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Sample records for lymphocyte receptors vlrs

  1. Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors

    Directory of Open Access Journals (Sweden)

    Robert Moot

    2016-01-01

    Full Text Available Chimeric antigen receptors (CARs are used to redirect effector cell specificity to selected cell surface antigens. Using CARs, antitumor activity can be initiated in patients with no prior tumor specific immunity. Although CARs have shown promising clinical results, the technology remains limited by the availability of specific cognate cell target antigens. To increase the repertoire of targetable tumor cell antigens we utilized the immune system of the sea lamprey to generate directed variable lymphocyte receptors (VLRs. VLRs serve as membrane bound and soluble immune effectors analogous but not homologous to immunoglobulins. They have a fundamentally different structure than immunoglobulin (Ig-based antibodies while still demonstrating high degrees of specificity and affinity. To test the functionality of VLRs as the antigen recognition domain of CARs, two VLR-CARs were created. One contained a VLR specific for a murine B cell leukemia and the other contained a VLR specific for the human T cell surface antigen, CD5. The CAR design consisted of the VLR sequence, myc-epitope tag, CD28 transmembrane domain, and intracellular CD3ζ signaling domain. We demonstrate proof of concept, including gene transfer, biosynthesis, cell surface localization, and effector cell activation for multiple VLR-CAR designs. Therefore, VLRs provide an alternative means of CAR-based cancer recognition.

  2. Variable Lymphocyte Receptor Recognition of the Immunodominant Glycoprotein of Bacillus anthracis Spores

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    Kirchdoerfer, Robert N.; Herrin, Brantley R.; Han, Byung Woo; Turnbough, Jr., Charles L.; Cooper, Max D.; Wilson, Ian A. (SNU); (Scripps); (Emory); (UAB); (Emory Vaccine)

    2012-07-25

    Variable lymphocyte receptors (VLRs) are the adaptive immune receptors of jawless fish, which evolved adaptive immunity independent of other vertebrates. In lieu of the immunoglobulin fold-based T and B cell receptors, lymphocyte-like cells of jawless fish express VLRs (VLRA, VLRB, or VLRC) composed of leucine-rich repeats and are similar to toll-like receptors (TLRs) in structure, but antibodies (VLRB) and T cell receptors (VLRA and VLRC) in function. Here, we present the structural and biochemical characterization of VLR4, a VLRB, in complex with BclA, the immunodominant glycoprotein of Bacillus anthracis spores. Using a combination of crystallography, mutagenesis, and binding studies, we delineate the mode of antigen recognition and binding between VLR4 and BclA, examine commonalities in VLRB recognition of antigens, and demonstrate the potential of VLR4 as a diagnostic tool for the identification of B. anthracis spores.

  3. Characterization of the lymphocyte substance P receptor

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    McGillis, J.P.; Organist, M.L.; Payan, D.G.

    1986-03-01

    Recent studies have provided evidence that tissues of the immune and reticuloendothelial systems are influenced by various hormones and neuropeptides. While the interrelationship between these peptides and the immune system, and the physiological relevance of their effects is not clear, a variety of highly specific, receptor-mediated effects has been demonstrated. One neuropeptide for which immunomodulatory effects have been identified is substance P (SP). SP acts as a potent T-cell mitogen, and enhances the mitogenic effects of PHA. Radioreceptor and FACS binding studies suggest that the SP receptor is present on a discrete population of T-cells and has a Kd of 0.87 nM and a density of 24,000. Studies have been initiated to biochemically characterize the lymphocyte SP receptor on IM-9 lymphoblasts. (/sup 125/I)-labeled SP was covalently crosslinked to the receptor using disuccinimidyl suberate and solubilized. Two radioactive bands of m.w. 55,000 and 33,000 were seen when the solubilized crosslinked receptor was electrophoresed on SDS gels. The authors are currently using a combination of HPLC immunoaffinity and reverse-phase chromatography to purify the receptor. The initial studies indicate that the receptor can be purified to homogeneity using this approach. The biochemical characterization of this receptor should provide a better understanding of its importance not only on lymphocytes, but in other tissues as well.

  4. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors

    DEFF Research Database (Denmark)

    Xochelli, Aliki; Baliakas, Panagiotis; Kavakiotis, Ioannis

    2017-01-01

    Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether...

  5. CYTOKINE RECEPTORS OF BLOOD LYMPHOCYTES IN CHILDREN WITH BRONCHIAL ASTHMA

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    I.A. Gromov

    2006-01-01

    Full Text Available Blood lymphocyte membrane receptors to IFNγ, IL 2, IL 4, IL 5, IL 8 and IL 10 have been investigated to assess cytokine sensitivity variations in children with asthma. Thirty children aged 5–17 with remission of atopic bronchial asthma ranging from mild to moderate persistent formed the study group. Ten children without any atopic disorders formed the group of controls. The flow cytometry with direct reaction of monoclonal antibodies to the mentioned above cytokine receptors has been used. An increased expression of IL 2 (due to high affinity CD122 subunit and IL 5 receptors has been registered in children with asthma, and so a numbers of cells bearing IL 4 and IL 8 receptors that has trended to be higher. At the same time, there has been a decrease of IFNγ receptor expression an a trend to lower expression of IL 10 receptor in these children.Key words: bronchial asthma, children, interferon-γ, interleukins.

  6. Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells.

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    Stroncek, David F; Lee, Daniel W; Ren, Jiaqiang; Sabatino, Marianna; Highfill, Steven; Khuu, Hanh; Shah, Nirali N; Kaplan, Rosandra N; Fry, Terry J; Mackall, Crystal L

    2017-03-16

    Clinical trials of Chimeric Antigen Receptor (CAR) T cells manufactured from autologous peripheral blood mononuclear cell (PBMC) concentrates for the treatment of hematologic malignancies have been promising, but CAR T cell yields have been variable. This variability is due in part to the contamination of the PBMC concentrates with monocytes and granulocytes. Counter-flow elutriation allows for the closed system separation of lymphocytes from monocytes and granulocytes. We investigated the use of PBMC concentrates enriched for lymphocytes using elutriation for manufacturing 8 CD19- and 5 GD2-CAR T cell products. When compared to PBMC concentrates, lymphocyte-enriched elutriation fractions contained greater proportions of CD3+ and CD56+ cells and reduced proportions of CD14+ and CD15+ cells. All 13 CAR T cell products manufactured using the elutriated lymphocytes yielded sufficient quantities of transduced CAR T cells to meet clinical dose criteria. The GD2-CAR T cell products contained significantly more T cells and transduced T cells than the CD19-CAR T cell products. A comparison of the yields of CAR T cells produced from elutriated lymphocytes with the yields of CAR T cells previous produced from cells isolated from PBMC concentrates by anti-CD3/CD28 bead selection or by anti-CD3/CD28 bead selection plus plastic adherence found that greater quantities of GD2-CAR T cells were produced from elutriated lymphocytes, but not CD19-CAR T cells. Enrichment of PBMC concentrates for lymphocytes using elutriation increased the quantity of GD2-CAR T cells produced. These results provide further evidence that CAR T cell expansion is inhibited by monocytes and granulocytes.

  7. LYRA, a webserver for lymphocyte receptor structural modeling

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    Klausen, Michael Schantz; Anderson, Mads Valdemar; Jespersen, Martin Closter

    2015-01-01

    a complete and automated method for building of B- and T-cell receptor structural models starting from their amino acid sequence alone. The webserver is freely available and easy to use for non-specialists. Upon submission, LYRA automatically generates alignments using ad hoc profiles, predicts...... the structural class of each hypervariable loop, selects the best templates in an automatic fashion, and provides within minutes a complete 3D model that can be downloaded or inspected online. Experienced users can manually select or exclude template structures according to case specific information. LYRA......The accurate structural modeling of B- and T-cell receptors is fundamental to gain a detailed insight in the mechanisms underlying immunity and in developing new drugs and therapies. The LYRA (LYmphocyte Receptor Automated modeling) web server (http://www.cbs.dtu.dk/services/LYRA/) implements...

  8. Requirement for sialic acid on the endothelial ligand of a lymphocyte homing receptor

    OpenAIRE

    1990-01-01

    The entry of blood-borne lymphocytes into most secondary lymphoid organs is initiated by a highly specific adhesive interaction with the specialized cuboidal endothelial cells of high endothelial venules (HEV). The adhesive receptors on lymphocytes that dictate interactions with HEV in different lymphoid organs are called homing receptors, signifying their critical role in controlling organ-selective lymphocyte migration. Considerable work has established that the mouse peripheral lymph node ...

  9. Isolation of labile Fcgamma-receptors from human peripheral blood lymphocytes and production of an antiserum.

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    Sandilands, G P; Peel, M G; Froebel, K S; Belch, J J; MacSween, R N

    1985-05-01

    In this study, we have isolated membranelabile Fcgamma-receptors (i.e. FcgammaR I) from normal human peripheral blood lymphocytes and have produced a rabbit antiserum to this protein. Using this antiserum, we have shown that membrane-labile and membrane-stable (i.e. FcgammaR II) Fcgamma-receptors are antigenically distinct and that these two forms of the receptors probably coexist on the same lymphocyte subpopulation. Moreover, it was apparent that lymphocyte FcgammaR Is are distinct from FcgammaRs expressed on other cell types (e.g. monocytes, polymorphs and spermatozoa). Preliminary evidence does suggest, however, that human platelets express an FcgammaR which is antigenically similar to human lymphocyte FcgammaR I.

  10. Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

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    Whelan, Jarrett T.; Wang, Lei; Chen, Jianming; Metts, Meagan E.; Nasser, Taj A.; McGoldrick, Liam J. [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); Bridges, Lance C., E-mail: bridgesl@ecu.edu [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); East Carolina Diabetes and Obesity Institute, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States)

    2014-11-28

    Highlights: • Transcription and translation are required for retinoid-induced lymphocyte adhesion. • RAR activation is sufficient to induced lymphocyte cell adhesion. • Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion. • Adhesion occurs through a novel binding site within ADAM disintegrin domains. • RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. - Abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH){sub 2}D{sub 3}, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.

  11. Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment

    OpenAIRE

    2000-01-01

    The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4+ and CD8+ T lymphocytes in the small intestine. Only a small subset of lymp...

  12. Requirement for sialic acid on the endothelial ligand of a lymphocyte homing receptor.

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    True, D D; Singer, M S; Lasky, L A; Rosen, S D

    1990-12-01

    The entry of blood-borne lymphocytes into most secondary lymphoid organs is initiated by a highly specific adhesive interaction with the specialized cuboidal endothelial cells of high endothelial venules (HEV). The adhesive receptors on lymphocytes that dictate interactions with HEV in different lymphoid organs are called homing receptors, signifying their critical role in controlling organ-selective lymphocyte migration. Considerable work has established that the mouse peripheral lymph node homing receptor (pnHR), defined by the mAb MEL-14, functions as a lectin-like adhesive protein. We have previously shown that sialidase treatment of peripheral lymph node (PN) HEV abrogates lymphocyte attachment to the HEV both in vivo and in vitro. We extend this evidence by demonstrating that Limax agglutinin (LA), a sialic acid-specific lectin, when reacted with HEV exposed in cryostat-cut tissue sections, blocks lymphocyte attachment to PN HEV and, unexpectedly, to the HEV of Peyer's patches (PP) as well. Using a recombinant form of the pnHR as a histochemical probe for its cognate adhesive site (HEV-ligand) on PN HEV, we demonstrate that both sialidase and Limax agglutinin functionally inactive this ligand. It is concluded that the requirement for sialic acid is at the level of the pnHR interaction with its HEV ligand. A distinct sialyloligosaccharide may encode the recognition determinant of a PP HEV ligand.

  13. B-Cell Receptor Epitope Recognition Correlates With the Clinical Course of Chronic Lymphocytic Leukemia

    NARCIS (Netherlands)

    Binder, Mascha; Mueller, Fabian; Jackst, Antje; Lechenne, Barbara; Pantic, Milena; Bacher, Ulrike; Eulenburg, Christine Zu; Veelken, Hendrik; Mertelsmann, Roland; Pasqualini, Renata; Arap, Wadih; Trepel, Martin

    2011-01-01

    BACKGROUND: B-cell receptors (BCRs) and their recognition of specific epitopes may play a pivotal role in the development and progression of chronic lymphocytic leukemia (CLL). In this study, the authors set up a model system to explore epitope reactivity and its clinical relevance in CLL. METHODS:

  14. Proinflammatory cytokines and their membrane-bound receptors are altered in the lymphocytes of schizophrenia patients.

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    Pandey, Ghanshyam N; Ren, Xinguo; Rizavi, Hooriyah S; Zhang, Hui

    2015-05-01

    Abnormalities of protein levels of proinflammatory cytokines and their soluble receptors have been reported in the plasma/serum of schizophrenia (SZ) patients. To examine if SZ is also associated with the abnormal gene expression of cytokines and their membrane-bound receptors, we studied mRNA expression of proinflammatory cytokines and their receptors in lymphocytes of SZ patients and normal control (NC) subjects. We determined the protein and mRNA expression of proinflammatory cytokines and mRNA expression of their receptors in lymphocytes from 30 SZ patients and 30 drug-free NC subjects. The subjects were diagnosed according to DSM-IV criteria. Protein levels of cytokines were determined by ELISA, and mRNA levels in lymphocytes were determined by the qPCR method. We found that the mRNA levels of IL-6, TNF-α, IL-1R1, TNFR1, and TNFR2, but not IL-1β, IL-1R2, IL-1RA, IL-6R, or GP130 were significantly increased in lymphocytes of SZ patients compared with NC subjects. We also found that the protein expression of IL-6 and TNF-α, but not IL-1β, was also significantly increased in SZ patients compared with NC subjects. These studies suggest that in addition to the reported abnormalities of proinflammatory cytokines and their soluble receptors in the plasma of SZ patients, an abnormal gene expression of these cytokines and their membrane-bound receptors may be involved in the pathogenesis of SZ.

  15. Expression of the Chemokine Receptors CCR4, CCR5, and CXCR3 by Human Tissue-Infiltrating Lymphocytes

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    Kunkel, Eric J.; Boisvert, Judie; Murphy, Kristine; Vierra, Mark A.; Genovese, Mark C.; Wardlaw, Andrew J.; Greenberg, Harry B.; Hodge, Martin R.; Wu, Lijun; Butcher, Eugene C.; Campbell, James J.

    2002-01-01

    Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4+ lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4+ populations in blood, as well as by tissue-infiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4+ lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69+). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in α4β7 expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation. PMID:11786428

  16. 5-HT7 receptors and tryptophan hydroxylase in lymphocytes of rats: mitogen activation, physical restraint or treatment with reserpine.

    Science.gov (United States)

    Urbina, Mary; Arroyo, Rubén; Lima, Lucimey

    2014-01-01

    Serotonin (5-HT)7 receptors in lymphocytes play a relevant role as modulators of T cell functions and might be modified by stress protocols. The aims of this work were to evaluate: (i) the presence of 5-HT7 receptors in specific lymphocyte populations, (ii) the probable modifications of them by inflammatory stress with mitogen and (iii) the effects of physical and pharmacological stress. Blood lymphocytes were isolated by density gradients and differential adhesion to plastic. Concanavalin A (Con A) was systemically administered (500 μg/kg) or added to lymphocyte cultures (2.5 μg/ml, final volume 200 μl). Physical restraint was performed in Plexiglass boxes for 5 h per day for 5 days. Reserpine administration was 2.5 mg/kg for 3 days. Immunocytochemical labeling of CD4+, CD8+ and 5-HT7 receptors, and also tryptophan hydroxylase cells was performed. mRNA of 5-HT7 receptors was evaluated by RT-PCR. Controls were included for each protocol. Con A treatment or culture exposure increased the number of lymphocytes expressing 5-HT7 receptors or tryptophan hydroxylase, as compared to absence of the mitogen. Receptors were present in 12-16% of total rat lymphocytes, in ∼10% of CD4+ and in ∼5% of CD8+ cells from control rats. CD4+ decreased, and CD8+ and 5-HT7 cells increased after physical restraint. Reserpine treatment elevated CD8+ and 5-HT7 cells. Con A and physical restraint, but not reserpine treatment, significantly augmented 5-HT7 receptor mRNA in lymphocytes. Rat lymphocytes, expressing tryptophan hydroxylase, could synthesize 5-HT, functioning as a direct autocrine modulator. The modifications of CD4+, CD8+ and 5-HT7 receptors in lymphocytes by three stress protocols could have an impact on immune responses. In addition, the differential distribution of 5-HT7 receptors indicates potential specific physiopathological roles. © 2014 S. Karger AG, Basel.

  17. Seasonal changes in haematology, lymphocyte transferrin receptors and intracellular iron in Ironman triathletes and untrained men.

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    Broadbent, Suzanne

    2011-01-01

    We investigated whether 12 months of chronic endurance training would affect haematology, CD4(+) lymphocyte transferrin receptor (CD71) expression, CD4(+) intracellular iron and the incidence of upper respiratory tract illnesses (URTI) in Ironman triathletes compared with untrained men. Resting venous blood samples were taken from 15 Ironman triathletes (TR 30 ± 5 year) and 12 untrained men (UT 30 ± 6 year) every 4 weeks for 12 months. Erythrocyte, leukocyte and platelet concentration, haematocrit, haemoglobin (Hb) and mean corpuscular haemoglobin (MCHC) were measured with a full blood count. CD4(+) lymphocytes were analysed for changes in transferrin receptor (CD71) expression (CD4(+)CD71(+)), and intracellular iron (Fe(3+)), by flow cytometry. The TR group had significantly lower Hb, MCHC, and platelets for 10, 9 and 11 months, respectively; lower CD4(+)CD71(+) (3 months) and Fe(3+) (1 month), respectively; higher CD4(+)CD71(+) (1 month); a higher lymphocyte count for 4 months. There were no between-group differences in other variables. In both groups haematology and lymphocytes increased during spring, early summer and winter and decreased during late summer/late winter, with an inverse relationship between CD4(+)CD71(+) and Fe(3+). The TR group reported significantly fewer URTI than the UT. Low Hb and MCHC suggest an iron deficiency which may affect triathlete performance. Monthly changes in lymphocytes, CD4(+)CD71(+) and Fe(3+) suggested that spring, summer and late autumn are associated with CD4(+) proliferation. There may be seasonal relationships between haematology and lymphocyte function, independent of endurance training, possibly affecting performance but not the incidence of URTI.

  18. Kinetic analysis of interleukin 2 (IL-2) production and expression of IL-2 receptors by uraemic and normal lymphocytes

    DEFF Research Database (Denmark)

    Langhoff, E; Hofmann, B; Ladefoged, J

    1987-01-01

    The in vitro immune response of lymphocytes from uraemic patients was studied by comparing the in vitro kinetics of interleukin 2 (IL-2) production, the mitogen-induced proliferative response, and the expression of IL-2 receptors by T lymphocytes. The IL-2 production in 26 uraemic cell cultures...

  19. Role of chemokines and their receptors in chronic lymphocytic leukemia: function in microenvironment and targeted therapy.

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    Han, Ting-Ting; Fan, Lei; Li, Jian-Yong; Xu, Wei

    2014-01-01

    Chemokines produced in distinct tissue microenvironments sustain migration of mature lymphocytes in lymphoglandula. Chemokine receptors expressed on chronic lymphocytic leukemia (CLL) cells regulate the migration of the leukemia cells within the bone marrow (BM), lymphoid organs in collaboration with chemokines. Chemokines form a pro-survival circuitry by regulating leukocyte trafficking, maintaining extended lymphocyte survival. Therefore, chemokines in tumor cell-microenvironment interactions represent a target for treatment of CLL. AMD3100 disrupts the CLL/microenvironment interactions and influences CXCL12/CXCR4 survival signaling. Fostamatinib, ibrutinib, and GS-1101 as B-cell receptor (BCR)-related kinase inhibitors inhibit BCR- and chemokine-receptor-signal-regulated kinase and have a good clinical response in CLL. Lenalidomide, sorafenib, and dasatinib are other additional drugs associated with chemokine in microenvironment. Inhibiting signaling through chemokine and microenvironment associated signaling are emerging as innovative therapeutic targets in CLL. In this article, we reviewed the role of chemokines in CLL microenvironment and novel therapeutics targeting CLL microenvironment.

