowed with immunoregulatory functions since they secrete cytokines such as IFN-γ, which favor the development of T helper 1 (Th1) cells, and chemokines such as CCL3/MIP-1α and CCL4/MIP- 1β, which recruit various inflammatory cells into sites of inflammation. In human blood, NK cells are divided into CD56 bright CD16 dim and CD56 dim CD16 bright subsets. These subsets have different phenotypic expression and may have different functions; the former subset is more immunoregulatory and the latter is more cytolytic. The CD5 6brightCD16 dim NK cells home into tissues such as the peripheral lymph nodes (LNs) under physiological conditions because they express the LN homing receptor CCR7 and they respond to CCL19/MIP-3β and CCL21/SLC chemokines. They also distribute into adenoid tissues or decidual uterus following the CXCR3/CXCL10 or CXCR4/CXCL12 axis. On the other hand, both NK cell subsets migrate into inflammatory sites, with more CD5 6dimCD16 bright NK cells distributing into inflamed liver and lungs. CCR5/CCL5 axis plays an important role in the accumulation of NK cells in virally infected sites as well as during parasitic infections. CD56 brightCD16 dim cells also migrate into autoimmune sites such as inflamed synovial fluids in patients having rheumatoid arthritis facilitated by the CCR5/CCL3/CCL4/CCL5 axis, whereas they distribute into inflamed brains aided by the CX3CR1/CX 3CL1 axis. On the other hand, CD56 dimCD16 bright NK cells accumulate in the liver of patients with primary biliary disease aided by the CXCR1/CXCL8 axis. However, the types of chemokines that contribute to their accumulation in target organs during graft vs. host (GvH) disease are not known. Further, chemokines activate NK cells to become highly cytolytic cells known as CC chemokine-activated killer (CHAK) cells that kill tumor cells. In summary, chemokines whether secreted in an autocrine or paracrine fashion regulate various biological functions of NK cells. Depending on the tissue and the chemokine secreted, NK cells may ameliorate the disease such as their roles in combating tumors or virally infected cells, and their therapeutic potentials in treating leukemias and other hematological malignancies, as well as reducing the incidence of GvH disease. In contrast, they may exacerbate the disease by damaging the affected tissues through direct cytotoxicity or by the release of multiple inflammatory cytokines and chemokines. Examples are their deleterious roles in autoimmune diseases such as rheumatoid arthritis and primary biliary cirrhosis. © Springer-Verlag Berlin Heidelberg 2010.

Szodoray P.,University of Oslo | Papp G.,Medical and Health science Center | Nakken B.,Institute of Basic Medical science | Harangi M.,Debrecen University | Zeher M.,Medical and Health science Center
Autoimmunity Reviews | Year: 2010

Extracorporeal photochemotherapy, or photopheresis is a low-risk therapeutical intervention, which has been introduced in a variety of hematological malignancies, autoimmune conditions and transplantation. The mode of action of photopheresis encompasses apoptosis-induction and modifications of immunoregulatory processes, leading to the elimination of malignant cells, as well as the down-modulation of harmful immune responses. Although the beneficial effects of the therapy have been depicted in numerous studies, little is known about the exact benefits and the molecular mechanisms behind. The aim of the present review was to portray some aspects of the molecular and clinical rationale of extracorporeal photochemotherapy in autoimmune diseases, malignancies and transplantation, and to provide an overview of the treatment in the modern clinical management of these diseases. © 2009 Elsevier B.V. All rights reserved.

Dammen T.,Institute of Basic Medical science | Papageorgiou C.,Priory Hospital Altrincham | Wells A.,Royal Infirmary
Nordic Journal of Psychiatry | Year: 2015

Background: Preliminary data support the implementation of individual metacognitive therapy (MCT) for depression. Given the focus of MCT on transpersonal processes, we hypothesized that this treatment should translate well to a group format. In this study, the effects and feasibility associated with group MCT for depression are reported. Methods: Eleven patients who were consecutively referred by general practitioners to a specialist psychiatric practice in Norway participated in an open trial of the effects and feasibility associated with group MCT for depression. All of the patients met the DSM-IV criteria for major depressive disorder (MDD) and were monitored in a baseline period before attending 90-min weekly treatment sessions of group MCT for 10 weeks. The primary symptom outcome measure was severity of depression whilst secondary outcome measures included levels of anxiety, rumination and metacognitive beliefs. We also assessed recovery rates and changes in comorbid Axis I and Axis II diagnoses. Results: Large clinically significant improvements across all measures were detected at post-treatment and these were maintained at follow-up. Based on objectively defined recovery criteria, all patients were classified as recovered at post-treatment and 91% at 6 months follow-up. The intervention was also associated with significant reductions in comorbid diagnoses. Conclusions: These preliminary data indicate that group MCT in the treatment of depression is effective, well accepted and it extends clinical application of MCT for depression to group formats as a potential cost-effective intervention. © 2014 Informa Healthcare.

Peripheral norepinephrine release is facilitated by presynaptic β-adrenoceptors, believed to involve the β2-subtype exclusively. However, β1-selective blockers are the most commonly used β-blockers in hypertension. Here the author tested the hypothesis that β1AR may function as presynaptic, release-facilitating auto-receptors. Since β1AR-blockers are injected during myocardial infarction, their influence on the cardiovascular response to acute norepinephrine release was also studied. By a newly established method, using tyramine-stimulated release through the norepinephrine transporter (NET), presynaptic control of catecholamine release was studied in normotensive and spontaneously hypertensive rats. β1AR-selective antagonists (CGP20712A, atenolol, metoprolol) reduced norepinephrine overflow to plasma equally efficient as β2AR-selective (ICI-118551) and β1+2AR (nadolol) antagonists in both strains. Neither antagonist lowered epinephrine secretion. Atenolol, which does not cross the blood-brain barrier, reduced norepinephrine overflow after adrenalectomy (AdrX), AdrX + ganglion blockade, losartan, or nephrectomy. Atenolol and metoprolol reduced resting cardiac work load. During tyramine-stimulated norepinephrine release, they had little effect on work load, and increased the transient rise in total peripheral vascular resistance, particularly atenolol when combined with losartan. In conclusion, β1AR, like β2AR, stimulated norepinephrine but not epinephrine release, independent of adrenal catecholamines, ganglion transmission, or renal renin release/angiotensin AT1 receptor activation. β1AR therefore functioned as a peripheral, presynaptic, facilitating auto-receptor. Like tyramine, hypoxia may induce NET-mediated release. Augmented tyramine-induced vasoconstriction, as observed after injection of β1AR-blocker, particularly atenolol combined with losartan, may hamper organ perfusion, and may have clinical relevance in hypoxic conditions such as myocardial infarction. © 2014 Berg.

Hsieh K.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Lee Y.K.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Londos C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Raaka B.M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | And 3 more authors.
Journal of Cell Science | Year: 2012

Perilipin family proteins (Plins) coat the surface of intracellular neutral lipid storage droplets in various cell types. Studies across diverse species demonstrate that Plins regulate lipid storage metabolism through recruitment of lipases and other regulatory proteins to lipid droplet surfaces. Mammalian genomes have distinct Plin gene members and additional protein forms derived from specific mRNA splice variants. However, it is not known if the different Plins have distinct functional properties. Using biochemical, cellular imaging and flow cytometric analyses, we now show that within individual cells of various types, the different Plin proteins preferentially sequester to separate pools of lipid storage droplets. By examining ectopically expressed GFP fusions and all endogenous Plin protein forms, we demonstrate that different Plins sequester to different types of lipid droplets that are composed of either triacylcerides or cholesterol esters. Furthermore, Plins with strong association preferences to triacylceride (or cholesterol ester) droplets can re-direct the relative intracellular triacylceride-cholesterol ester balance toward the targeted lipid. Our data suggest diversity of Plin function, alter previous assumptions about shared collective actions of the Plins, and indicate that each Plin can have separate and unique functions. © 2012.

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