  20. Expression of membrane receptor for tumour necrosis factor on human blood lymphocytes.

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    Zola, H; Flego, L; Weedon, H

    1993-08-01

    Using a monoclonal antibody against the human p75 tumour necrosis factor receptor (TNFR-I) combined with a high-sensitivity immunofluorescence flow cytometric procedure, a proportion of peripheral blood lymphocytes can be shown to express TNFR-I constitutively. Approximately 50% of peripheral blood lymphocytes consisting mostly of CD4 cells and including most CD45R0-positive cells, express TNFR-I. Receptor expression is increased by a variety of activation signals. Only a minority (up to 30%) of tonsil B cells express measurable levels of TNFR-I. The tonsil B cells which express TNFR-I include both cells with a germinal centre cell phenotype and cells with the phenotype of the follicular mantle zone. Activation of B cells with anti-immunoglobulin, alone or in combination with interleukin-4 or interleukin-2, increases receptor expression, particularly in cells with the phenotype of mantle zone cells. The functional significance of constitutive expression of TNFR by blood and tissue lymphocytes is discussed.

  1. Expression of Fas receptor on peripheral blood lymphocytes from patients with non-small cell lung cancer.

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    Joanna Domagała-Kulawik

    2005-02-01

    Full Text Available In recent years many data indicate that lymphocytes from cancer patients undergo increased apoptosis. The objective of this study was to evaluate the expression of Fas receptor on lymphocytes obtained from patients with lung cancer. Eighteen patients with non-small cell lung cancer and 18 healthy volunteers were investigated. Expression of Fas (CD95 on CD4+ and CD8+ blood lymphocytes was evaluated by flow cytometry. The proportion of blood Fas+ lymphocytes was significantly higher in lung cancer patients when compared with healthy individuals and in smokers when compared with nonsmokers.

  2. Expression of IL-4 receptor on human T and B lymphocytes.

    Science.gov (United States)

    Zola, H; Flego, L; Weedon, H

    1993-08-01

    The expression of the interleukin-4 receptor on human blood and tonsil lymphocytes has been studied using a monoclonal antibody and high-sensitivity immunofluorescence flow cytometry. While no receptor expression could be detected on circulating or tonsil T cells, a subset of B cells was shown to express the receptor. The IL-4R-positive B cells in tonsil had a phenotype suggesting that they included both germinal centre B cells and B cells outside the germinal centre. The subset of B cells in the blood that expressed the receptor included CD23-positive B cells. Activation of tonsil B cells using anti-IgM, IL-4, IL-2, or combinations of these reagents led to increases in IL-4R expression, but these changes were small compared to changes in the expression of IL-2R p55 (CD25), a known marker of activation. Similarly, activation of T cells led to low-level expression of IL-4R, with IL-4 itself up-regulating IL-4R, especially in CD4 cells. The majority of chronic lymphocytic leukaemia samples were positive for IL-4R expression, whilst most other leukemic samples were negative.

  3. mRNA expression of dopamine receptors in peripheral blood lymphocytes of computer game addicts.

    Science.gov (United States)

    Vousooghi, Nasim; Zarei, Seyed Zeinolabedin; Sadat-Shirazi, Mitra-Sadat; Eghbali, Fatemeh; Zarrindast, Mohammad Reza

    2015-10-01

    Excessive playing of computer games like some other behaviors could lead to addiction. Addictive behaviors may induce their reinforcing effects through stimulation of the brain dopaminergic mesolimbic pathway. The status of dopamine receptors in the brain may be parallel to their homologous receptors in peripheral blood lymphocytes (PBLs). Here, we have investigated the mRNA expression of dopamine D3, D4 and D5 receptors in PBLs of computer game addicts (n = 20) in comparison to normal subjects (n = 20), using a real-time PCR method. The results showed that the expression level of D3 and D4 dopamine receptors in computer game addicts were not statistically different from the control group. However, the expression of the mRNA of D5 dopamine receptor was significantly down-regulated in PBLs of computer game addicts and reached 0.42 the amount of the control group. It is concluded that unlike with drug addiction, the expression levels of the D3 and D4 dopamine receptors in computer game addicts are not altered compared to the control group. However, reduced level of the D5 dopamine receptor in computer game addicts may serve as a peripheral marker in studies where the confounding effects of abused drugs are unwanted.

  4. Gene expression of lymphocyte prolactin receptor was suppressed in lactating mothers.

    Science.gov (United States)

    Maeda, Hironobu; Izumi, Shun-ichiro; Kato, Yukio; Cai, Li-yi; Kato, Takako; Suzuki, Takahiro; Nakamura, Eri; Sugiyama, Taro; Fuda, Takayo; Takahashi, Kazumi; Kondo, Akane; Matsumoto, Tadashi; Ishimoto, Hitoshi

    2010-07-20

    Prolactin (PRL) receptor (PRL-R) was proven to be ubiquitously expressed by cells in the immune system, while the physiological role of PRL was established in milk production in mammary glands. We analyzed the mRNA content of PRL-R in human lymphocytes in normo- and hyperprolactinemic conditions to document the presence of functioning PRL-R of human lymphocytes. Blood samples were obtained prior to treatment, and with written informed consent, from outpatients with ovarian dysfunction and hyperprolactinemia (n = 8; 19 ~ 41 y/o), from breast-feeding mothers after normal delivery (n = 12; 27 ~ 36 y/o), and from healthy volunteers: men (n = 9; 33 ~ 40 y/o) and women (n = 9; 26 ~ 36 y/o). Subsequently, total RNA was prepared from the lymphocytes separated. The quantity of PRL-R mRNA was examined by reverse transcription and polymerase chain reaction and normalized with a simultaneously measured amount of b actin. The resultant mRNA level of PRL-R was analyzed for its correlation with serum concentration of PRL measured by immunoassay. PRL-R mRNA levels of lymphocytes were significantly suppressed in lactating mothers, while there was a statistically significant negative correlation between PRL-R mRNA and serum PRL levels. However, there was no significant difference of PRL-R mRNA in the pathological condition of outpatients with ovarian dysfunction and/or hyperprolactinemia. While a few investigators reported the extra-mammary regulation on PRL-R by PRL, our data suggest that the PRL-R levels of circulating lymphocytes could be down-regulated by the elevated serum levels of PRL and that pituitary PRL may participate in regulating the expression of PRL-R genes on cells of the human immune system, especially in physiological circumstances such as in the postpartum period.

  5. Suicide Gene Therapy to Increase the Safety of Chimeric Antigen Receptor-Redirected T Lymphocytes

    Directory of Open Access Journals (Sweden)

    Monica Casucci, Attilio Bondanza

    2011-01-01

    Full Text Available Chimeric antigen receptors (CARs are generated by fusing the antigen-binding motif of a monoclonal antibody (mAb with the signal transduction machinery of the T-cell receptor (TCR. The genetic modification of T lymphocytes with chimeric receptors specific for tumor-associated antigens (TAAs allows for the redirection towards tumor cells. Clinical experience with CAR-redirected T cells suggests that antitumor efficacy associates with some degree of toxicity, especially when TAA expression is shared with healthy tissues. This situation closely resembles the case of allogeneic hematopoietic stem cell transplantation (HSCT, wherein allorecognition causes both the graft-versus-leukemia (GVL effect and graft-versus-host disease (GVHD. Suicide gene therapy, i.e. the genetic induction of a conditional suicide phenotype into donor T cells, enables dissociating the GVL effect from GVHD. Applying suicide gene modification to CAR-redirected T cells may therefore greatly increase their safety profile and facilitate their clinical development.

  6. The Innate Immune Receptor CD14 Mediates Lymphocyte Migration in EAE

    Directory of Open Access Journals (Sweden)

    Ramona Halmer

    2015-08-01

    Full Text Available Background: Multiple sclerosis is the most common autoimmune disease of the central nervous system in young adults and histopathologically characterized by inflammation, demyelination and gliosis. It is considered as a CD4+ T cell-mediated disease, but also a disease-promoting role of the innate immune system has been proposed, based e.g. on the observation that innate immune receptors modulate disease severity of experimental autoimmune encephalomyelitis. Recent studies of our group provided first evidence for a key role of the innate immune LPS receptor (CD14 in pathophysiology of experimental autoimmune encephalomyelitis. CD14-deficient experimental autoimmune encephalomyelitis mice showed increased clinical symptoms and enhanced infiltration of monocytes and neutrophils in brain and spinal cord. Methods: In the current study, we further investigated the causes of the disease aggravation by CD14-deficiency and examined T cell activation, also focusing on the costimulatory molecules CTLA-4 and CD28, and T cell migration capacity over the blood brain barrier by FACS analysis, in vitro adhesion and transmigration assays. Results: In the results, we observed a significantly increased migration of CD14-deficient lymphocytes across an endothelial monolayer. In contrast, we did not see any differences in expression levels of TCR/CTLA-4 or TCR/CD28 and lymphocyte adhesion to endothelial cells from CD14-deficient compared to wildtype mice. Conclusion: The results demonstrate an important role of CD14 in migration of lymphocytes, and strengthen the importance of innate immune receptors in adaptive immune disorders, such as multiple sclerosis.

  7. Single Particle Tracking reveals two distinct environments for CD4 receptors at the surface of living T lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Mascalchi, Patrice; Lamort, Anne Sophie; Salome, Laurence [CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse (France); Universite de Toulouse, UPS, IPBS (Institut de Pharmacologie et de Biologie Structurale), F-31077 Toulouse (France); Dumas, Fabrice, E-mail: fabrice.dumas@ipbs.fr [CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse (France); Universite de Toulouse, UPS, IPBS (Institut de Pharmacologie et de Biologie Structurale), F-31077 Toulouse (France)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer We studied the diffusion of single CD4 receptors on living lymphocytes. Black-Right-Pointing-Pointer This study reveals that CD4 receptors have either a random or confined diffusion. Black-Right-Pointing-Pointer The dynamics of unconfined CD4 receptors was accelerated by a temperature raise. Black-Right-Pointing-Pointer The dynamics of confined CD4 receptors was unchanged by a temperature raise. Black-Right-Pointing-Pointer Our results suggest the existence of two different environments for CD4 receptors. -- Abstract: We investigated the lateral diffusion of the HIV receptor CD4 at the surface of T lymphocytes at 20 Degree-Sign C and 37 Degree-Sign C by Single Particle Tracking using Quantum Dots. We found that the receptors presented two major distinct behaviors that were not equally affected by temperature changes. About half of the receptors showed a random diffusion with a diffusion coefficient increasing upon raising the temperature. The other half of the receptors was permanently or transiently confined with unchanged dynamics on raising the temperature. These observations suggest that two distinct subpopulations of CD4 receptors with different environments are present at the surface of living T lymphocytes.

  8. Role of Sphingosine 1-Phosphate Receptor Type 1 in Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus

    Institute of Scientific and Technical Information of China (English)

    Kenji Chiba; Hirofumi Matsuyuki; Yasuhiro Maeda; Kunio Sugahara

    2006-01-01

    Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13,and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism(s) of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I (myriocin). FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of iymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to (S)-enantiomer of FTY720-phosphate[(S)-FTY720-P] by sphingosine kinase 2 in vivo. (S)-FTY720-P acting as a potent agonist of S1P receptor type 1(S1P1), induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite (S)-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.

  9. Expression of the Chemokine Receptors CCR4, CCR5, and CXCR3 by Human Tissue-Infiltrating Lymphocytes

    OpenAIRE

    2002-01-01

    Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4+ lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4+ populations in blood, as well as by tis...

  10. Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment

    Science.gov (United States)

    Kunkel, Eric J.; Campbell, James J.; Haraldsen, Guttorm; Pan, Junliang; Boisvert, Judie; Roberts, Arthur I.; Ebert, Ellen C.; Vierra, Mark A.; Goodman, Stuart B.; Genovese, Mark C.; Wardlaw, Andy J.; Greenberg, Harry B.; Parker, Christina M.; Butcher, Eugene C.; Andrew, David P.; Agace, William W.

    2000-01-01

    The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4+ and CD8+ T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9+, and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9−. TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses. PMID:10974041

  11. Expression of T-Lymphocyte Markers in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

    Science.gov (United States)

    Lee, Changro; Kim, Joo Heung; Lim, Sung Mook; Park, Hyung Seok; Kim, Seung Il; Park, Byeong-Woo

    2016-01-01

    Purpose The present study aimed to examine the clinical implications of CD4, CD8, and FOXP3 expression on the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer using a web-based database, and to compare the immunohistochemical expression of T-lymphocyte markers using primary and metastatic HER2-positive tumor tissues before and after HER2-targeted therapy. Methods Using the cBioPortal for Cancer Genomics and Kaplan-Meier plotter, the mRNA expression, association between T-lymphocyte markers, and survival in HER2-positive cancers were investigated according to various cutoff levels. Immunohistochemistry analysis was performed using paired primary and metastatic tissues of 29 HER2-positive tumors treated with systemic chemotherapy and HER2-directed therapy. Results HER2 mRNA was mutually exclusive of T-lymphocyte markers, and a significant correlation between T-cell markers was observed in the cBioPortal for Cancer Genomics. According to analysis of the Kaplan-Meier plotter, the impact of T-lymphocyte marker expression on survival was statistically insignificant in clinical HER2-positive tumors, irrespective of the cutoff levels. However, in the intrinsic HER2-positive subtype, the individual analyses of T-cell markers except for FOXP3 and combined analysis showed significantly favorable survival irrespective of cutoff points. Although the small clinical sample size made it difficult to show the statistical relevance of immunohistochemistry findings, good responses to neoadjuvant treatments might be associated with positive expression of combined T-lymphocyte markers, and approximately half of the samples showed discordance of combined markers between baseline and resistant tumors. Conclusion T-lymphocyte markers could be favorable prognostic factors in HER2-positive breast cancers; however, a consensus on patient section criteria, detection methods, and cutoff value could not be reached. The resistance to HER2-directed therapy might

  12. Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication

    Directory of Open Access Journals (Sweden)

    E. Roda

    2016-01-01

    Full Text Available Introduction. Chronic poisoning may result in home setting after mercury (Hg vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg monitoring were performed from admission (t0, until 1 year later (t2, paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs. At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1–4.5; UHg 0.1–4.5, associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0–16.0. At t1 (two days after DMSA-mobilization test, BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes. At t2 (eight months after two cycles of DMSA chelating therapy ending, gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp. and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes. Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

  13. Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication

    Science.gov (United States)

    Roda, E.; Vecchio, S.; Apostoli, P.

    2016-01-01

    Introduction. Chronic poisoning may result in home setting after mercury (Hg) vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg) monitoring were performed from admission (t0), until 1 year later (t2), paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs). At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1–4.5; UHg 0.1–4.5), associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0–16.0). At t1 (two days after DMSA-mobilization test), BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes). At t2 (eight months after two cycles of DMSA chelating therapy ending), gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp.) and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes). Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring. PMID:27872646

  14. β2 Adrenergic receptor on T lymphocytes and its clinical implications

    Institute of Scientific and Technical Information of China (English)

    Xuelai Fan; Yuedan Wang

    2009-01-01

    Sustained complex cross-talk between the immune system and the nervous system plays a vital role in retaining homeostasis in a healthy individual.One of the central regulatory mechanisms involved is the existence and functions of β2-adrenergic receptors (β2AR) on T lymphocytes.This article reviews research progress made recently,including the expression of adrenergic receptors on Tlymphocytes,the structure and intracellular pathways of β2AR,the activation of I32AR by either endogenous or exogenous agonists,and the effect of β2AR stimulation on T cells which alters T cell proliferation,differentiation,cytokine production and T-helper-mediated antibody production.Furthermore,we discuss the roles of β2AR played in the pathogenesis and treatment of autoimmune diseases.

  15. Abnormal adenosine and dopamine receptor expression in lymphocytes of Lesch-Nyhan patients.

    Science.gov (United States)

    García, M G; Puig, J G; Torres, R J

    2009-11-01

    Self-injurious behavior is the most outstanding feature of Lesch-Nyhan syndrome and has recently been ascribed to an obsessive-compulsive behavior. Lesch-Nyhan syndrome results from the complete enzyme deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) but the link between abnormal purine metabolism and its neurological and behavioral manifestations remains largely unknown. Previous studies led us to hypothesize that adenosine and dopamine receptor expression could be altered in HPRT-deficient cells. To test this hypothesis, we examined mRNA expressions of adenosine (ADORA2A and ADORA2B) and dopamine receptors (DRD1 and DRD2 like), and dopamine transporter (DAT1) in peripheral blood lymphocytes (PBLs) from Lesch-Nyhan patients. We also examined the influence of hypoxanthine in these expressions. As compared to normal PBLs, both ADORA2A and DRD5 expression were abnormal in PBLs from Lesch-Nyhan patients. In contrast, DAT1 expression was similar to control values in HPRT deficient PBLs. These results indicate an abnormal adenosine and dopamine receptor expression in HPRT-deficient cells and suggest disrupted adenosine and dopamine neurotransmission may have a significant role in the pathogenesis of the neurological manifestations of Lesch-Nyhan syndrome.

  16. Expression of the chemokine receptor CXCR4 on lymphocytes of leprosy patients

    Directory of Open Access Journals (Sweden)

    V.A. Mendonça

    2011-12-01

    Full Text Available Leprosy is caused by Mycobacterium leprae, which induces chronic granulomatous infection of the skin and peripheral nerves. The disease ranges from the tuberculoid to the lepromatous forms, depending on the cellular immune response of the host. Chemokines are thought to be involved in the immunopathogenesis of leprosy, but few studies have investigated the expression of chemokine receptors on leukocytes of leprosy patients. In the present study, we evaluated 21 leprosy patients (M/F: 16/5 with a new diagnosis from the Dermatology Outpatient Clinic of the University Hospital, Federal University of Minas Gerais. The control group was composed of 20 healthy members (M/F: 15/5 of the community recruited by means of announcements. The expression of CCR2, CCR3, CCR5, and CXCR4 was investigated by flow cytometry on the surface of peripheral blood lymphocytes. There was a decrease in percentage of CD3+CXCR4+ and CD4+CXCR4+ lymphocytes in the peripheral blood of leprosy patients (median [range], 17.6 [2.7-41.9] and 65.3 [3.9-91.9], respectively compared to the control group (median [range], 43.0 [3.7-61.3] and 77.2 [43.6-93.5], respectively. The percentage of CD4+CXCR4+ was significantly lower in patients with the tuberculoid form (median [range], 45.7 [0.0-83.1] of the disease, but not in lepromatous patients (median [range], 81.5 [44.9-91.9]. The CXCR4 chemokine receptor may play a role in leprosy immunopathogenesis, probably directing cell migration to tissue lesions in tuberculoid leprosy patients.

  17. Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors.

    Science.gov (United States)

    Ishii, Akihiro; Matsuo, Aya; Sawa, Hirofumi; Tsujita, Tadayuki; Shida, Kyoko; Matsumoto, Misako; Seya, Tsukasa

    2007-01-01

    Fish express mammalian-type (M-type) TLRs consisting of leucine-rich repeats (LRRs) and Toll-IL-1R (TIR) homology domain for immunity, whereas invertebrates in deuterostomes appear to have no orthologs of M-type TLRs. Lampetra japonica (lamprey) belongs to the lowest class of vertebrates with little information about its TLRs. We have identified two cDNA sequences of putative TLRs in the lamprey (laTLRs) that contain LRRs and TIR domains. The two laTLRs were 56% homologous to each other, and their TIRs were similar to those of members of the human TLR2 subfamily, most likely orthologs of fish TLR14. We named them laTLR14a and laTLR14b. We raised a rabbit polyclonal Ab against laTLR14b and identified a 85-kDa protein in a human HEK293 transfectant by immunoblotting using the Ab. FACS, histochemical, and confocal analyses showed that laTLR14b is expressed intracellularly in lamprey gill cells and that the overexpressed protein resides in the endoplasmic reticulum of human and fish (medaka) cell lines. Because natural agonists of TLR14 remained unidentified, we made a chimera construct of extracellular CD4 and the cytoplasmic domain of laTLR14. The chimera molecule of laTLR14b, when expressed in HEK293 cells, elicited activation of NF-kappaB and, consequently, weak activation of the IFN-beta promoter. laTLR14b mRNA was observed in various organs and leukocytes. This lamprey species expressed a variable lymphocyte receptor structurally independent of laTLR14 in leukocytes. Thus, the jawless vertebrate lamprey possesses two LRR-based recognition systems, the variable lymphocyte receptor and TLR, and the M-type TLRs are conserved across humans, fish, and lampreys.

  18. Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors

    Science.gov (United States)

    Le Cleach, L; Delaire, S; Boumsell, L; Bagot, M; Bourgault-Villada, I; Bensussan, A; Roujeau, J C

    2000-01-01

    Toxic epidermal necrolysis (TEN) is a rare life-threatening adverse drug reaction characterized by a massive destruction of the epidermis. Immunohistological studies of skin biopsies of TEN showed infiltrates of predominantly CD8+ T lymphocytes even though other authors reported a prominent involvement of cells of the monocyte-macrophage lineage. The aim of this study was to characterize phenotypically and functionally the cells present in the cutaneous blister fluid of four patients with TEN. We first determined that lymphocytes were predominant in blister fluid obtained early, while monocytes/macrophages later became the most important population. We then showed that this lymphocyte population, mainly CD3+CD8+, corresponded to a peculiar cell subset as they expressed cutaneous leucocyte antigen, killer inhibitory receptors KIR/KAR and failed to express CD28 molecule. Functionally, we determined that blister T lymphocytes had a cytotoxic T lymphocyte (CTL)- and NK-like cytotoxicity. The role of this cytotoxic lymphocyte population present at the site of lesions during TEN remains to be understood. PMID:10606987

  19. NTB-A Receptor Crystal Structure: Insights into Homophilic Interactions in the Signaling Lymphocytic Activation Molecule Receptor Family

    Energy Technology Data Exchange (ETDEWEB)

    Cao,E.; Ramagopal, U.; Fedorov, A.; Fedorov, E.; Yan, Q.; Lary, J.; Cole, J.; Nathenson, S.; Almo, S.

    2006-01-01

    The signaling lymphocytic activation molecule (SLAM) family includes homophilic and heterophilic receptors that regulate both innate and adaptive immunity. The ectodomains of most SLAM family members are composed of an N-terminal IgV domain and a C-terminal IgC2 domain. NK-T-B-antigen (NTB-A) is a homophilic receptor that stimulates cytotoxicity in natural killer (NK) cells, regulates bactericidal activities in neutrophils, and potentiates T helper 2 (Th2) responses. The 3.0 {angstrom} crystal structure of the complete NTB-A ectodomain revealed a rod-like monomer that self-associates to form a highly kinked dimer spanning an end-to-end distance of {approx}100 {angstrom}. The NTB-A homophilic and CD2-CD58 heterophilic dimers show overall structural similarities but differ in detailed organization and physicochemical properties of their respective interfaces. The NTB-A structure suggests a mechanism responsible for binding specificity within the SLAM family and imposes physical constraints relevant to the colocalization of SLAM-family proteins with other signaling molecules in the immunological synapse.

  20. Oxidative stress effect on progesterone-induced blocking factor (PIBF) binding to PIBF-receptor in lymphocytes.

    Science.gov (United States)

    de la Haba, Carlos; Palacio, José R; Palkovics, Tamas; Szekeres-Barthó, Júlia; Morros, Antoni; Martínez, Paz

    2014-01-01

    Receptor-ligand binding is an essential interaction for biological function. Oxidative stress can modify receptors and/or membrane lipid dynamics, thus altering cell physiological functions. The aim of this study is to analyze how oxidative stress may alter receptor-ligand binding and lipid domain distribution in the case of progesterone-induced blocking factor/progesterone-induced blocking factor-receptor. For membrane fluidity regionalization analysis of MEC-1 lymphocytes, two-photon microscopy was used in individual living cells. Lymphocytes were also double stained with AlexaFluor647/progesterone-induced blocking factor and Laurdan to evaluate -induced blocking factor/progesterone-induced blocking factor-receptor distribution in the different membrane domains, under oxidative stress. A new procedure has been developed which quantitatively analyzes the regionalization of a membrane receptor among the lipid domains of different fluidity in the plasma membrane. We have been able to establish a new tool which detects and evaluates lipid raft clustering from two-photon microscopy images of individual living cells. We show that binding of progesterone-induced blocking factor to progesterone-induced blocking factor-receptor causes a rigidification of plasma membrane which is related to an increase of lipid raft clustering. However, this clustering is inhibited under oxidative stress conditions. In conclusion, oxidative stress decreases membrane fluidity, impairs receptor-ligand binding and reduces lipid raft clustering.

  1. Effect of Cardiopulmonary Bypass on Beta Adrenergic ReceptorAdenylate Cyclase System on Surfaces of Peripheral Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    LUO Ailin; TIAN Yuke; JIN Shiao

    2000-01-01

    The experimental results showed that the level of CAMP, the ratio of cAPM to cGMP,IL-2R expression and IL-2 production in vitro in lymphocytes immediate and 2 weeks after cardiopulmonary bypass (CPB) were significantly lower than those before anesthetics in the patients undergoing cardiac surgery with CPB. These findings suggested that CPB could cause serious damage to adrenergic beta receptor-adenylate cyclase system on circulating lymphocytes surfaces,which might be one of the mechanisms resulting in immunosuppression after open heart surgery with CPB.

  2. The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukemia.

    Science.gov (United States)

    Stevenson, Freda K; Forconi, Francesco; Packham, Graham

    2014-07-01

    The B-cell receptor (BCR) is of critical importance for normal B cells and for the majority of B-cell malignancies, especially chronic lymphocytic leukemia (CLL). The two major subsets of CLL are biologically distinct, being derived from B cells at different stages of differentiation and carrying unmutated (U-CLL) or mutated (M-CLL) IGHV genes. U-CLL, which has a poorer prognosis, often has relatively conserved (stereotypic) IGHV-HD-HJ sequences, indicative of interaction with large (super)antigens and similar to those in normal naive innate B cells. Conserved sequences are less evident in M-CLL, in keeping with its postfollicular origin. However, both subsets exhibit features of chronic antigen exposure in tissue sites, with local proliferative events, but also downregulation of surface immunoglobulin M but not surface immunoglobulin D, a characteristic of normal anergic B cells. BCR-mediated anergy can spread to other receptors such as CXCR4. Circulating CLL cells retain a shadow of tissue-based events that can reverse over time, but the overall extent of anergy is greater in M-CLL. Despite this stereotypic variety and more genomic complexity, BCR-mediated responses in vitro appear relatively homogeneous in U-CLL, but M-CLL is more heterogeneous. The differential balance between antigen-induced proliferation or anergy is the likely determinant of clinical behavior and possibly of response to kinase inhibitors.

  3. Association between lymphocyte expression of the apoptotic receptor Fas and pain in critically ill patients

    Science.gov (United States)

    Papathanassoglou, Elizabeth DE; Mpouzika, Meropi DA; Giannakopoulou, Margarita; Bozas, Evangelos; Middleton, Nicos; Tsiaousis, George; Karabinis, Andreas

    2017-01-01

    Objective Lymphocyte apoptosis in critical illness is associated with immunosuppression. We explored for the first time the associations between pain ratings and expression of the apoptotic receptor Fas on B and T cells in critically ill patients and the potential mediating effects of adrenocorticotropic hormone (ACTH), cortisol, and substance P (SP). Design This is an exploratory correlational study with repeated measurements (14 days followup) and cross-sectional comparisons. Setting This study was conducted in a state hospital in the metropolitan area of Athens, Greece. Participants The participants were 36 consecutive critically ill patients and 36 matched controls. Outcome measures Pain measured by the self-reported numeric rating scale [NRS], the behavioral pain scale, and the pain assessment scale was the primary outcome measure. Flow cytometry (Fas), electrochemiluminescence (ACTH and cortisol) and enzyme-linked immunosorbent assay (SP) were used. Mixed linear models for repeated measurements and bivariable associations at discrete time points were employed. Results Significant pain at rest was noted. Pain ratings associated with Fas expression on cytotoxic T cells (P=0.041) and B cells (P=0.005), even after adjustment for a number of clinical treatment factors (P=0.006 and P=0.052, respectively). On the day that more patients were able to communicate, Fas on B cells (r=0.897, P=0.029) and cytotoxic T cells (r=0.832; P=0.037) associated with NRS ratings. Associations between pain ratings and ACTH serum levels were noted (P<0.05). When stress neuropeptide levels were added to the model, the statistical significance of the associations between pain ratings and Fas expression was attenuated (P=0.052–0.063), suggesting that stress neuropeptides may partially mediate the association. Conclusion Preliminary evidence for the association between pain and lymphocyte apoptotic susceptibility is provided. The role of pain management in maintaining immunocompetence

  4. DNA damage in blood lymphocytes in patients after {sup 177}Lu peptide receptor radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Eberlein, Uta; Bluemel, Christina; Buck, Andreas Konrad; Werner, Rudolf Alexander; Lassmann, Michael [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Nowak, Carina; Scherthan, Harry [Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich (Germany)

    2015-10-15

    The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with {sup 177}Lu-labelled DOTATATE/DOTATOC. The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with {sup 131}I and {sup 177}Lu. The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. Measurements of RIF and the absorbed dose to the blood after systemic administration of {sup 177}Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair. (orig.)

  5. Association between lymphocyte expression of the apoptotic receptor Fas and pain in critically ill patients

    Directory of Open Access Journals (Sweden)

    Papathanassoglou EDE

    2017-01-01

    Full Text Available Elizabeth DE Papathanassoglou,1,* Meropi DA Mpouzika,2,* Margarita Giannakopoulou,3 Evangelos Bozas,3 Nicos Middleton,2 George Tsiaousis,2 Andreas Karabinis4,5 1Faculty of Nursing, University of Alberta, Edmonton, AB, Canada; 2Department of Nursing, Cyprus University of Technology, Limassol, Cyprus; 3Department of Nursing, School of Health Sciences, National and Kapodistrian University of Athens, 4Surgical Care Unit, The Onassis Cardiac Surgery Center, Kallithea, 5School of Medicine, National and Kapodistrian University of Athens, Athens, Greece *These authors contributed equally to this work Objective: Lymphocyte apoptosis in critical illness is associated with immunosuppression. We explored for the first time the associations between pain ratings and expression of the apoptotic receptor Fas on B and T cells in critically ill patients and the potential mediating effects of adrenocorticotropic hormone (ACTH, cortisol, and substance P (SP.Design: This is an exploratory correlational study with repeated measurements (14 days follow-up and cross-sectional comparisons.Setting: This study was conducted in a state hospital in the metropolitan area of Athens, Greece.Participants: The participants were 36 consecutive critically ill patients and 36 matched controls.Outcome measures: Pain measured by the self-reported numeric rating scale [NRS], the behavioral pain scale, and the pain assessment scale was the primary outcome measure. Flow cytometry (Fas, electrochemiluminescence (ACTH and cortisol and enzyme-linked immunosorbent assay (SP were used. Mixed linear models for repeated measurements and bivariable associations at discrete time points were employed.Results: Significant pain at rest was noted. Pain ratings associated with Fas expression on cytotoxic T cells (P=0.041 and B cells (P=0.005, even after adjustment for a number of clinical treatment factors (P=0.006 and P=0.052, respectively. On the day that more patients were able to communicate, Fas

  6. Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Newsom-Davis, J.; Willcox, N.; Calder, L.

    1981-11-26

    We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.

  7. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

    DEFF Research Database (Denmark)

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis

    2016-01-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations...... in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia...... subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s)....

  8. The dual Syk/JAK inhibitor cerdulatinib antagonises B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia

    OpenAIRE

    Blunt, Matthew; Koehrer, S.; Dobson, R; Larrayoz, M; Wilmore, S.; Hayman, A.; Parnell, J; Smith, L D; Davies, A.; Johnson, P. W.; Conley, P B; Pandey, A.; Strefford, J C; Stevenson, F.K. (Freda K.); Packham, G

    2016-01-01

    Purpose: B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/J...

  9. Silenced B-Cell Receptor Response To Autoantigen In A Poor-Prognostic Subset Of Chronic Lymphocytic Leukemia

    DEFF Research Database (Denmark)

    Bergh, Ann-Charlotte; Evaldsson, Chamilly; Pedersen, Lone Bredo

    2014-01-01

    receptor-signal transduction events, since it is more faithful to B-cell physiology than anti-IgM. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen binding induced prompt receptor...... clustering followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca(2+) mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase 1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein......Chronic lymphocytic leukemia B cells express auto/xeno antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde that is present on low-density lipoprotein...

  10. Inhibition of antigen receptor-dependent Ca(2+) signals and NF-AT activation by P2X7 receptors in human B lymphocytes.

    Science.gov (United States)

    Pippel, Anja; Beßler, Björn; Klapperstück, Manuela; Markwardt, Fritz

    2015-04-01

    One of the first intracellular signals after antigen binding by the antigen receptor of B lymphocytes is the increased intracellular Ca(2+) concentration ([Ca(2+)]i), which is followed by several intracellular signaling events like the nuclear translocation of the transcription factor NF-AT controlling the fate of B lymphocytes after their activation. Extracellular ATP, which is released from cells under several pathological conditions, is considered a danger-associated signal serving as an immunomodulator. We investigated the interaction of antigen receptor (BCR) and P2X7 receptor (P2X7R) activation on [Ca(2+)]i signaling and on nuclear translocation of the transcription factor NF-AT in human B lymphocytes. Although the P2X7R is an ATP-gated Ca(2+)-permeable ion channel, P2X7R activation inhibits the BCR-mediated [Ca(2+)]i responses. This effect is mimicked by cell membrane depolarization induced by an increase in the extracellular K(+) concentration or by application of the Na(+) ionophore gramicidin, but is abolished by stabilization of the membrane potential using the K(+) ionophore valinomycin, by extracellular Mg(2+), which is known to inhibit P2X7R-dependent effects, or by replacing Na(+) by the less P2X7R-permeable Tris(+) ion. Furthermore, P2X7R activation by ATP inhibits the BCR-dependent translocation of the transcription factor NF-ATc1 to the nucleus. We therefore conclude that extracellular ATP via the P2X7R mediates inhibitory effects on B cell activation. This may be of relevance for understanding of the activation of the BCR under pathological conditions and for the development of therapeutic strategies targeting human B lymphocytes or P2X7 receptors.

  11. Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia.

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    Mohammad Hojjat-Farsangi

    Full Text Available ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients.Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9 and healthy donors (n = 6. IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay.The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05.ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.

  12. T cell receptor transgenic lymphocytes infiltrating murine tumors are not induced to express foxp3

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    Quatromoni Jon G

    2011-11-01

    Full Text Available Abstract Regulatory T cells (Treg that express the transcription factor Foxp3 are enriched within a broad range of murine and human solid tumors. The ontogeny of these Foxp3 Tregs - selective accumulation or proliferation of natural thymus-derived Treg (nTreg or induced Treg (iTreg converted in the periphery from naïve T cells - is not known. We used several strains of mice in which Foxp3 and EGFP are coordinately expressed to address this issue. We confirmed that Foxp3-positive CD4 T cells are enriched among tumor-infiltrating lymphocytes (TIL and splenocytes (SPL in B16 murine melanoma-bearing C57BL/6 Foxp3EGFP mice. OT-II Foxp3EGFP mice are essentially devoid of nTreg, having transgenic CD4 T cells that recognize a class II-restricted epitope derived from ovalbumin; Foxp3 expression could not be detected in TIL or SPL in these mice when implanted with ovalbumin-transfected B16 tumor (B16-OVA. Likewise, TIL isolated from B16 tumors implanted in Pmel-1 Foxp3EGFP mice, whose CD8 T cells recognize a class I-restricted gp100 epitope, were not induced to express Foxp3. All of these T cell populations - wild-type CD4, pmel CD8 and OTII CD4 - could be induced in vitro to express Foxp3 by engagement of their T cell receptor (TCR and exposure to transforming growth factor β (TGFβ. B16 melanoma produces TGFβ and both pmel CD8 and OTII CD4 express TCR that should be engaged within B16 and B16-OVA respectively. Thus, CD8 and CD4 transgenic T cells in these animal models failed to undergo peripheral induction of Foxp3 in a tumor microenvironment.

  13. The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL cells.

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    Mohammad Hojjat-Farsangi

    Full Text Available Phosphorylation of receptor tyrosine kinases (RTKs has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL. Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38 applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature and glycosylated (mature ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03. The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa isoform was significantly higher in progressive than in non-progressive disease (p<0.001. Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.

  14. Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells.

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    Mascha Binder

    Full Text Available Chronic lymphocytic leukemia (CLL is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR, we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as "subset 1" recognize antigens highly expressed in stromal cells--vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20-45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.

  15. Distribution of T-cell receptor-bearing lymphocytes in the synovial membrane from patients with rheumatoid arthritis.

    Science.gov (United States)

    Chaouni, I; Radal, M; Simony-Lafontaine, J; Combe, B; Sany, J; Rème, T

    1990-12-01

    Using immunohistology and monoclonal antibodies directed to the T-cell receptor (TCR) chains, we have analysed the distribution of TCR-bearing lymphocytes within the membrane of rheumatoid arthritis (RA) patients. Alkaline phosphatase staining for TCR alpha beta-bearing lymphocytes showed a distribution paralleling that of the total T cells. Staining for the TCR gamma delta chains revealed a moderate and rather homogeneous distribution of T gamma delta lymphocytes within the RA synovium. As evidenced by simultaneous staining for alpha beta and gamma delta receptors, the relative count of T gamma delta to alpha beta-expressing cells is close to the peripheral count (e.g.5%), and lower than that previously observed in the synovial fluid. Interestingly, the peripheral type V gamma 9-J gamma P rearrangement using the T gamma delta cell subset was relatively decreased in the synovial membrane, as compared to synovial fluid and peripheral blood, suggesting that the T gamma delta distribution in the rheumatoid synovium resembles a thymic-like situation.

  16. Expression of lymphocyte-derived growth hormone (GH) and GH-releasing hormone receptors in aging rats.

    Science.gov (United States)

    Weigent, Douglas A

    2013-04-01

    In the present study, we show that higher levels of lymphocyte GH are expressed in spleen cells from aging animals compared to young animals. Further, leukocytes from primary and secondary immune tissues and splenic T and B cells from aging rats all express higher levels of GHRH receptors compared to younger animals. Bone marrow and splenic T cells express the highest levels of GHRH receptor in aging animals. Spleen cells from aging animals showed no significant change in proliferation or GH induction after treatment with GHRH. Taken together, the data for the first time show alterations in GH synthesis and expression of the GHRH receptor on cells of the immune system that may play a role in the immune response in aging.

  17. The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis

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    Yin Cui

    2015-11-01

    Full Text Available Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2, DRD3, and dopamine and cyclic adenosine 3′,5′-monophosphate regulated phosphoprotein-32 (DARPP-32 in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls.

  18. The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency.

    Science.gov (United States)

    Partiseti, M; Le Deist, F; Hivroz, C; Fischer, A; Korn, H; Choquet, D

    1994-12-23

    Stimulation of antigen receptors of lymphocytes triggers a transitory release of Ca2+ from internal stores and the opening of a transmembrane Ca2+ conductive pathway. The latter underlies the sustained increase of intracellular free calcium concentration, and it seems to be a key event in the Ca(2+)-dependent biochemical cascade leading to T cell proliferation. Alternatively, pharmacological depletion of internal stores by itself activates Ca2+ influx. This has led to the hypothesis that antigen-triggered Ca2+ influx is secondary to Ca2+ release from internal stores. However, the precise relationship between antigen and Ca2+ release-activated Ca2+ currents remains unclear, particularly since neither of them has been electrophysiologically recorded in normal lymphocytes. Using the whole-cell and the perforated configurations of the patch clamp technique on peripheral blood lymphocytes, we found that a low amplitude Ca(2+)-selective current was triggered when intracellular stores were depleted by stimuli such as the intracellular perfusion of inositol triphosphate or thapsigargin and the extracellular perfusion of ionomycin. A similar current was elicited by the cross-linking of the T cell receptor-CD3 complex. This current displayed an inward rectification below 0 mV and was completely blocked by the divalent cation Cd2+. It was very selective for Ca2+ over Na+ and insensitive to changes in chloride concentration. The physiological relevance of this conductance was investigated with the analysis of abnormal Ca2+ signaling in lymphocytes from a patient suffering from a primary immunodeficiency associated with a defective T cell proliferation. Using fura-2 video imaging, an absence of Ca2+ influx was established in the patient's lymphocytes, whereas the Ca2+ release from internal stores was normal. This was the case whether cells were stimulated physiologically through their antigen receptors or with store depleting pharmacological agents. Most importantly, no Ca(2

  19. Homing receptor expression is deviated on CD56+ blood lymphocytes during pregnancy in Type 1 diabetic women.

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    Suzanne D Burke

    Full Text Available Type 1 Diabetes Mellitus (T1DM is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56bright NK cells, into early decidua basalis and a 2nd trimester shift towards Type 2 immunity. Decidual CD56bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. In vitro studies show that T1DM reduces interactions between blood CD56+ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1+ and Type 2 (IL1RL1+ CD56bright NK, CD56dim NK, NKT and T cells from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2nd trimester. At this time, these receptors were expressed at very low levels by CD56bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56bright NK cells. This implicates CD56bright NK cells in diabetic pregnancy complications.

  20. Stimulation of AIDS lymphocytes with calcium ionophore (A23187) and phorbol ester (PMA): studies of cytoplasmic free Ca, IL-2 receptor expression, IL-2 production, and proliferation

    DEFF Research Database (Denmark)

    Hofmann, B; Moller, J; Langhoff, E

    1989-01-01

    nine patients with AIDS with the response of lymphocytes from nine control subjects showed that the response of AIDS lymphocytes was severely decreased when stimulated with PHA and no further response could be achieved by stimulation with A23187/PMA. On the other hand, no significant difference between...... the PHA-induced rise of cytoplasmic free calcium concentration ([Ca2+]1) in normal and AIDS lymphocytes was observed. The percentage of cells expressing IL-2 receptors (CD25) was also normal both after addition of PHA and after addition of A23187/PMA and the expression was normal on both CD4 and CD8 cells....... The production of IL-2 in normal lymphocytes stimulated with A23187/PMA was 33 times higher than that after stimulation with PHA. In AIDS lymphocytes the production of IL-2 induced by all activators was severely decreased compared to control subjects, although the production of IL-2 after stimulation with A23187...

  1. Broad T-cell receptor repertoire in T-lymphocytes derived from human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Chia-Wei Chang

    Full Text Available Human induced pluripotent stem cells (hiPSCs have enormous potential for the treatment of inherited and acquired disorders. Recently, antigen-specific T lymphocytes derived from hiPSCs have been reported. However, T lymphocyte populations with broad T cell receptor (TCR diversity have not been generated. We report that hiPSCs derived from skin biopsy are capable of producing T lymphocyte populations with a broad TCR repertoire. In vitro T cell differentiation follows a similar developmental program as observed in vivo, indicated by sequential expression of CD7, intracellular CD3 and surface CD3. The γδ TCR locus is rearranged first and is followed by rearrangement of the αβ locus. Both γδ and αβ T cells display a diverse TCR repertoire. Upon activation, the cells express CD25, CD69, cytokines (TNF-α, IFN-γ, IL-2 and cytolytic proteins (Perforin and Granzyme-B. These results suggest that most, if not all, mechanisms required to generate functional T cells with a broad TCR repertoire are intact in our in vitro differentiation protocol. These data provide a foundation for production of patient-specific T cells for the treatment of acquired or inherited immune disorders and for cancer immunotherapy.

  2. Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans

    Directory of Open Access Journals (Sweden)

    Jurcevic S

    2016-12-01

    Full Text Available Stipo Jurcevic,1 Pierre-Eric Juif,2 Colleen Hamid,3 Roseanna Greenlaw,3 Daniele D’Ambrosio,2 Jasper Dingemanse2 1Department of Biomedical Sciences, University of Westminster, London, UK; 2Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; 3Division of Transplantation Immunology & Mucosal Biology, King’s College London, London, UK Abstract: This study investigated the effects of ponesimod, a selective S1P1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days or placebo (ratio 3:1. The overall change from baseline in lymphocyte count was -1,292±340×106 cells/L and 275±486×106 cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naïve CD4+ T cells (CD45RA+CCR7+ from baseline was observed only after ponesimod treatment (-113±98×106 cells/L, placebo: 0±18×106 cells/L. The number of T-cytotoxic (CD3+CD8+ and T-helper (CD3+CD4+ cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4+ T-central memory (CD45RA-CCR7+ cells (-437±164×106 cells/L and CD4+ T-effector memory (CD45RA-CCR7- cells (-131±57×106 cells/L. In addition, ponesimod treatment led to a decrease of -228±90×106 cells/L of gut-homing T cells (CLA-integrin β7+. In contrast, when compared with placebo, CD8+ T-effector memory and natural killer (NK cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4+ cells was dramatically reduced, whereas

  3. ANTI-APOPTOTIC EFFECT OF CD95 RECEPTOR IN NA VE CD8+ T-LYMPHOCYTES IN CHILDREN WITH ACUTE INFECTIOUS MONONUCLEOSIS

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    E. N. Filatova

    2016-01-01

    Full Text Available Acute infectious mononucleosis is a widespread viral disease, which most often manifests in childhood. The development of acute infectious mononucleosis is accompanied by the change of the CD4+/CD8+ T-lymphocytes ratio and the increase of the virus-specific CD8+ cytotoxic T-lymphocytes number. One of the T-lymphocytes number regulation mechanisms is the modulation of their progenitor cells apoptosis. The death receptor CD95 takes part in the regulation of T-lymphocytes apoptosis, including naïve T-cells. We studied the effect of CD95 receptor activation on apoptosis of naïve CD4+ and naïve cytotoxic CD8+ T-lymphocytes in healthy children and children with acute infectious mononucleosis. In this study children with acute infectious mononucleosis at the age of 9 to 16 years were included. For comparison healthy children of the same age with no clinical and laboratory signs of the disease were used. Naïve CD4+ and naïve cytotoxic CD8+ T-lymphocytes were isolated by negative magnetic immunoseparation. The analysis of naïve T-cells apoptosis and the CD95 receptor surface expression density was performed by using the flow cytometry analysis. The analysis of T-cells was performed in three variants: freshly isolated naïve CD4+ T-lymphocytes and naïve cytotoxic CD8+ T-lymphocytes, and also cells after 24 hours of the cultivation with anti-CD95 monoclonal antibodies or without them. In healthy children both CD95– and CD95+ naïve CD4+ T-lymphocytes underwent apoptosis. In children with acute infectious mononucleosis CD95– naïve CD4+ T-lymphocytes lost their susceptibility to apoptosis induction. In healthy children and children with acute infectious mononucleosis CD95– naïve cytotoxic CD8+ T-lymphocytes were resistant to apoptosis in contrast to CD95+ naïve CD4+ T-lymphocytes. In healthy children CD95 receptor did not induce apoptosis of isolated naïve CD4+ T-lymphocytes and naïve cytotoxic CD8+ T-lymphocytes. In children with acute

  4. Limited T-cell receptor diversity in liver-infiltrating lymphocytes from patients with primary biliary cirrhosis.

    Science.gov (United States)

    Diu, A; Moebius, U; Ferradini, L; Genevée, C; Roman-Roman, S; Claudon, M; Delorme, D; Meuer, S; Hercend, T; Praz, F

    1993-10-01

    Primary biliary cirrhosis is associated with the presence of high-titer anti-mitochondrial autoantibodies as well as T-cell infiltration of the liver, suggesting the involvement of autoimmune mechanisms. We have studied here the sequences of T-cell receptor alpha and beta chains expressed by T-cell clones derived from liver-infiltrating lymphocytes of two patients with primary biliary cirrhosis. Among the eight clones studied from the first patient, four expressed the same member of the V beta 6 subfamily, associated with either V alpha 4 (three clones) or V alpha 21 (one clone) gene segment. Two other clones expressed an identical V beta 12 transcript, and two in-frame alpha chain transcripts, involving V alpha 2 and V alpha 7 gene segments. From the second patient, eight out of the nine clones were found to rearrange V beta 17-J beta 2.1 and V alpha 3 gene segments. The remaining clone expressed distinct T-cell receptor chains, involving V beta 9 and V alpha 11 gene segments. As deduced from the analysis of their junctional regions, the eight T-cell clones expressing V beta 17/V alpha 3 gene segments derived from only three different T cells. Furthermore, conserved amino acid motifs were found to be encoded in both the alpha and the beta-chain junctional regions. Together, these data show a local amplification of unique T lymphocytes in both patients. The use of identical V beta J beta and V alpha gene segments with similar junctional sequences by three different cells, evidenced in one of the two cases, strengthens the view that liver-infiltrating T lymphocytes are selected locally by autoantigens in PBC.

  5. Analysis of T cell receptor alpha beta variability in lymphocytes infiltrating melanoma primary tumours and metastatic lesions

    DEFF Research Database (Denmark)

    Schøller, J; thor Straten, P; Jakobsen, Annette Birck;

    1994-01-01

    The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse-transcription-couple......The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse...... usage of the TCR V gene families V alpha 4, V alpha 5, V alpha 22 and V beta 8, whereas the V beta 3 gene family appeared to be expressed together with HLA-A1. Other highly expressed V gene families, apparently not restricted to either HLA-A1 or -A2, were V alpha 1 (expressed in three of four primary...... tumours) and V alpha 21 (expressed in two of four tumours). We found no evidence suggesting any correlations between the haplotypes HLA-A1 and -A2 and preferential V gene family expression in the metastatic lesions, and the only common feature was V alpha 8, which was found to be highly expressed in two...

  6. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: implications for disease pathogenesis and treatment

    Science.gov (United States)

    ten Hacken, Elisa; Burger, Jan A.

    2015-01-01

    Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. PMID:26193078

  7. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment.

    Science.gov (United States)

    Ten Hacken, Elisa; Burger, Jan A

    2016-03-01

    Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. The role of Ly49E receptor expression on murine intraepithelial lymphocytes in intestinal cancer development and progression.

    Science.gov (United States)

    Van Acker, Aline; Louagie, Els; Filtjens, Jessica; Taveirne, Sylvie; Van Ammel, Els; Kerre, Tessa; Elewaut, Dirk; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Leclercq, Georges

    2016-11-01

    Ly49E is a member of the Ly49 family of NK receptors and is distinct from other members of this family on the basis of its structural properties, expression pattern and ligand recognition. Importantly, Ly49E receptor expression is high on small intestinal and colonic intraepithelial lymphocytes (IELs). Intestinal IELs are regulators of the mucosal immune system and contribute to front-line defense at the mucosal barrier, including anti-tumor immune response. Whereas most Ly49 receptors have MHC class-I ligands, we showed that Ly49E is instead triggered by urokinase plasminogen activator (uPA). uPA has been extensively implicated in tumor development, where increased uPA expression correlates with poor prognosis. As such, we investigated the role of Ly49E receptor expression on intestinal IELs in the anti-tumor immune response. For this purpose, we compared Ly49E wild-type mice to Ly49E knockout mice in two established tumor models: Apc(Min/+)-mediated and azoxymethane-induced intestinal cancer. Our results indicate that Ly49E expression on IELs does not influence the development or progression of intestinal cancer.

  9. Vascular endothelial growth factor receptor inhibitor SU5416 suppresses lymphocyte generation and immune responses in mice by increasing plasma corticosterone.

    Directory of Open Access Journals (Sweden)

    Jamison J Grailer

    Full Text Available Inhibitors of vascular endothelial growth factor and its receptors (VEGFRs are attractive therapeutic candidates for cancer treatment. One such small molecule VEGFR inhibitor, SU5416, limits angiogenesis in vivo and is widely used for investigating VEGFR signaling in tumor pathophysiology. Herein, we describe novel actions of SU5416 on the immune system. Treatment of mice with SU5416 for 3 days induced significant reductions in size and cellularity of peripheral lymph nodes. Interestingly, SU5416 did not affect initial lymphocyte localization to peripheral lymph nodes but did reduce lymphocyte accumulation during long-term migration assays. Treatment with SU5416 also induced severe loss of double-positive thymocytes resulting in thymic atrophy and a reduction in peripheral B cells. Furthermore, immune responses following immunization were reduced in mice treated with SU5416. Findings of thymic atrophy and reduced weight gain during SU5416 treatment suggested elevated corticosterone levels. Indeed, a significant 5-fold increase in serum corticosterone was found 4 hours after treatment with SU5416. Importantly, adrenalectomy negated the effects of SU5416 treatment on primary immune tissues, and partial reversal of SU5416-induced changes was observed following blockade of glucocorticoid receptors. SU5416 has been reported to inhibit the activation of latent transforming growth factor (TGF-β, a cytokine involved in the regulation of glucocorticoid release by the adrenal glands. Interestingly, treatment with a TGF-β receptor inhibitor, showed a similar phenotype as SU5416 treatment, including elevated serum corticosterone levels and thymic atrophy. Therefore, these results suggest that SU5416 induces glucocorticoid release directly from the adrenal glands, possibly by inhibition of TGF-β activation.

  10. CXCR3, CCR5, and CRTH2 Chemokine Receptor Expression in Lymphocytes Infiltrating Thyroid Nodules with Coincident Hashimoto’s Thyroiditis Obtained by Fine Needle Aspiration Biopsy

    Directory of Open Access Journals (Sweden)

    Jan Jiskra

    2016-01-01

    Full Text Available Objective. To determine the expression of chemokine receptors in lymphocytes from thyroid nodules and peripheral blood in patients with and without Hashimoto’s thyroiditis (HT. Patients and Methods. The study included 46 women with thyroid nodules and HT and 60 women with thyroid nodules without HT (controls who underwent a fine needle aspiration biopsy (FNAB. Expression of chemokine receptors CXCR3, CCR5, and CRTH2 was assessed by flow cytometry in lymphocytes from FNAB samples and from peripheral blood. Results. The percentage of CRTH2+ lymphocytes was higher in nodules with HT in comparison with controls, both in FNAB samples (13.95 versus 6.7%, p=0.008 and in peripheral blood (6.7 versus 5.13%, p=0.047, and positively correlated with serum antibodies to thyroid peroxidase (r=0.243; p=0.026 and negatively correlated with thyroid volume (r=-0.346; p=0.008. Lymphocytes from neoplastic nodules showed a higher expression of both CXCR3 and CCR5 than those from hyperplastic ones. Conclusion. Flow cytometry performed in FNAB samples may serve as a good tool in investigation of intrathyroidal expression of immunological parameters. In our study, the CRTH2 expression on thyroid-infiltrating lymphocytes as well as on lymphocytes from peripheral blood was increased in HT as compared to controls.

  11. CXCR3, CCR5, and CRTH2 Chemokine Receptor Expression in Lymphocytes Infiltrating Thyroid Nodules with Coincident Hashimoto's Thyroiditis Obtained by Fine Needle Aspiration Biopsy

    Science.gov (United States)

    Antošová, Marie; Krátký, Jan; Vítková, Hana; Límanová, Zdeňka; Marečková, Helena; Potluková, Eliška

    2016-01-01

    Objective. To determine the expression of chemokine receptors in lymphocytes from thyroid nodules and peripheral blood in patients with and without Hashimoto's thyroiditis (HT). Patients and Methods. The study included 46 women with thyroid nodules and HT and 60 women with thyroid nodules without HT (controls) who underwent a fine needle aspiration biopsy (FNAB). Expression of chemokine receptors CXCR3, CCR5, and CRTH2 was assessed by flow cytometry in lymphocytes from FNAB samples and from peripheral blood. Results. The percentage of CRTH2+ lymphocytes was higher in nodules with HT in comparison with controls, both in FNAB samples (13.95 versus 6.7%, p = 0.008) and in peripheral blood (6.7 versus 5.13%, p = 0.047), and positively correlated with serum antibodies to thyroid peroxidase (r = 0.243; p = 0.026) and negatively correlated with thyroid volume (r = −0.346; p = 0.008). Lymphocytes from neoplastic nodules showed a higher expression of both CXCR3 and CCR5 than those from hyperplastic ones. Conclusion. Flow cytometry performed in FNAB samples may serve as a good tool in investigation of intrathyroidal expression of immunological parameters. In our study, the CRTH2 expression on thyroid-infiltrating lymphocytes as well as on lymphocytes from peripheral blood was increased in HT as compared to controls. PMID:27872865

  12. Receptor Activator of Nuclear Factor κB Ligand (RANKL) Protein Expression by B Lymphocytes Contributes to Ovariectomy-induced Bone Loss*

    Science.gov (United States)

    Onal, Melda; Xiong, Jinhu; Chen, Xinrong; Thostenson, Jeff D.; Almeida, Maria; Manolagas, Stavros C.; O'Brien, Charles A.

    2012-01-01

    Production of the cytokine receptor activator of NFκB ligand (RANKL) by lymphocytes has been proposed as a mechanism by which sex steroid deficiency causes bone loss. However, there have been no studies that functionally link RANKL expression in lymphocytes with bone loss in this condition. Herein, we examined whether RANKL expression in either B or T lymphocytes contributes to ovariectomy-induced bone loss in mice. Mice harboring a conditional RANKL allele were crossed with CD19-Cre or Lck-Cre mice to delete RANKL in B or T lymphocytes, respectively. Deletion of RANKL from either cell type had no impact on bone mass in estrogen-replete mice up to 7 months of age. However, mice lacking RANKL in B lymphocytes were partially protected from the bone loss caused by ovariectomy. This protection occurred in cancellous, but not cortical, bone and was associated with a failure to increase osteoclast numbers in the conditional knock-out mice. Deletion of RANKL from T lymphocytes had no impact on ovariectomy-induced bone loss. These results demonstrate that lymphocyte RANKL is not involved in basal bone remodeling, but B cell RANKL does contribute to the increase in osteoclasts and cancellous bone loss that occurs after loss of estrogen. PMID:22782898

  13. Sequence analysis of morbillivirus CD150 receptor-Signaling Lymphocyte Activation Molecule (SLAM) of different animal species.

    Science.gov (United States)

    Sarkar, J; Balamurugan, V; Sen, A; Saravanan, P; Sahay, B; Rajak, K K; Rasool, T J; Bhanuprakash, V; Singh, R K

    2009-12-01

    Signaling Lymphocyte Activation Molecule-SLAM (CD150) molecule has been reported as a putative receptor for most morbilliviruses for their respective host species. In this study, we determined the complete nucleotide sequence of the gene coding for the morbillivirus receptor-SLAM from the four species, namely, goat (Capra hircus), sheep (Ovis aries), Indian cattle (Bos indicus), and buffalo (Bubalus bubalis). The nucleotide (nt) open reading frame sequence of SLAM gene in all the four species studied was 1017 nucleotides in length encoding a polypeptide of 339 amino acids (aa), similar to Bos taurus, but different from canine, human, marmoset, and mouse SLAM, which were 1029, 1008, 1011, and 1032 nts, respectively, in length, and coding for 343, 336, 337, and 344 aa, respectively. Sequence analysis revealed 96.3-98.5% and 92.9-96.8% identities among the four species at the nt and aa level, respectively. Sequence diversity at aa level between various species revealed that the critical functional region of SLAM protein among different species is relatively conserved, thereby facilitating this molecule to act as a receptor for morbillivirus. Phylogenetic relationship based on the aa sequences of SLAM protein revealed that caprine, ovine, cattle, and buffalo fall under a defined cluster but caprine SLAM is more closely related to ovine, followed by bovine.

  14. Over-Expression of Dopamine D2 Receptor and Inwardly Rectifying Potassium Channel Genes in Drug-Naive Schizophrenic Peripheral Blood Lymphocytes as Potential Diagnostic Markers

    OpenAIRE

    Ágnes Zvara; György Szekeres; Zoltán Janka; Kelemen, János Z.; Csongor Cimmer; Miklós Sántha; Puskás, László G.

    2005-01-01

    Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-exp...

  15. Recognition of antigen-specific B-cell receptors from chronic lymphocytic leukemia patients by synthetic antigen surrogates.

    Science.gov (United States)

    Sarkar, Mohosin; Liu, Yun; Morimoto, Jumpei; Peng, Haiyong; Aquino, Claudio; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2014-12-18

    In patients with chronic lymphocytic leukemia (CLL), a single neoplastic antigen-specific B cell accumulates and overgrows other B cells, leading to immune deficiency. CLL is often treated with drugs that ablate all B cells, leading to further weakening of humoral immunity, and a more focused therapeutic strategy capable of targeting only the pathogenic B cells would represent a significant advance. One approach to this would be to develop synthetic surrogates of the CLL antigens allowing differentiation of the CLL cells and healthy B cells in a patient. Here, we describe nonpeptidic molecules capable of targeting antigen-specific B cell receptors with good affinity and selectivity using a combinatorial library screen. We demonstrate that our hit compounds act as synthetic antigen surrogates and recognize CLL cells and not healthy B cells. Additionally, we argue that the technology we developed can be used to identify other classes of antigen surrogates.

  16. Autoantigenic targets of B-cell receptors derived from chronic lymphocytic leukemias bind to and induce proliferation of leukemic cells.

    Science.gov (United States)

    Zwick, Carsten; Fadle, Natalie; Regitz, Evi; Kemele, Maria; Stilgenbauer, Stephan; Bühler, Andreas; Pfreundschuh, Michael; Preuss, Klaus-Dieter

    2013-06-06

    Antigenic targets of the B-cell receptor (BCR) derived from malignant cells in chronic lymphocytic leukemia (CLL) might play a role in the pathogenesis of this neoplasm. We screened human tissue-derived protein macroarrays with antigen-binding fragments derived from 47 consecutive cases of CLL. An autoantigenic target was identified for 12/47 (25.5%) of the cases, with 3 autoantigens being the target of the BCRs from 2 patients each. Recombinantly expressed autoantigens bound specifically to the CLL cells from which the BCR used for the identification of the respective autoantigen was derived. Moreover, binding of the autoantigen to the respective leukemic cells induced a specific activation and proliferation of these cells. In conclusion, autoantigens are frequent targets of CLL-BCRs. Their specific binding to and induction of proliferation in the respective leukemic cells provide the most convincing evidence to date for the long-time hypothesized role of autoantigens in the pathogenesis of CLL.

  17. CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse

    NARCIS (Netherlands)

    Romero, [No Value; Zapater, N; Calvo, M; Kalko, SG; de la Fuente, MA; Tovar, [No Value; Ockeloen, C; Pizcueta, P; Engel, P

    2005-01-01

    CD229 is a member of the CD150 family of the Ig superfamily expressed on T and B cells. Receptors of this family regulate cytokine production and cytotoxicity of lymphocytes and NK cells. The cytoplasmic tail of CD229 binds to SAP, a protein that is defective in X-linked lymphoproliferative syndrome

  18. CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse

    NARCIS (Netherlands)

    Romero, [No Value; Zapater, N; Calvo, M; Kalko, SG; de la Fuente, MA; Tovar, [No Value; Ockeloen, C; Pizcueta, P; Engel, P

    2005-01-01

    CD229 is a member of the CD150 family of the Ig superfamily expressed on T and B cells. Receptors of this family regulate cytokine production and cytotoxicity of lymphocytes and NK cells. The cytoplasmic tail of CD229 binds to SAP, a protein that is defective in X-linked lymphoproliferative syndrome

  19. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

    Science.gov (United States)

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Moysiadis, Theodoros; Plevova, Karla; Rossi, Davide; Kminkova, Jana; Stalika, Evangelia; Pedersen, Lone Bredo; Malcikova, Jitka; Agathangelidis, Andreas; Davis, Zadie; Mansouri, Larry; Scarfò, Lydia; Boudjoghra, Myriam; Navarro, Alba; Muggen, Alice F.; Yan, Xiao-Jie; Nguyen-Khac, Florence; Larrayoz, Marta; Panagiotidis, Panagiotis; Chiorazzi, Nicholas; Niemann, Carsten Utoft; Belessi, Chrysoula; Campo, Elias; Strefford, Jonathan C.; Langerak, Anton W.; Oscier, David; Gaidano, Gianluca; Pospisilova, Sarka; Davi, Frederic; Ghia, Paolo; Stamatopoulos, Kostas; Rosenquist, Richard

    2016-01-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22–34%), often in association with trisomy 12, and was significantly different (Pimmunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s). PMID:27198719

  20. Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans

    Science.gov (United States)

    Jurcevic, Stipo; Juif, Pierre-Eric; Hamid, Colleen; Greenlaw, Roseanna; D’Ambrosio, Daniele; Dingemanse, Jasper

    2017-01-01

    This study investigated the effects of ponesimod, a selective S1P1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was −1,292±340×106 cells/L and 275±486×106 cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naïve CD4+ T cells (CD45RA+CCR7+) from baseline was observed only after ponesimod treatment (−113±98×106 cells/L, placebo: 0±18×106 cells/L). The number of T-cytotoxic (CD3+CD8+) and T-helper (CD3+CD4+) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4+ T-central memory (CD45RA−CCR7+) cells (−437±164×106 cells/L) and CD4+ T-effector memory (CD45RA−CCR7−) cells (−131±57×106 cells/L). In addition, ponesimod treatment led to a decrease of −228±90×106 cells/L of gut-homing T cells (CLA−integrin β7+). In contrast, when compared with placebo, CD8+ T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4+ cells was dramatically reduced, whereas CD8+ and NK cells were less affected, allowing the body to preserve critical viral-clearing functions. PMID:28096659

  1. ROLE OF CD95 AND DR3 RECEPTORS IN NA VE T-LYMPHOCYTES APOPTOSIS IN CHILDREN WITH INFECTIOUS MONONUCLEOSIS DURING CONVALESCENCE

    Directory of Open Access Journals (Sweden)

    E. N. Filatova

    2017-01-01

    Full Text Available Infectious mononucleosis is a widespread disease caused by certain members of Herpesviridae family. Acute infectious mononucleosis develops predominantly in children and is accompanied by an increase of the number of circulating naive CD4+ and naive CD8+ T-lymphocytes in the peripheral blood. The normalization of immunological parameters is achieved within 4–6 months after recovery and that is an indicator of a proper functioning of the immune system. CD95 and DR3 death receptors are involved in the initiation of apoptosis of naive T-lymphocytes in healthy people and in patients with infectious mononucleosis. The aim of the study was to evaluate the ability of CD95 and DR3 receptors to initiate apoptosis of naive CD4+ and naive CD8+ T-lymphocytes in children with infectious mononucleosis during convalescence. The material for the study was the samples of the peripheral blood of children who previously had infectious mononucleosis. The blood sampling was carried out again after 4–6 months after the disease. At the time of the study, children did not display clinical and laboratory signs of infectious mononucleosis. Same children who were examined earlier in the period of the development of acute infectious mononucleosis, as well as relatively healthy children were used as the comparison groups. Isolation of naive CD4+ and naive CD8+ T-lymphocytes was performed by negative magnetic immunoseparation. For specific stimulation of CD95 and DR3 receptors monoclonal antibodies were used. The level of apoptosis and expression of death receptors were evaluated by flow cytometry. Freshly isolated cells were analyzed, as well as cells cultured with the addition of appropriate monoclonal antibodies. It was shown that the recovery period was accompanied by increased apoptosis of freshly isolated naive CD4+ and naive CD8+ T-lymphocytes compared with the acute phase of infectious mononucleosis. Thus in both populations of naive T-cells showed an increase of

  2. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Agathangelidis, Andreas; Darzentas, Nikos; Hadzidimitriou, Anastasia

    2012-01-01

    Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency...... as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may...... be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR...

  3. Redirecting Therapeutic T Cells against Myelin-Specific T Lymphocytes Using a Humanized Myelin Basic Protein-HLA-DR2-{zeta} Chimeric Receptor

    DEFF Research Database (Denmark)

    Moisini, Ioana; Nguyen, Phuong; Fugger, Lars

    2008-01-01

    Therapies that Ag-specifically target pathologic T lymphocytes responsible for multiple sclerosis (MS) and other autoimmune diseases would be expected to have improved therapeutic indices compared with Ag-nonspecific therapies. We have developed a cellular immunotherapy that uses chimeric receptors...... to selectively redirect therapeutic T cells against myelin basic protein (MBP)-specific T lymphocytes implicated in MS. We generated two heterodimeric receptors that genetically link the human MBP(84-102) epitope to HLA-DR2 and either incorporate or lack a TCRzeta signaling domain. The Ag-MHC domain serves...... as a bait, binding the TCR of MBP-specific target cells. The zeta signaling region stimulates the therapeutic cell after cognate T cell engagement. Both receptors were well expressed on primary T cells or T hybridomas using a tricistronic (alpha, beta, green fluorescent protein) retroviral expression system...

  4. Ontogenic development of kidney, thymus and spleen and phenotypic expression of CD3 and CD4 receptors on the lymphocytes of cobia (Rachycentroncanadum).

    Science.gov (United States)

    Klosterhoff, Marta C; Pereira Júnior, Joaber; Rodrigues, Ricardo V; Gusmão, Emeline P; Sampaio, Luís A; Tesser, Marcelo B; Romano, Luis A

    2015-01-01

    In the present study was evaluated the ontogenic of immunocompetent organs of cobia up to 53 days after hatching (dah) through histology and immunohistochemistry techniques. The kidney was the first lymphohematopoietic organ to appear, at 1 dah, followed by the spleen at 5 dah and the thymus at 7 dah. The first CD3 receptors on the lymphocytes were observed in 27% of the thymic tissue at 7 dah and in 99% at 53 dah. The phenotypic expression of CD3 receptors was registered in 10% of the kidney at 8 dah and in 32% at 53 dah. CD4 receptors were observed in 5% and 63% of the thymic area at 7 and 53 dah, respectively. In the kidney, T4 lymphocytes were first observed at 13 dah in 9% of the organ and in 28% at 53 dah, defining the functional development of the specific system associated with immunological memory capacity.

  5. Measles virus glycoprotein-pseudotyped lentiviral vector-mediated gene transfer into quiescent lymphocytes requires binding to both SLAM and CD46 entry receptors.

    Science.gov (United States)

    Frecha, Cecilia; Lévy, Camille; Costa, Caroline; Nègre, Didier; Amirache, Fouzia; Buckland, Robin; Russell, Steven J; Cosset, François-Loïc; Verhoeyen, Els

    2011-06-01

    Gene transfer into quiescent T and B cells is of importance for gene therapy and immunotherapy approaches to correct hematopoietic disorders. Previously, we generated lentiviral vectors (LVs) pseudotyped with the Edmonston measles virus (MV) hemagglutinin and fusion glycoproteins (Hgps and Fgps) (H/F-LVs), which, for the first time, allowed efficient transduction of quiescent human B and T cells. These target cells express both MV entry receptors used by the vaccinal Edmonston strain, CD46 and signaling lymphocyte activation molecule (SLAM). Interestingly, LVs pseudotyped with an MV Hgp, blind for the CD46 binding site, were completely inefficient for resting-lymphocyte transduction. Similarly, SLAM-blind H mutants that recognize only CD46 as the entry receptor did not allow stable LV transduction of resting T cells. The CD46-tropic LVs accomplished vector-cell binding, fusion, entry, and reverse transcription at levels similar to those achieved by the H/F-LVs, but efficient proviral integration did not occur. Our results indicate that both CD46 and SLAM binding sites need to be present in cis in the Hgp to allow successful stable transduction of quiescent lymphocytes. Moreover, the entry mechanism utilized appears to be crucial: efficient transduction was observed only when CD46 and SLAM were correctly engaged and an entry mechanism that strongly resembles macropinocytosis was triggered. Taken together, our results suggest that although vector entry can occur through the CD46 receptor, SLAM binding and subsequent signaling are also required for efficient LV transduction of quiescent lymphocytes to occur.

  6. Novel primary thymic defect with T lymphocytes expressing gamma delta T cell receptor

    DEFF Research Database (Denmark)

    Geisler, C; Pallesen, G; Platz, P

    1989-01-01

    Flow cytometric analysis of the peripheral blood mononuclear cells in a six year old girl with a primary cellular immune deficiency showed a normal fraction of CD3 positive T cells. Most (70%) of the CD3 positive cells, however, expressed the gamma delta and not the alpha beta T cell receptor....... Immunoprecipitation and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that most of the gamma delta T cell receptors existed as disulphide-linked heterodimers. Proliferative responses to mitogens were severely reduced, but specific antibody responses after vaccination could be detected...... deficiency associated with a high proportion of T cells expressing the gamma delta T cell receptor has been described in nude mice, and it is suggested that the immune deficiency of this patient may represent a human analogue....

  7. Attachment of an anti-receptor antibody to non-target cells renders them susceptible to lysis by a clone of cytotoxic T lymphocytes.

    OpenAIRE

    Kranz, D M; Tonegawa, S.; Eisen, H N

    1984-01-01

    The molecular basis for the dependence of antigen recognition by T cells on products of the major histocompatibility complex (MHC) is unknown, and the antigenic structures that are actually bound by T-cell receptors are ill-defined. In this study, we asked whether a monoclonal antibody (mAb) that reacts with the T-cell receptor of a clone of murine cytotoxic T lymphocytes (CTL) and not with the receptors of other CTL clones can substitute for that clone's natural ligand in specific cytolytic ...

  8. Characterization of a novel human scavenger receptor cysteine-rich molecule SCART1 expressed by lymphocytes

    DEFF Research Database (Denmark)

    Holm, D.; Fink, D. R.; Steffensen, M. A.;

    2013-01-01

    of hSCART1 in the small intestine and colon. An antibody raised against an N-terminal hSCART1 peptide stains a subset of cells in the small intestine, stomach, and gall bladder, and it also stains placental villi. In conclusion, the characterization of hSCART1 at the mRNA and protein level suggests......The scavenger receptor cysteine-rich (SRCR) superfamily is a group of membrane bound and secreted proteins expressed by cells of the immune system. Several members act as pattern recognition receptors that bind to conserved molecular structures of pathogens. We have previously characterized...

  9. T lymphocyte antigen 4-modified dendritic cell therapy for asthmatic mice guided by the CCR7 chemokine receptor.

    Science.gov (United States)

    Chen, Yan; Wang, Yongming; Fu, Zhou

    2014-08-29

    The CD80/CD86-CD28 axis is a critical pathway for immuno-corrective therapy, and the cytotoxic T lymphocyte antigen 4 (CTLA4) is a promising immunosuppressor targeting the CD80/CD86-CD28 axis; however, its use for asthma therapy needs further optimization. A human CTLA4 fused with the IgCγ Fc (CTLA4Ig) and mouse CC chemokine receptor type7 (CCR7) coding sequences were inserted into a recombinant adenovirus (rAdV) vector to generate rAdV-CTLA4Ig and rAdV-CCR7. The naive dendritic cells (DCs) were infected with these rAdVs to ensure CCR7 and CTLA4Ig expression. The therapeutic effects of modified DCs were evaluated. rAdV-CTLA4Ig and rAdV-CCR7 infected DCs improved all asthma symptoms. Inflammatory cell infiltration and cytokine analysis showed that rAdV-CTLA4Ig and rAdV-CCR7-modified DC therapy reduced the number of eosinophils and lymphocyte and neutrophil infiltration in the lung. Interestingly, assessment of the humoral immunity showed that the IL-4 and IFNγ levels of the rAdV-CTLA4Ig and rAdV-CCR7-modified DC-treated mice decreased significantly and did not reverse the Th1/Th2 balance. DCs expressing CCR7 displayed guidance ability for DC migration, primarily for DCs in the inflammatory lung. Additionally, the rAdVs caused an inflammatory response by inducing DC differentiation, inflammatory cell infiltration and changes in cytokines; however, mice transplanted with rAdV-green fluorescent protein (GFP)-infected DCs displayed no asthma manifestations. In conclusion, CTLA4Ig-modified DCs exhibited a therapeutic effect on asthma, and CCR7 may guide DC homing. The combination of these two molecules may be a model for precision-guided immunotherapy.

  10. Adoptive transfer of MART-1 T cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma

    Science.gov (United States)

    Chodon, Thinle; Comin-Anduix, Begonya; Chmielowski, Bartosz; Koya, Richard C; Wu, Zhongqi; Auerbach, Martin; Ng, Charles; Avramis, Earl; Seja, Elizabeth; Villanueva, Arturo; McCannel, Tara A.; Ishiyama, Akira; Czernin, Johannes; Radu, Caius G.; Wang, Xiaoyan; Gjertson, David W.; Cochran, Alistair J.; Cornetta, Kenneth; Wong, Deborah J.L.; Kaplan-lefko, Paula; Hamid, Omid; Samlowski, Wolfram; Cohen, Peter A.; Daniels, Gregory A.; Mukherji, Bijay; Yang, Lili; Zack, Jerome A.; Kohn, Donald B.; Heath, James R.; Glaspy, John A.; Witte, Owen N.; Baltimore, David; Economou, James S.; Ribas, Antoni

    2014-01-01

    Purpose It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. Experimnetal Design A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. Results 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Conclusion Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. PMID:24634374

  11. Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Suresh K Mendu

    Full Text Available γ-Aminobutyric acid (GABA is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronal GABA-A receptors (GABA-A channels located at synapses and outside of synapses. The GABA-A receptors are primary targets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. We have examined in human, mouse and rat CD4(+ and CD8(+ T cells which subunit isoforms of the GABA-A channels are expressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn is determined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoforms identified in human, mouse and rat CD4(+ and CD8(+ T cells, respectively. Importantly, the γ2 subunit that imposes benzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots and immunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activated whole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline, antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed but the subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal models to study the physiological role and pharmacological properties of GABA-A channels in CD4(+ and CD8(+ T cells and when selecting drugs aimed at modulating the human T cells function.

  12. Adenosine, dopamine and serotonin receptors imbalance in lymphocytes of Lesch-Nyhan patients.

    Science.gov (United States)

    García, Marta G; Puig, Juan G; Torres, Rosa J

    2012-11-01

    Lesch-Nyhan disease (LND) is caused by complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase enzyme. It is characterized by overproduction of uric acid, jointly with severe motor disability and self-injurious behaviour which physiopathology is unknown. These neurological manifestations suggest a dysfunction in the basal ganglia, and three neurotransmitters have been implicated in the pathogenesis of the disease: dopamine, adenosine and serotonin. All of them are implicated in motor function and behaviour, and act by binding to specific G-protein coupled receptors in the synaptic membrane where they seem to be integrated through receptor-receptor interactions. In this work we have confirmed at protein level the previously reported increased expression of DRD5 and the variably aberrant expression of ADORA2A, in LND PBL respect to control PBL. We have also described, for the first time, a decreased expression and protein level of 5-HTR1A in LND PBL respect to control PBL. If these results were confirmed in the Lesch-Nyhan patients basal ganglia cells, this would support the hypothesis that pathogenesis of neurological manifestations of Lesch-Nyhan patients may be related to an imbalance of neurotransmitters, rather than to the isolated disturbance of one of the neurotransmitters, and this fact should be taken into account in the design of pharmacologic treatment for their motor and behavioural disturbances.

  13. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    Energy Technology Data Exchange (ETDEWEB)

    Girolami, Flavia, E-mail: flavia.girolami@unito.it [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Spalenza, Veronica, E-mail: veronica.spalenza@unito.it [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Carletti, Monica, E-mail: monica.carletti@unito.it [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Sacchi, Paola, E-mail: paola.sacchi@unito.it [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Rasero, Roberto, E-mail: roberto.rasero@unito.it [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Nebbia, Carlo, E-mail: carlo.nebbia@unito.it [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy)

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring.

  14. Curcumin blocks interleukin (IL)-2 signaling in T-lymphocytes by inhibiting IL-2 synthesis, CD25 expression, and IL-2 receptor signaling

    Energy Technology Data Exchange (ETDEWEB)

    Forward, Nicholas A.; Conrad, David M. [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Power Coombs, Melanie R.; Doucette, Carolyn D. [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Furlong, Suzanne J. [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Lin, Tong-Jun [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia (Canada); Hoskin, David W., E-mail: d.w.hoskin@dal.ca [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

    2011-04-22

    Highlights: {yields} Curcumin inhibits CD4{sup +} T-lymphocyte proliferation. {yields} Curcumin inhibits interleukin-2 (IL-2) synthesis and CD25 expression by CD4{sup +} T-lymphocytes. {yields} Curcumin interferes with IL-2 receptor signaling by inhibiting JAK3 and STAT5 phosphorylation. {yields} IL-2-dependent regulatory T-lymphocyte function and Foxp3 expression is downregulated by curcumin. -- Abstract: Curcumin (diferulomethane) is the principal curcuminoid in the spice tumeric and a potent inhibitor of activation-induced T-lymphocyte proliferation; however, the molecular basis of this immunosuppressive effect has not been well studied. Here we show that micromolar concentrations of curcumin inhibited DNA synthesis by mouse CD4{sup +} T-lymphocytes, as well as interleukin-2 (IL-2) and CD25 ({alpha} chain of the high affinity IL-2 receptor) expression in response to antibody-mediated cross-linking of CD3 and CD28. Curcumin acted downstream of protein kinase C activation and intracellular Ca{sup 2+} release to inhibit I{kappa}B phosphorylation, which is required for nuclear translocation of the transcription factor NF{kappa}B. In addition, IL-2-dependent DNA synthesis by mouse CTLL-2 cells, but not constitutive CD25 expression, was impaired in the presence of curcumin, which demonstrated an inhibitory effect on IL-2 receptor (IL-2R) signaling. IL-2-induced phosphorylation of STAT5A and JAK3, but not JAK1, was diminished in the presence of curcumin, indicating inhibition of critical proximal events in IL-2R signaling. In line with the inhibitory action of curcumin on IL-2R signaling, pretreatment of CD4{sup +}CD25{sup +} regulatory T-cells with curcumin downregulated suppressor function, as well as forkhead box p3 (Foxp3) expression. We conclude that curcumin inhibits IL-2 signaling by reducing available IL-2 and high affinity IL-2R, as well as interfering with IL-2R signaling.

  15. T-cell receptor Vβ repertoire of CD8+ T-lymphocyte subpopulations in cutaneous leishmaniasis patients from the state of Rio de Janeiro, Brazil

    Directory of Open Access Journals (Sweden)

    Raquel Ferraz

    2015-08-01

    Full Text Available In human cutaneous leishmaniasis (CL, the immune response is mainly mediated by T-cells. The role of CD8+ T-lymphocytes, which are related to healing or deleterious functions, in affecting clinical outcome is controversial. The aim of this study was to evaluate T-cell receptor diversity in late-differentiated effector (LDE and memory CD8+ T-cell subsets in order to create a profile of specific clones engaged in deleterious or protective CL immune responses. Healthy subjects, patients with active disease (PAD and clinically cured patients were enrolled in the study. Total CD8+ T-lymphocytes showed a disturbance in the expression of the Vβ2, Vβ9, Vβ13.2, Vβ18 and Vβ23 families. The analyses of CD8+T-lymphocyte subsets showed high frequencies of LDE CD8+T-lymphocytes expressing Vβ12 and Vβ22 in PAD, as well as effector-memory CD8+ T-cells expressing Vβ22. We also observed low frequencies of effector and central-memory CD8+ T-cells expressing Vβ2 in PAD, which correlated with a greater lesion size. Particular Vβ expansions point to CD8+ T-cell clones that are selected during CL immune responses, suggesting that CD8+ T-lymphocytes expressing Vβ12 or Vβ22 are involved in a LDE response and that Vβ2 contractions in memory CD8+T-cells are associated with larger lesions.

  16. T-cell receptor Vβ repertoire of CD8+ T-lymphocyte subpopulations in cutaneous leishmaniasis patients from the state of Rio de Janeiro, Brazil

    Science.gov (United States)

    Ferraz, Raquel; Cunha, Clarissa Ferreira; Pimentel, Maria Inês; Lyra, Marcelo Rosandiski; Schubach, Armando Oliveira; de Mendonça, Sérgio Coutinho Furtado; Da-Cruz, Alda Maria; Bertho, Alvaro Luiz

    2015-01-01

    In human cutaneous leishmaniasis (CL), the immune response is mainly mediated by T-cells. The role of CD8+ T-lymphocytes, which are related to healing or deleterious functions, in affecting clinical outcome is controversial. The aim of this study was to evaluate T-cell receptor diversity in late-differentiated effector (LDE) and memory CD8+ T-cell subsets in order to create a profile of specific clones engaged in deleterious or protective CL immune responses. Healthy subjects, patients with active disease (PAD) and clinically cured patients were enrolled in the study. Total CD8+ T-lymphocytes showed a disturbance in the expression of the Vβ2, Vβ9, Vβ13.2, Vβ18 and Vβ23 families. The analyses of CD8+T-lymphocyte subsets showed high frequencies of LDE CD8+T-lymphocytes expressing Vβ12 and Vβ22 in PAD, as well as effector-memory CD8+ T-cells expressing Vβ22. We also observed low frequencies of effector and central-memory CD8+ T-cells expressing Vβ2 in PAD, which correlated with a greater lesion size. Particular Vβ expansions point to CD8+ T-cell clones that are selected during CL immune responses, suggesting that CD8+ T-lymphocytes expressing Vβ12 or Vβ22 are involved in a LDE response and that Vβ2 contractions in memory CD8+T-cells are associated with larger lesions. PMID:26107186

  17. Glucocorticoid receptors in Epstein-Barr virus-transformed lymphocytes from patients with glucocorticoid resistance and a glucocorticoid-resistant New World primate species.

    Science.gov (United States)

    Tomita, M; Brandon, D D; Chrousos, G P; Vingerhoeds, A C; Foster, C M; Fowler, D; Loriaux, D L; Lipsett, M B

    1986-06-01

    Members of a previously reported family with glucocorticoid resistance and several New World primates have high plasma cortisol concentrations without any signs of glucocorticoid excess. The glucocorticoid receptor in circulating leukocytes and cultured skin fibroblasts from these patients and the animals is characterized by a decreased affinity for dexamethasone. On the other hand, the cell content of receptor is similar to that of corresponding tissues of normal humans. Detailed biochemical-biophysical studies of the glucocorticoid receptor in this familial syndrome and animal model became possible with the use of Epstein-Barr virus-transformed lymphocyte lines. Cell lines from patients with this syndrome and from the marmoset (Saguinus oedipus) contained decreased amounts of glucocorticoid receptors with concomitant decreases in nuclear receptor content compared to cultured Epstein-Barr virus-transformed lymphocytes from normal human subjects. This may reflect diminished induction of glucocorticoid receptor during viral transformation of cells from the patients and the animal model. Receptors from a severely affected glucocorticoid-resistant patient and the marmoset had decreased affinity for dexamethasone. Evidence for a mild affinity defect of the glucocorticoid receptor in a patient with asymptomatic glucocorticoid resistance was obtained by increased hormone-receptor dissociation at an elevated temperature. Thermal stability, mero-receptor formation, thermal activation of cytosolic receptor, and mol wt of receptors from all cell lines were normal. Only the receptors of the severely affected patient had a discernible defect in temperature-induced activation of intact cells. We conclude that the major detectable change in the receptor in both the patients and the animal model is the decreased affinity for glucocorticoid. Viral receptor induction is decreased in both patient and marmoset cells. The physiological relevance of this phenomenon is not known. Gross

  18. Dynamic T-lymphocyte chemokine receptor expression induced by interferon-beta therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Krakauer, M; Sorensen, P S; Khademi, M;

    2006-01-01

    as these influence central nervous system (CNS) transmigration and inflammation. At 'steady state' (>/=1 day after the most recent IFN-beta injection), IFN-beta treatment increased CD4(+) T-cell surface expression of CC chemokine receptor (CCR)4, CCR5 and CCR7 after 3 months of treatment, whereas that of CXC...... chemokine receptor (CXCR)3 was unaltered. Conversely, at 9-12 h after the most recent IFN-beta injection, CCR4, CCR5 and CCR7 expressions were unaltered, while CXCR3 expression was reduced. CD4(+) T-cell surface expression of CCR4 was significantly lower in untreated MS patients compared with healthy...... volunteers. Of the plasma chemokines, only CXCL10 was increased by IFN-beta treatment; CCL3, CCL4, CCL5 and CXCL9 were unaltered. CCR5 mRNA expression in blood mononuclear cells correlated with the expression of T-helper type 1 (Th1)-associated genes whereas CCR4 and CCR7 mRNA expression correlated with Th2...

  19. Immunotherapy of acute leukemia by chimeric antigen receptor-modified lymphocytes using an improved Sleeping Beauty transposon platform.

    Science.gov (United States)

    Magnani, Chiara F; Turazzi, Nice; Benedicenti, Fabrizio; Calabria, Andrea; Tenderini, Erika; Tettamanti, Sarah; Giordano Attianese, Greta M P; Cooper, Laurence J N; Aiuti, Alessandro; Montini, Eugenio; Biondi, Andrea; Biagi, Ettore

    2016-08-09

    Chimeric antigen receptor (CAR)-modified T-cell adoptive immunotherapy is a remarkable therapeutic option proven effective in the treatment of hematological malignancies. In order to optimize cell manufacturing, we sought to develop a novel clinical-grade protocol to obtain CAR-modified cytokine-induced killer cells (CIKs) using the Sleeping Beauty (SB) transposon system. Administration of irradiated PBMCs overcame cell death of stimulating cells induced by non-viral transfection, enabling robust gene transfer together with efficient T-cell expansion. Upon single stimulation, we reached an average of 60% expression of CD123- and CD19- specific 3rd generation CARs (CD28/OX40/TCRzeta). Furthermore, modified cells displayed persistence of cell subsets with memory phenotype, specific and effective lytic activity against leukemic cell lines and primary blasts, cytokine secretion, and proliferation. Adoptive transfer of CD123.CAR or CD19.CAR lymphocytes led to a significant anti-tumor response against acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) disseminated diseases in NSG mice. Notably, we found no evidence of integration enrichment near cancer genes and transposase expression at the end of the differentiation. Taken all together, our findings describe a novel donor-derived non-viral CAR approach that may widen the repertoire of available methods for T cell-based immunotherapy.

  20. Activation of the signaling cascade in response to T lymphocyte receptor stimulation and prostanoids in a case of cutaneous lupus

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu-Velez

    2011-01-01

    Full Text Available Context: Discoid lupus erythematosus is a chronic inflammatory skin disorder presenting with scarring lesions that occur predominately on sun exposed areas of the face and scalp. Case Report: A 22-year-old male was evaluated after presenting with reddish-purple, atrophic and erythematous plaques on the scalp, with loss of hair within the plaques. Biopsies for hematoxylin and eosin examination, direct immunofluorescence and immunohistochemistry analysis were performed. The hematoxylin and eosin staining demonstrated classic features of cutaneous lupus. Direct immunofluorescence revealed strong deposits of immunoglobulins IgG and IgM, fibrinogen and Complement/C3, present in 1 a shaggy pattern at the epidermal basement membrane zone, and 2 focal pericytoplasmic and perinuclear staining within epidermal keratynocytes. Immunohistochemisty staining revealed strongly positive staining with antibodies to cyclooxygenase-2, Zeta-chain-associated protein kinase 70, and HLA-DPDQDR in areas where the inflammatory infiltrate was predominant, as well as around dermal blood vessels and within the dermal extracellular matrix. Conclusions : Noting the autoimmune nature of lupus and its strong inflammatory component, we present a patient with active discoid lupus erythematosus and strong expression of Zeta-chain-associated protein kinase 70, cyclo-oxygenase-2, and HLA-DPDQDR in the inflammatory areas. We suggest that these molecules may play a significant role in the immune response of discoid cutaneous lupus, possibly including 1 the biosynthesis of the prostanoids and 2 activation of the signaling cascade in response to T-lymphocyte receptor stimulation.

  1. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Rozovski, Uri; Wu, Ji Yuan; Harris, David M; Liu, Zhiming; Li, Ping; Hazan-Halevy, Inbal; Ferrajoli, Alessandra; Burger, Jan A; O'Brien, Susan; Jain, Nitin; Verstovsek, Srdan; Wierda, William G; Keating, Michael J; Estrov, Zeev

    2014-06-12

    In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined.

  2. Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation.

    Science.gov (United States)

    Chatterjee, Madhumouli; Rauen, Thomas; Kis-Toth, Katalin; Kyttaris, Vasileios C; Hedrich, Christian M; Terhorst, Cox; Tsokos, George C

    2012-02-01

    Altered T cell function in systemic lupus erythematosus (SLE) is determined by various molecular and cellular abnormalities, including increased IL-17 production. Recent evidence suggests a crucial role for signaling lymphocyte activation molecules (SLAMs) in the expression of autoimmunity. In this study, we demonstrate that SLAMF3 and SLAMF6 expression is increased on the surface of SLE T cells compared with normal cells. SLAM coengagement with CD3 under Th17 polarizing conditions results in increased IL-17 production. SLAMF3 and SLAMF6 T cell surface expression and IL-17 levels significantly correlate with disease activity in SLE patients. Both naive and memory CD4(+) T cells produce more IL-17 in response to SLAM costimulation as compared with CD28 costimulation. In naive CD4(+) cells, IL-17 production after CD28 costimulation peaks on day 3, whereas costimulation with anti-SLAMF3 and anti-SLAMF6 Abs results in a prolonged and yet increasing production during 6 d. Unlike costimulation with anti-CD28, SLAM costimulation requires the presence of the adaptor molecule SLAM-associated protein. Thus, engagement of SLAMF3 and SLAMF6 along with Ag-mediated CD3/TCR stimulation represents an important source of IL-17 production, and disruption of this interaction with decoy receptors or blocking Abs should mitigate disease expression in SLE and other autoimmune conditions.

  3. Chemokines, lymphocytes, and HIV

    Directory of Open Access Journals (Sweden)

    Farber J.M.

    1998-01-01

    Full Text Available Chemokines are members of a family of more than 30 human cytokines whose best-described activities are as chemotactic factors for leukocytes and that are presumed to be important in leukocyte recruitment and trafficking. While many chemokines can act on lymphocytes, the roles of chemokines and their receptors in lymphocyte biology are poorly understood. The recent discoveries that chemokines can suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate co-receptors for HIV-1 entry have lent urgency to studies on the relationships between chemokines and lymphocytes. My laboratory has characterized Mig and Crg-2/IP-10, chemokines that are induced by IFN-g and that specifically target lymphocytes, particularly activated T cells. We have demonstrated that the genes for these chemokines are widely expressed during experimental infections in mice with protozoan and viral pathogens, but that the patterns of mig and crg-2 expression differed, suggesting non-redundant roles in vivo. Our related studies to identify new chemokine receptors from activated lymphocytes resulted in the cloning of STRL22 and STRL33. We and others have shown that STRL22 is a receptor for the CC chemokine MIP-3a, and STRL22 has been re-named CCR6. Although STRL33 remains an orphan receptor, we have shown that it can function as a co-receptor for HIV-1 envelope glycoproteins, and that it is active with a broader range of HIV-1 envelope glycoproteins than the major co-receptors described to date. The ability of STRL33 to function with a wide variety of envelope glycoproteins may become particularly important if therapies are instituted to block other specific co-receptors. We presume that investigations into the roles of chemokines and their receptors in lymphocyte biology will provide information important for understanding the pathogenesis of AIDS and for manipulating immune and inflammatory responses for clinical benefit

  4. Rotavirus activates lymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Jessica A Pane

    2014-03-01

    Full Text Available It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I

  5. JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes.

    Science.gov (United States)

    Yin, T; Tsang, M L; Yang, Y C

    1994-10-28

    Interleukin (IL)-4 and IL-9 regulate the proliferation of T lymphocytes through interactions with their receptors. Previous studies have shown that unknown tyrosine kinases are involved in the proliferative signaling triggered by IL-4 and IL-9. Here we show that IL-4 and IL-9 induce overlapping (170, 130, and 125 kilodalton (kDa)) and distinct (45 and 88/90 kDa, respectively) protein tyrosine phosphorylation in T lymphocytes. We further identify the 170-kDa tyrosine-phosphorylated protein as 4PS/insulin receptor substrate-1-like (IRS-1L) protein and 130-kDa protein as JAK1 kinase. Furthermore, we demonstrate for the first time that JAK1 forms complexes with the IL-4 receptor and 4PS/IRS-1L protein following ligand-receptor interaction. In addition, we demonstrate that IL-9, but not IL-4, induced tyrosine phosphorylation of Stat 91 transcriptional factor. The overlapping and distinct protein tyrosine phosphorylation and activation of the same JAK1 kinase in T lymphocytes strongly suggests that IL-4 and IL-9 share the common signal transduction pathways and that the specificity for each cytokine could be achieved through the unique tyrosine-phosphorylated proteins triggered by individual cytokines.

  6. Recent host range expansion of canine distemper virus and variation in its receptor, the signaling lymphocyte activation molecule, in carnivores.

    Science.gov (United States)

    Ohishi, Kazue; Suzuki, Rintaro; Maeda, Taro; Tsuda, Miwako; Abe, Erika; Yoshida, Takao; Endo, Yasuyuki; Okamura, Maki; Nagamine, Takashi; Yamamoto, Hanae; Ueda, Miya; Maruyama, Tadashi

    2014-07-01

    The signaling lymphocyte activation molecule (SLAM) is a receptor for morbilliviruses. To understand the recent host range expansion of canine distemper virus (CDV) in carnivores, we determined the nucleotide sequences of SLAMs of various carnivores and generated three-dimensional homology SLAM models. Thirty-four amino acid residues were found for the candidates binding to CDV on the interface of the carnivore SLAMs. SLAM of the domestic dog (Canis lupus familiaris) were similar to those of other members of the suborder Caniformia, indicating that the animals in this group have similar sensitivity to dog CDV. However, they were different at nine positions from those of felids. Among the nine residues, four of domestic cat (Felis catus) SLAM (72, 76, 82, and 129) and three of lion (Panthera leo persica) SLAM (72, 82, and 129) were associated with charge alterations, suggesting that the felid interfaces have lower affinities to dog CDV. Only the residue at 76 was different between domestic cat and lion SLAM interfaces. The domestic cat SLAM had threonine at 76, whereas the lion SLAM had arginine, a positively charged residue like that of the dog SLAM. The cat SLAM with threonine is likely to have lower affinity to CDV-H and to confer higher resistance against dog CDV. Thus, the four residues (72, 76, 82, and 129) on carnivore SLAMs are important for the determination of affinity and sensitivity with CDV. Additionally, the CDV-H protein of felid strains had a substitution of histidine for tyrosine at 549 of dog CDV-H and may have higher affinity to lion SLAM. Three-dimensional model construction is a new risk assessment method of morbillivirus infectivity. Because the method is applicable to animals that have no information about virus infection, it is especially useful for morbillivirus risk assessment and wildlife conservation.

  7. The glucocorticoid receptor 1A3 promoter correlates with high sensitivity to glucocorticoid-induced apoptosis in human lymphocytes.

    Science.gov (United States)

    Liddicoat, Douglas R; Kyparissoudis, Konstantinos; Berzins, Stuart P; Cole, Timothy J; Godfrey, Dale I

    2014-11-01

    Glucocorticoids (GCs) are powerful inhibitors of inflammation and immunity. Although glucocorticoid-induced cell death (GICD) is an important part of GCs actions, the cell types and molecular mechanisms involved are not well understood. Untranslated exon 1A3 of the human glucocorticoid receptor (GR) gene is a major determinant of GICD in GICD-sensitive human cancer cell lines, operating to dynamically upregulate GR levels in response to GCs. We measured the GICD sensitivity of freshly isolated peripheral blood mononuclear cells and thymocytes to dexamethasone in vitro, relating this to GR exon 1A3 expression. A clear GICD sensitivity hierarchy was detected: B cells>thymocytes/natural killer (NK) cells>peripheral T cells. Within thymocyte populations, GICD sensitivity decreased with maturation. Interestingly, NK cell subsets were differentially sensitive to GICD, with CD16(+)CD56(int) (cytotoxic) NK cells being highly resistant to GICD, whereas CD16(-)CD56(hi) (cytokine producing) NK cells were highly sensitive (similar to B cells). B-cell GICD was rescued by co-culture with interleukin-4. Strikingly, although no significant increases in GR protein were observed during 48 h of culture of GICD-sensitive and -resistant cells alike, GR 1A3 expression was increased over pre-culture levels in a manner directly proportional to the GICD sensitivity of each cell type. Accordingly, this is the first evidence that the GR exon 1A3 promoter is differentially regulated during thymic development and maturation of human T cells. Furthermore, human peripheral blood B cells are exquisitely GICD-sensitive in vitro, giving new insight into how GCs may downregulate immunity. Collectively, these data show that GR 1A3 expression is tied with GICD sensitivity in human lymphocytes, underscoring the potential for GR 1A3 expression to be used as a biomarker for sensitivity to GICD.

  8. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia.

    Science.gov (United States)

    Cui, Bing; Chen, Liguang; Zhang, Suping; Mraz, Marek; Fecteau, Jessie-F; Yu, Jian; Ghia, Emanuela M; Zhang, Ling; Bao, Lei; Rassenti, Laura Z; Messer, Karen; Calin, George A; Croce, Carlo M; Kipps, Thomas J

    2014-07-24

    High-level leukemia cell expression of micro-RNA 155 (miR-155) is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with a low-level expression of ζ-chain-associated protein of 70 kD. CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 and were more responsive to B-cell receptor (BCR) ligation than CLL with low-level miR-155. Transfection with miR-155 enhanced responsiveness to BCR ligation, whereas transfection with a miR-155 inhibitor had the opposite effect. CLL in lymphoid tissue expressed higher levels of miR155HG than CLL in the blood of the same patient. Also, isolated CD5(bright)CXCR4(dim) cells, representing CLL that had been newly released from the microenvironment, expressed higher levels of miR-155 and were more responsive to BCR ligation than isolated CD5(dim)CXCR4(bright) cells of the same patient. Treatment of CLL or normal B cells with CD40-ligand or B-cell-activating factor upregulated miR-155 and enhanced sensitivity to BCR ligation, effects that could be blocked by inhibitors to miR-155. This study demonstrates that the sensitivity to BCR ligation can be enhanced by high-level expression of miR-155, which in turn can be induced by crosstalk within the tissue microenvironment, potentially contributing to its association with adverse clinical outcome in patients with CLL.

  9. The use of low density lipoprotein receptor activity of lymphocytes to determine the prevalence of familial hypercholesterolaemia in a rural South African community.

    Science.gov (United States)

    Steyn, K; Weight, M J; Dando, B R; Christopher, K J; Rossouw, J E

    1989-01-01

    The diagnosis of heterozygous familial hypercholesterolaemia in three rural South African communities in which hypercholesterolaemia is very prevalent could be confirmed by the measurement of low density lipoprotein (LDL) receptor activity in circulating lymphocytes. A nominal cut off point could be proposed which separated the LDL receptor activity of 24 clinically diagnosed heterozygous FH patients and 31 healthy people. LDL receptor activity was measured as total degradation of 125I-LDL and expressed as ng LDL/mg cell protein/6 hours. The cut off point was set at 970 ng/mg protein/6 hours. This proposed cut off point was tested by assaying the LDL receptor of three homozygous FH patients and seven of their obligate heterozygous FH first degree relatives. The three homozygous FH patients showed no receptor activity and the activity of the seven obligate heterozygous first degree relatives fell below the proposed cut off point. To determine the prevalence of FH in the study population, all persons aged 15 to 24 years whose total cholesterol levels fell above the 80th centile for their age and sex, as well as their families, were approached (n = 114). The LDL receptor activity in lymphocytes of 77 of these persons aged 15 to 24 years was determined after applying the exclusion criteria. Ten of the 77 participants had LDL receptor activity below 970 ng LDL/mg protein/6 hours and were therefore diagnosed as being heterozygous FH patients. The calculation of the prevalence (corrected for exclusions) revealed that one in 71 of the 15 to 24 year old permanent residents in the predominantly Afrikaans speaking community suffered from heterozygous FH. This is higher than any FH prevalence previously reported for any group. PMID:2918524

  10. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model.

    Science.gov (United States)

    Di Stasi, Antonio; De Angelis, Biagio; Rooney, Cliona M; Zhang, Lan; Mahendravada, Aruna; Foster, Aaron E; Heslop, Helen E; Brenner, Malcolm K; Dotti, Gianpietro; Savoldo, Barbara

    2009-06-18

    For the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably need to be a match between the chemokines the tumor produces and the chemokine receptors the effector T cells express. The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment. By contrast, effector CD8(+) T cells lack CCR4, are nonresponsive to these chemokines and are rarely detected at the tumor site. We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic function and cytokine secretion in vitro, and produce enhanced tumor control when infused intravenously in mice engrafted with human HL. This approach may be of value in patients affected by HL.

  11. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model

    OpenAIRE

    Di Stasi, Antonio; De Angelis, Biagio; Rooney, Cliona M; Zhang, Lan; Mahendravada, Aruna; Foster, Aaron E; Heslop, Helen E; Brenner, Malcolm K.; Dotti, Gianpietro; Savoldo, Barbara

    2009-01-01

    For the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably need to be a match between the chemokines the tumor produces and the chemokine receptors the effector T cells express. The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tre...

  12. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson’s Disease

    Science.gov (United States)

    Kustrimovic, Natasa; Rasini, Emanuela; Legnaro, Massimiliano; Bombelli, Raffaella; Aleksic, Iva; Blandini, Fabio; Comi, Cristoforo; Mauri, Marco; Minafra, Brigida; Riboldazzi, Giulio; Sanchez-Guajardo, Vanesa; Marino, Franca; Cosentino, Marco

    2016-01-01

    Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D1-like DR decrease, while in T memory cells D2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs. PMID:27652978

  13. Identification of Grb2 as a novel binding partner of the signaling lymphocytic activation molecule-associated protein binding receptor CD229.

    Science.gov (United States)

    Martín, Margarita; Del Valle, Juana M; Saborit, Ifigènia; Engel, Pablo

    2005-05-15

    Ag recognition by the TCR determines the subsequent fate of the T cell and is regulated by the involvement of other cell surface molecules, termed coreceptors. CD229 is a lymphocyte cell surface molecule that belongs to the CD150 family of receptors. Upon tyrosine phosphorylation, CD229 recruits various signaling molecules to the membrane. One of these molecules is the signaling lymphocytic activation molecule-associated protein, of which a deficiency leads to the X-linked lymphoproliferative syndrome. We report that CD229 interacts in a phosphorylation-dependent manner with Grb2. We mapped this interaction showing that the Src homology 2 domain of Grb2 and the tyrosine residue Y606 in CD229 are required for CD229-Grb2 complex formation. The Grb2 motif in the cytoplasmic tail of CD229 is distinct and independent from the two tyrosines required for efficient signaling lymphocytic activation molecule-associated protein recruitment. CD229, but not other members of the CD150 family, directly bound Grb2. We also demonstrate that CD229 precipitates with Grb2 in T lymphocytes after pervanadate treatment, as well as CD229 or TCR ligation. Interestingly, the CD229 mutant lacking the Grb2 binding site is not internalized after CD229 engagement with specific Abs. Moreover, a dominant negative form of Grb2 (containing only Src homology 2 domain) impaired CD229 endocytosis. Unexpectedly, Erk phosphorylation was partially inhibited after activation of CD229 plus CD3. Consistent with this, CD229 ligation partially inhibited TCR signaling in peripheral blood cells and CD229-Jurkat cells transfected with the 3XNFAT-luciferase reporter construct. Altogether, the data suggest a model whereby CD229 ligation attenuates TCR signaling and Grb2 recruitment to CD229 controls its rate of internalization.

  14. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death.

    Science.gov (United States)

    Purton, Jared F; Monk, Julie A; Liddicoat, Douglas R; Kyparissoudis, Konstantinos; Sakkal, Samy; Richardson, Samantha J; Godfrey, Dale I; Cole, Timothy J

    2004-09-15

    Glucocorticoid (GC) hormones cause pronounced T cell apoptosis, particularly in immature thymic T cells. This is possibly due to tissue-specific regulation of the glucocorticoid receptor (GR) gene. In mice the GR gene is transcribed from five separate promoters designated: 1A, 1B, 1C, 1D, and 1E. Nearly all cells express GR from promoters 1B-1E, but the activity of the 1A promoter has only been reported in the whole thymus or lymphocyte cell lines. To directly assess the role of GR promoter use in sensitivity to glucocorticoid-induced cell death, we have compared the activity of the GR 1A promoter with GC sensitivity in different mouse lymphocyte populations. We report that GR 1A promoter activity is restricted to thymocyte and peripheral lymphocyte populations and the cortex of the brain. The relative level of expression of the 1A promoter to the 1B-1E promoters within a lymphocyte population was found to directly correlate with susceptibility to GC-induced cell death, with the extremely GC-sensitive CD4+CD8+ thymocytes having the highest levels of GR 1A promoter activity, and the relatively GC-resistant alphabetaTCR+CD24(int/low) thymocytes and peripheral T cells having the lowest levels. DNA sequencing of the mouse GR 1A promoter revealed a putative glucocorticoid-response element. Furthermore, GR 1A promoter use and GR protein levels were increased by GC treatment in thymocytes, but not in splenocytes. These data suggest that tissue-specific differences in GR promoter use determine T cell sensitivity to glucocorticoid-induced cell death. Copyright 2004 The American Association of Immunologists, Inc.

  15. Re-Evaluation of Binding Properties of Recombinant Lymphocyte Receptors NKR-P1A and CD69 to Chemically Synthesized Glycans and Peptides

    Directory of Open Access Journals (Sweden)

    Daniel Rozbeský

    2014-01-01

    Full Text Available The binding of monosaccharides and short peptides to lymphocyte receptors (human CD69 and rat NKR-P1A was first reported in 1994 and then in a number of subsequent publications. Based on this observation, numerous potentially high-affinity saccharide ligands have been synthesized over the last two decades in order to utilize their potential in antitumor therapy. Due to significant inconsistencies in their reported binding properties, we decided to re-examine the interaction between multiple ligands and CD69 or NKR-P1A. Using NMR titration and isothermal titration calorimetry we were unable to detect the binding of the tested ligands such as N-acetyl-d-hexosamines and oligopeptides to both receptors, which contradicts the previous observations published in more than twenty papers over the last fifteen years.

  16. Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4- and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes

    DEFF Research Database (Denmark)

    Janssens, Rik; Mortier, Anneleen; Boff, Daiane

    2017-01-01

    -inhibiting conditions. In conclusion, CD26-cleavage skews CXCL12 towards β-arrestin dependent recruitment through ACKR3 and destroys the CXCR4-mediated lymphocyte chemoattractant properties of CXCL12 in vivo. Hence, pharmacological CD26-blockade in tissues may enhance CXCL12-induced inflammation....

  17. Attachment of an anti-receptor antibody to non-target cells renders them susceptible to lysis by a clone of cytotoxic T lymphocytes.

    Science.gov (United States)

    Kranz, D M; Tonegawa, S; Eisen, H N

    1984-12-01

    The molecular basis for the dependence of antigen recognition by T cells on products of the major histocompatibility complex (MHC) is unknown, and the antigenic structures that are actually bound by T-cell receptors are ill-defined. In this study, we asked whether a monoclonal antibody (mAb) that reacts with the T-cell receptor of a clone of murine cytotoxic T lymphocytes (CTL) and not with the receptors of other CTL clones can substitute for that clone's natural ligand in specific cytolytic reactions. To answer the question, a mAb (1B2) to the receptor of a CTL clone (2C) was attached covalently to 51Cr-labeled cells that were not otherwise susceptible to lysis by clone 2C, and the cells thus modified were then tested as targets for clone 2C and other CTL clones of similar specificity. All labeled cells modified in this way, including a murine cell line that expresses no cell-surface MHC class I molecules and a human cell line, were lysed by clone 2C but not by other CTL clones. If, however, instead of attaching the mAb to the receptor of clone 2C, the cells were modified by attaching to them mAbs to other surface antigens on CTL [lymphocyte function-associated antigen (LFA-1), Thy-1.2], they were not lysed. In cytolytic titrations, the cells that had been converted by attachment of mAb 1B2 into specific targets for clone 2C were just as susceptible to lysis by that clone as the clone's natural H-2d targets (e.g., P815 cells). However, some accessory surface molecules (LFA-1, Lyt-2) that are required for clone 2C to lyse its natural H-2d targets seemed not to be required for this clone to lyse the mAb-converted target cells. By demonstrating that a variety of different cell types can be thus converted into target cells for CTL, the approach described in this study may provide opportunities to analyze further the mechanisms by which CTL destroy target cells.

  18. Effect of acute and regular exercise on growth hormone secretagogue receptor-1a expression in human lymphocytes, T cell subpopulation and monocytes.

    Science.gov (United States)

    Bishop, Nicolette C; Hayashida, Harumi; Clark, Megan; Coombs, Charlotte; Miller, Sean; Stensel, David J

    2014-07-01

    The orexigenic peptide hormone ghrelin exerts potent inhibitory effects on pro-inflammatory cytokine release via the growth hormone secretagogue receptor-1a (GHS-R1a) on T cells and monocytes. As such, ghrelin is a promising therapeutic agent for the treatment of inflammatory conditions, but these effects depend on the availability of GHS-R1a. The aim of this study was to determine the effect of acute exercise on GHS-R1a expression on circulating CD14+ monocytes, total lymphocytes and CD3+ T cells. Nine male club-standard cyclists cycled for 1h at 75% V̇O2peak (EX) or rested (REST) in a randomised cross-over design. Compared with the equivalent times in REST, the concentration of circulating GHS-R1a+ lymphocytes and monocytes was higher in EX at immediately and 1 and 2h post-exercise (all pexercise only (258 (203)cellsμl(-1) vs. 62 (42)cellsμl(-1), pexercise. Given that the anti-inflammatory effects of ghrelin depend on the availability of GHS-R1a, the preferential recruitment of subpopulations with high anti-inflammatory potential found here add a novel aspect to the potential mechanisms by which exercise acts to reduce pro-inflammatory cytokine levels.

  19. Over-Expression of Dopamine D2 Receptor and Inwardly Rectifying Potassium Channel Genes in Drug-Naive Schizophrenic Peripheral Blood Lymphocytes as Potential Diagnostic Markers

    Directory of Open Access Journals (Sweden)

    Ágnes Zvara

    2005-01-01

    Full Text Available Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3 was found to be over-expressed in schizophrenic PBL and proposed to be a diagnostic and follow-up marker for schizophrenia. In this study we screened PBL of 13 drug-naive/drug-free schizophrenic patients to identify additional markers of schizophrenia. One of the benefits of our study is the use of blood samples of non-medicated, drug-naive patients. This excludes the possibility that changes detected in gene expression levels might be attributed to the medication rather than to the disorder itself. Among others, genes for dopamine receptor D2 (DRD2 and the inwardly rectifying potassium channel (Kir2.3 were found to be over-expressed in microarray analysis. Increased mRNA levels were confirmed by quantitative real-time PCR (QRT-PCR using the SybrGreen method and dual labeled TaqMan probes. The use of both molecular markers allows a more rapid and precise prediction of schizophrenia and might help find the optimal medication for schizophrenic patients.

  20. Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers.

    Science.gov (United States)

    Zvara, Agnes; Szekeres, György; Janka, Zoltán; Kelemen, János Z; Cimmer, Csongor; Sántha, Miklós; Puskás, László G

    2005-01-01

    Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-expressed in schizophrenic PBL and proposed to be a diagnostic and follow-up marker for schizophrenia. In this study we screened PBL of 13 drug-naive/drug-free schizophrenic patients to identify additional markers of schizophrenia. One of the benefits of our study is the use of blood samples of non-medicated, drug-naive patients. This excludes the possibility that changes detected in gene expression levels might be attributed to the medication rather than to the disorder itself. Among others, genes for dopamine receptor D2 (DRD2) and the inwardly rectifying potassium channel (Kir2.3) were found to be over-expressed in microarray analysis. Increased mRNA levels were confirmed by quantitative real-time PCR (QRT-PCR) using the SybrGreen method and dual labeled TaqMan probes. The use of both molecular markers allows a more rapid and precise prediction of schizophrenia and might help find the optimal medication for schizophrenic patients.

  1. Evidence favoring the involvement of CC chemokine receptor (CCR) 5 in T-lymphocyte accumulation in optic neuritis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Ransohoff, R M; Jensen, J;

    2003-01-01

    To define the relationships between levels of chemokine receptor (CCR)5+ T-cells in blood and cerebrospinal fluid (CSF) of optic neuritis (ON) and control patients (CON).......To define the relationships between levels of chemokine receptor (CCR)5+ T-cells in blood and cerebrospinal fluid (CSF) of optic neuritis (ON) and control patients (CON)....

  2. Recombinant human growth-regulated oncogene-alpha induces T lymphocyte chemotaxis. A process regulated via IL-8 receptors by IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-13

    DEFF Research Database (Denmark)

    Jinquan, T; Frydenberg, Jane; Mukaida, N

    1995-01-01

    receptors on the cells. This process can be augmented by IFN-gamma and TNF-alpha, and inhibited by IL-4, IL-10, and IL-13. In addition, we also document that on T lymphocytes there exist IL-8 receptors that can be up-regulated by IFN-gamma, TNF-alpha, and IL-2. Our results demonstrate that rhGRO-alpha gene...

  3. Identification of amino acid residues involved in the interaction between measles virus Haemagglutin (MVH) and its human cell receptor (signaling lymphocyte activation molecule, SLAM).

    Science.gov (United States)

    Xu, Qin; Zhang, Peng; Hu, Chunling; Liu, Xin; Qi, Yipeng; Liu, Yingle

    2006-07-31

    Signaling lymphocyte activation molecule (SLAM; also known as CD150) is a newly identified cellular receptor for measles virus (MV). The interaction between MV Haemagglutin (MVH) and SLAM is an initial step for MV entry. We have identified several novel SLAM binding sites at residues S429, T436 and H437 of MVH protein and MVH mutants in these residues dramatically decrease the ability to interaction with the cell surface SLAM and fail to coprecipitation with SLAM in vivo as well as malfunction in syncytium formation. At the same time, K58, S59 and H61 of SLAM was also identified to be critical for MVH and SLAM binding. Further, these residues may be useful targets for the development of measles therapy.

  4. Properties of a specific interleukin 1 (IL 1) receptor on human Epstein Barr virus-transformed B lymphocytes. Identity of receptor for IL 1-. cap alpha. and IL 1-. beta

    Energy Technology Data Exchange (ETDEWEB)

    Matsushima, K.; Akahoshi, T.; Yamada, M.; Furutani, Y.; Oppenheim, J.J.

    1986-01-01

    The properties of specific human interleukin 1 (IL 1) receptors on human Epstein Barr virus-transformed B lymphocytes (EBV-B) were studied. Purified human IL 1-..beta.. from a myelomonocytic cell line (THP-1) was labeled with /sup 125/I. Among four EBV-B cell lines tested, a pre-B cell type (VDS-O) specifically bound the highest amount of /sup 125/I-IL 1-..beta... The binding of /sup 125/I-IL 1-..beta.. to VDS-O cells was inhibited by F(ab)'/sub 2/ fragments of anti-human IL 1 and recombinant human IL 1-..cap alpha.., as well as by unlabeled human IL 1-..beta.. but not by recombinant lymphotoxin, recombinant tumor necrosis factor, or phorbol myristic acid, suggesting that IL 1-..cap alpha.. and IL 1-..beta.. bind specifically to the same receptor. The m.w. of IL 1 receptor on human EBV-B cells was estimated to be 60,000 by both the chemical cross-linking method and high pressure liquid chromatography (HPLC). The isoelectric point of solubilized human IL 1 receptor was 7.3 on HPLC chromatofocusing. The evidence of existence of IL 1 receptor on human EBV-B cells additionally supports the hypothesis that IL 1 may be an autocrine signal for these cells.

  5. Reactivation of persistent Epstein-Barr virus (EBV) causes secretion of thyrotropin receptor antibodies (TRAbs) in EBV-infected B lymphocytes with TRAbs on their surface.

    Science.gov (United States)

    Nagata, Keiko; Nakayama, Yuji; Higaki, Katsumi; Ochi, Marika; Kanai, Kyosuke; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Iwasaki, Takeshi; Nanba, Eiji; Kimura, Hiroshi; Hayashi, Kazuhiko

    2015-01-01

    Epstein-Barr virus (EBV) is a ubiquitous virus that infects most adults latently. It persists in B lymphocytes and reactivates occasionally. Graves' disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). We have reported that Graves' disease patients and healthy controls have EBV-infected lymphocytes that have TRAbs on their surface (TRAb(+)EBV(+) cells) in peripheral blood mononuclear cells (PBMCs). EBV reactivation is known to be associated with plasma cell differentiation and antibody production of B cells. In this study, we investigated whether TRAb(+)EBV(+) cells really produce TRAbs or not when persistent EBV is reactivated. We cultured PBMCs from 12 Graves' disease patients and 12 healthy controls for several days with cyclosporine A to expand the EBV-infected cell population, and then compared TRAb levels between EBV reactivation by 33 °C culture and EBV nonreactivation by 37 °C culture of PBMCs. Flow cytometry confirmed that all samples at day 0 (reactivation starting point) contained TRAb(+)EBV(+) cells. During 33 °C culture, EBV-reactivated cells with EBV-gp350/220 expression increased from about 1 to 4%. We quantified TRAb levels in culture fluids by radio-receptor assay, and detected an increased concentration for at least one sampling point at 33 °C (from days 0 to 12) for all patients and healthy controls. TRAb levels were significantly higher in supernatants of 33 °C culture than of 37 °C culture, and also significantly higher in supernatants from patients than those from controls. This study revealed TRAb production from TRAb(+)EBV(+) cells in response to reactivation induction of persistent EBV in different efficiencies between patients and controls.

  6. Cloning of Encoding Sequences for Chemokine Receptors CXCR4 and CCR5 from a Chinese Lymphocyte cDNAs

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    @@ It has been known recently that cofactors, which belong to the family of seven-transmembrane GTP-binding protein-coupled receptors, are necessary for the entry of HIV-1 into CD4+cells. The CXC chemokine receptor 4(CXCR4) was first found to act as the coreceptor for the infection of T cell line-tropic HIV-1 strains to T helper cells in 1996. Keeping in step with this find the CC chemokine receptor 5(CCR5)was also identified as a coreceptor for macrophage-tropic virus. Both of the coreceptors could be used in basic research and application design for AIDS.

  7. [Changes of content of regulatory lymphocytes and concentration of soluble interleukine-2 receptor in blood of patients with ischemic heart disease after coronary artery angioplasty with implantation of stents with rapamycin covering].

    Science.gov (United States)

    Potekhina, A V; Sokolov, V O; Pylaeva, E A; Provatorov, S I; Masenko, V P; Bosykh, E G; Noeva, E A; Krasnikova, T L; Aref'eva, T I

    2011-01-01

    We studied dynamics of content of subpopulation of lymphocytes including regulatory and effector T-lymphocytes as well as concentration of soluble form of interleukine-2 receptor (sCD25) in peripheral blood of patients after coronary stenting (CS) with implantation of stents with rapamycin covering (SRC). We included into the study 62 patients with stable effort II-III functional class angina. Coronary angiography (CA) was carried out in all, CS with implantation of 1 - 2 SRC - in 42 patients. Blood samples were taken before CA/CS, in 24, 48 hours, 7 days, 1 and 3 months after intervention. Content of T-, helper and cytotoxic T-cells, -, NK-, NKT-cells, activated effector T-lymphocytes (CD4+CD251owCD127high) and regulatory T-lymphocytes (CD4+CD25highCD1271ow) were measured by direct immunofluorescence and flow cytometry. CD4+ lymphocytes were isolated from mononuclear cell fraction of donor blood by magnetic separation. Content of regulatory T-lymphocytes in culture were determined by expression of a specific marker FOXP3+. Concentration of sCD25 was measured by chemiluminescent method. It was shown that content of main subpopulations of lymphocytes in blood changed after CS or CF. Blood content of regulatory T-lymphocytes and sCD25 significantly increased after 7 days and 1 month after CS but not after CA. Plasma sCD25 concentration correlated with content of regulatory T-lymphocytes in 1 month after SRC implantation. During cultivation of CD4+ lymphocytes in the presence of rapamycin we noted antiproliferative effect relative to FOXP3-cells and accumulation of regulatory +-lymphocytes. Thus implantation of SRC in coronary arteries leads to increase of number of circulating regulatory T-lymphocytes and blood concentration of sCD25. Changes of these parameters after CS can reflect peculiarities of local and systemic reaction arising in response to introduction of stent with drug covering and be significant for assessment of prognosis of the disease.

  8. Antigen receptors on immature, but not mature, B and T cells are coupled to cytosolic phospholipase A2 activation: expression and activation of cytosolic phospholipase A2 correlate with lymphocyte maturation.

    Science.gov (United States)

    Gilbert, J J; Stewart, A; Courtney, C A; Fleming, M C; Reid, P; Jackson, C G; Wise, A; Wakelam, M J; Harnett, M M

    1996-03-15

    The Ag receptors on mature B and T cells are not coupled to the activation of cytosolic phospholipase A2 (cPLA2) and arachidonic acid release. Moreover, phorbol esters such as PMA, which can activate cPLA2 via mitogen-activated protein (MAP) kinase in most cell types, also failed to induce the release of arachidonate from mature cells, suggesting that the cPLA2 pathway may not be functional in mature lymphocytes. Interestingly, Western blot analysis revealed that cPLA2, which had previously been thought to be expressed ubiquitously, is not expressed in mature B or T cells and that cytosolic phospholipase A2 expression could not be up-regulated in lymphocytes following culture with a range of cytokines most likely to be involved in an immune response such as IL-1 alpha, IL-3, or TNF-alpha. In contrast, cPLA2 was shown to be expressed and activated in thymocytes and immature B cells under conditions in which ligation of the Ag receptors led to growth arrest and/or apoptosis. Taken together, these data suggest that cPLA2 does not play a role in Ag receptor-mediated lymphocyte activation, but may be involved in the molecular mechanisms underlying lymphocyte maturation and/or self tolerance by clonal deletion.

  9. Lymphocyte 'homing' and chronic inflammation.

    Science.gov (United States)

    Sakai, Yasuhiro; Kobayashi, Motohiro

    2015-07-01

    Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV-like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV-like vessel-mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others.

  10. Emotional stress induced by parachute jumping enhances blood nerve growth factor levels and the distribution of nerve growth factor receptors in lymphocytes.

    Science.gov (United States)

    Aloe, L; Bracci-Laudiero, L; Alleva, E; Lambiase, A; Micera, A; Tirassa, P

    1994-10-25

    We examined the plasma nerve growth factor (NGF) level and the distribution of NGF receptors in peripheral lymphocytes of young soldiers (mean age, 20-24 yr) experiencing the thrill of a novice about to make their first parachute jumps. Blood was collected from soldiers who knew they were selected to jump (n = 26), as well as from soldiers who knew they were not selected (n = 17, controls). The former group was sampled the evening before the jump and 20 min after landing. Compared with controls, NGF levels increased 84% in prejump and 107% in postjump sampling. Our studies also showed that the increase of NGF levels preceded the increase of plasma cortisol and adrenocorticotropic hormone. No changes in the baseline levels of circulating interleukin 1 beta or tumor necrosis factor were found, suggesting that the increased levels of NGF were not correlated with change in these cytokines. Moreover, immunofluorescence analysis demonstrated that parachuting stress enhances the distribution of low-affinity p75LNGFR and high-affinity p140trkA NGF receptors in circulating peripheral blood mononuclear cells. These observations suggest that the release of NGF might be involved in the activation of cells of the immune system and is most probably associated with homeostatic adaptive mechanisms, as previously shown for stressed rodents.

  11. Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction.

    Science.gov (United States)

    Robinson, Rebecca Hartzell; Meissler, Joseph J; Breslow-Deckman, Jessica M; Gaughan, John; Adler, Martin W; Eisenstein, Toby K

    2013-12-01

    Cannabinoids are known to have anti-inflammatory and immunomodulatory properties. Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes. This study tested the capacity of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation. Both CB2-selective agonists and Δ(9)-THC significantly suppressed the MLR in a dose dependent fashion. The inhibition was via CB2, as suppression could be blocked by pretreatment with a CB2-selective antagonist, but not by a CB1 antagonist, and none of the compounds suppressed the MLR when splenocytes from CB2 deficient mice were used. The CB2 agonists were shown to act directly on T-cells, as exposure of CD3(+) cells to these compounds completely inhibited their action in a reconstituted MLR. Further, the CB2-selective agonists completely inhibited proliferation of purified T-cells activated by anti-CD3 and anti-CD28 antibodies. T-cell function was decreased by the CB2 agonists, as an ELISA of MLR culture supernatants revealed IL-2 release was significantly decreased in the cannabinoid treated cells. Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients.

  12. CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse.

    Science.gov (United States)

    Romero, Xavier; Zapater, Nuria; Calvo, María; Kalko, Susana G; de la Fuente, Miguel Angel; Tovar, Victoria; Ockeloen, Charlotte; Pizcueta, Pilar; Engel, Pablo

    2005-06-01

    CD229 is a member of the CD150 family of the Ig superfamily expressed on T and B cells. Receptors of this family regulate cytokine production and cytotoxicity of lymphocytes and NK cells. The cytoplasmic tail of CD229 binds to SAP, a protein that is defective in X-linked lymphoproliferative syndrome. To identify the CD229 ligand, we generated a soluble Ig fusion protein containing the two N-terminal extracellular domains of human CD229 (CD229-Ig). CD229-Ig bound to CD229-transfected cells, whereas no binding was detected on cells expressing other CD150 family receptors, showing that CD229 binds homophilically. Both human and mouse CD229 interacted with itself. Domain deletion mutants showed that the N-terminal Ig-domain mediates homophilic adhesion. CD229-CD229 binding was severely compromised when the charged amino acids E27 and E29 on the predicted B-C loop and R89 on the F-G loop of the N-terminal domain were mutated to alanine. In contrast, one mutation, R44A, enhanced the homophilic interaction. Confocal microscopy image analysis revealed relocalization of CD229 to the contact area of T and B cells during Ag-dependent immune synapse formation. Thus, CD229 is its own ligand and participates in the immunological synapse.

  13. Serum Levels of IL-6 Type Cytokines and Soluble IL-6 Receptors in Active B-Cell Chronic Lymphocytic Leukemia and in Cladribine Induced Remission

    Directory of Open Access Journals (Sweden)

    T. Robak

    1999-01-01

    Full Text Available We have investigated the serum concentrations of interleukin-6 (IL-6 and two IL-6 family cytokines-oncostatin M (OSM and leukemia inhibitory factor (LIF-in 63 patients with B-cell chronic lymphocytic leukemia (B-CLL and 17 healthy controls using the enzyme-linked immunosorbent assay (ELISA method. Simultaneously, we measured the serum levels of the soluble forms of two subunits of the IL-6 receptor complex-ligand binding glycoprotein 80 (sIL-6R and glycoprotein 130 (sgp130. The cytokines and receptors were evaluated in 25 untreated patients and 38 patients treated with cladribine (2-CdA, as well as in 17 healthy controls. We have correlated the serum levels of these proteins with Rai's clinical stage of the disease, the response to 2-CdA treatment and some hematological parameters. We have also evaluated the correlation of the IL-6 serum level with the concentration of OSM and IL-6 soluble receptors. IL-6 was measurable in 62/63 (98.4%, OSM in 20/25 (80% of untreated and 14/38 (37.8% of the treated patients. sIL-6R and sgp130 were detectable in all 63 patients and LIF in none of the CLL patients. IL-6 serum level in untreated patients was not significantly different as compared to its concentration in the control group (P>0.05. However, in the patients treated with 2-CdA the IL-6 level was significantly lower (P0.05. We have found significant positive correlation between the levels of sIL6R and the lymphocytes count in CLL patients (Ρ=0.423; P<0.001. In addition, sIL-6R and OSM serum concentrations correlated also with CLL Rai stage. In conclusion, the serum level of IL-6, OSM and sIL-6R, but not LIF and sgp130, are useful indicators of CLL activity.

  14. Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease

    Science.gov (United States)

    Karuppuchamy, Thangaraj; Behrens, En-hui; González-Cabrera, Pedro; Sarkisyan, Gor; Gima, Lauren; Boyer, Joshua D.; Bamias, Giorgos; Jedlicka, Paul; Veny, Marisol; Clark, David; Peach, Robert; Scott, Fiona; Rosen, Hugh; Rivera-Nieves, Jesús

    2016-01-01

    The sphingosine-1-phosphate receptor-1 (S1P1) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here we examine the cell subsets that express S1P1 in intestine using S1P1-eGFP mice, the regulation of S1P1 expression in lymphocytes after administration of DSS, after colitis induced by transfer of CD4+CD45RBhi cells and by crossing a mouse with TNF-driven ileitis with S1P1-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P1 expression. We found that not only T and B cells express S1P1, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P1 expression, while the enzymes that control tissue S1P levels in mice and humans with IBD were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T cell velocity and induced S1P1 degradation and retention of naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P1 expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function. PMID:27049060

  15. An anti-interleukin-2 receptor drug attenuates T- helper 1 lymphocytes-mediated inflammation in an acute model of endotoxin-induced uveitis.

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    Salvador Mérida

    Full Text Available The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-γ, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60-70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFγ. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration.

  16. A Novel Antagonist of the Immune Checkpoint Protein Adenosine A2a Receptor Restores Tumor-Infiltrating Lymphocyte Activity in the Context of the Tumor Microenvironment

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    Melanie Mediavilla-Varela

    2017-07-01

    Full Text Available BACKGROUND: Therapeutic strategies targeting immune checkpoint proteins have led to significant responses in patients with various tumor types. The success of these studies has led to the development of various antibodies/inhibitors for the different checkpoint proteins involved in immune evasion of the tumor. Adenosine present in high concentrations in the tumor microenvironment activates the immune checkpoint adenosine A2a receptor (A2aR, leading to the suppression of antitumor responses. Inhibition of this checkpoint has the potential to enhance antitumor T-cell responsiveness. METHODS: We developed a novel A2aR antagonist (PBF-509 and tested its antitumor response in vitro, in a mouse model, and in non-small cell lung cancer patient samples. RESULTS: Our studies showed that PBF-509 is highly specific to the A2aR as well as inhibitory of A2aR function in an in vitro model. In a mouse model, we found that lung metastasis was decreased after treatment with PBF-509 compared with its control. Furthermore, freshly resected tumor-infiltrating lymphocytes from lung cancer patients showed increased A2aR expression in CD4+ cells and variable expression in CD8+ cells. Ex vivo studies showed an increased responsiveness of human tumor-infiltrating lymphocytes when PBF-509 was combined with anti-PD-1 or anti-PD-L1. CONCLUSIONS: Our studies demonstrate that inhibition of the A2aR using the novel inhibitor PBF-509 could lead to novel immunotherapeutic strategies in non-small cell lung cancer.

  17. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE)

    DEFF Research Database (Denmark)

    Marquart, H V; Svendsen, Anders Jørgen; Rasmussen, J M

    1995-01-01

    It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that n...

  18. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE)

    DEFF Research Database (Denmark)

    Marquart, H V; Svendsen, A; Rasmussen, J M

    1995-01-01

    It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that n...

  19. Regulation of the PKCθ-NF-κB Axis in T lymphocytes by the Tumor Necrosis Factor Receptor Family Member OX40

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    Takanori eSo

    2012-05-01

    Full Text Available Antigen primed T lymphocytes need to expand and persist to promote adaptive immunity. The growth and survival signals that control this are in large part provided by the NF-κB pathway in activated or effector/memory T cells. Although several membrane receptors impact NF-κB activation, signaling from OX40 (CD134, TNFRSF4, a member of the tumor necrosis factor receptor (TNFR superfamily, has proven to be important for T cell immunity and a strong contributor to NF-κB activity. PKCθ directs the TCR and CD28-dependent assembly of a CBM complex (CARMA1, BCL10, and MALT1 for efficient activation of NF-κB, raising the question of whether other membrane bound receptors that activate NF-κB also require this PKCθ-CBM axis to control TCR-independent T cell activity. We discuss here our recent data demonstrating that after ligation by OX40L (CD252, TNFSF4 expressed on antigen-presenting cells, OX40 translocates into detergent-insoluble membrane lipid microdomains (DIM or lipid rafts in T cells irrespective of TCR signals, and assembles into a novel signaling complex containing PKCθ, together with TRAF2, RIP1, the CBM complex, and the IKKα/β/γ complex. PKCθ is required for optimal NF-κB activation mediated by OX40 and thus works as an essential component of this OX40 signalosome. We also discuss the likelihood that other TNFR superfamily molecules might complex with PKCθ in T cells, and whether PKC isoforms may be critical to the function of TNFR molecules in general. 

  20. Characterization of lymphocytic choriomeningitis virus-binding protein(s): a candidate cellular receptor for the virus.

    Science.gov (United States)

    Borrow, P; Oldstone, M B

    1992-12-01

    The attachment of lymphocytic choriomeningitis virus (LCMV) to murine and primate cell lines was quantitated by a fluorescence-activated cell sorter assay in which binding of biotinylated virus was detected with streptavidin-fluorescein isothiocyanate. Cell lines that were readily infected by LCMV (e.g., MC57, Rin, BHK, Vero, and HeLa) bound virus in a dose-dependent manner, whereas no significant binding was observed to lymphocytic cell lines (e.g., RMA and WIL 2) that were not readily infected. Binding was specific and competitively blocked by nonbiotinylated LCMV. It was also blocked by LCMV-specific antiserum and a neutralizing monoclonal antibody to the virus glycoprotein GP-1 but not by antibodies specific for GP-2, indicating that attachment was likely mediated by GP-1. Treatment of cells with any of several proteases abolished LCMV binding, whereas phospholipases including phosphatidylinositol-specific phospholipase C had no effect, indicating that one or more membrane proteins were involved in virus attachment. These proteins were characterized with a virus overlay protein blot assay. Virus bound to protein(s) with a molecular mass of 120 to 140 kDa in membranes from cell lines permissive for LCMV but not from nonpermissive cell lines. Binding was specific, since unlabeled LCMV, but not the unrelated enveloped virus herpes simplex virus type 1, competed with 125I-labeled LCMV for binding to the 120- to 140-kDa band. The proteinaceous nature of the LCMV-binding substance was confirmed by the lack of virus binding to proteinase K-treated membrane components. By contrast, glycosidase treatment of membranes did not abolish virus binding. However, in membranes treated with endoglycosidase F/N-glycosidase F, and/or neuraminidase and in membranes from cells grown in tunicamycin, the molecular mass of the LCMV-binding entity was reduced. Hence, LCMV attachment to rodent fibroblastic cell lines is mediated by a glycoprotein(s) with a molecular mass of 120 to 140 k

  1. Patterns of resistance to B cell-receptor pathway antagonists in chronic lymphocytic leukemia and strategies for management.

    Science.gov (United States)

    Woyach, Jennifer A

    2015-01-01

    Small-molecule kinase inhibitors, especially the two Food and Drug Administration-approved agents idelalisib and ibrutinib, have changed the treatment landscape for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). However, with these positive changes comes the new challenge of managing patients who relapse after these agents. The number of patients who have relapsed after taking idelalisib and ibrutinib is low, but as the drugs gain wider use and patients are treated for longer, this number is likely to grow. Because these patients can be challenging to manage effectively, coordinated efforts now to determine how and why patients relapse along with optimal treatment strategies are required to better serve our patients in the future. As well, identification of mechanisms of resistance is crucial to develop rational strategies for management. Current work has identified mechanisms of resistance to ibrutinib, and resistance to idelalisib is also under active investigation. In this review, we will discuss these mechanisms of resistance, as well as current and potential strategies for the management of kinase inhibitor-resistant CLL. © 2015 by The American Society of Hematology. All rights reserved.

  2. CD19-Chimeric Antigen Receptor T Cells for Treatment of Chronic Lymphocytic Leukaemia and Acute Lymphoblastic Leukaemia

    DEFF Research Database (Denmark)

    Lorentzen, C L; thor Straten, Per

    2015-01-01

    Adoptive cell therapy (ACT) for cancer represents a promising new treatment modality. ACT based on the administration of cytotoxic T cells genetically engineered to express a chimeric antigen receptor (CAR) recognizing CD19 expressed by B cell malignancies has been shown to induce complete lasting......-associated toxicities, which needs attention. Herein we review current data and discuss key aspects of this powerful approach to treat and potentially cure B cell malignancies....

  3. LYMPHOCYTE APOPTOSIS IN PSORIASIS

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    О. M. Kapuler

    2006-01-01

    Full Text Available Abstract. Forty-two patients with progressive vulgar psoriasis (PASI = 19.7 ± 1.5 and 40 healthy volunteers were under investigation. Psoriatic patients were characterized by increased number of CD4+ CD95+ peripheral blood T lymphocytes, which correlates with clinical psoriatic score, and by increased levels of soluble Fas (sFas in serum, as compared to controls (resp., 1868.1 ± 186.8 pg/ml vs. 1281.4 ± 142.5 pg/ml, PLSD = 0.019. The levels of spontaneous lymphocyte apoptosis and anti-Fas (Mab-induced apoptosis in psoriatic patients did not differ from the controls. However, apoptosis induced by “oxidative stress” (50 M Н202, 4 hrs was depressed in the patients. Moreover, a simultaneous assessment of cell cycle structure (metachromatic staining with Acridine Orange, apoptosis and Fas receptor expression (AnnV-FITC/antiFas mAbs-PE staining following a short-term mitogenic stimulation (PHA-P, 5 µg/ml, 24 hrs were performed. We found no marked differences in mitogenic reactivity, activation-induced apoptosis, and activation-induced Fas receptor expression when studying lymphocytes from healthy donors and psoriatic patients. However, PHA-activated lymphocytes from psoriatic patients displayed a significantly decreased ratio of AnnV+CD95+ to the total AnnV+ subpopulation, thus suggesting a decreased role of Fas-dependent mechanisms of apoptosis during the cell activation. The data obtained confirm a view, that an abnormal lymphocyte “apoptotic reactivity”, which plays a crucial role in the mechanisms of autoimmunity, may also of importance in the pathogenesis of psoriasis.

  4. CXC chemokine receptor 4 expression and stromal cell-derived factor-1alpha-induced chemotaxis in CD4+ T lymphocytes are regulated by interleukin-4 and interleukin-10

    DEFF Research Database (Denmark)

    Jinquan, T; Quan, S; Jacobi, H H

    2000-01-01

    We report that interleukin (IL)-4 and IL-10 can significantly up- or down-regulate CXC chemokine receptor 4 (CXCR4) expression on CD4+ T lymphocytes, respectively. Stromal cell-derived factor-1alpha (SDF-1alpha)-induced CD4+ T-lymphocyte chemotaxis was also correspondingly regulated by IL-4 and IL......,000 SDF-1alpha-binding sites per cell, among freshly isolated CD4+ T lymphocytes, and two types of CXCR4 with different affinities (Kd1 approximately 4.4 nM and Kd2 approximately 14.6 nM), and a total of approximately 130,000 SDF-1alpha-binding sites per cell, among IL-4-stimulated CD4+ T lymphocytes......-mobilization stimulation. These results indicate that the effects of IL-4 and IL-10 on the CXCR4-SDF-1 receptor-ligand pair may be of particular importance in the cytokine/chemokine environment concerning the inflammatory processes and in the progression of human immunodeficiency virus (HIV) infection....

  5. Neisserial outer membrane vesicles bind the coinhibitory receptor carcinoembryonic antigen-related cellular adhesion molecule 1 and suppress CD4+ T lymphocyte function.

    Science.gov (United States)

    Lee, Hannah S W; Boulton, Ian C; Reddin, Karen; Wong, Henry; Halliwell, Denise; Mandelboim, Ofer; Gorringe, Andrew R; Gray-Owen, Scott D

    2007-09-01

    Pathogenic Neisseria bacteria naturally liberate outer membrane "blebs," which are presumed to contribute to pathology, and the detergent-extracted outer membrane vesicles (OMVs) from Neisseria meningitidis are currently employed as meningococcal vaccines in humans. While the composition of these vesicles reflects the bacteria from which they are derived, the functions of many of their constituent proteins remain unexplored. The neisserial colony opacity-associated Opa proteins function as adhesins, the majority of which mediate bacterial attachment to human carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs). Herein, we demonstrate that the Opa proteins within OMV preparations retain the capacity to bind the immunoreceptor tyrosine-based inhibitory motif-containing coinhibitory receptor CEACAM1. When CD4(+) T lymphocytes were exposed to OMVs from Opa-expressing bacteria, their activation and proliferation in response to a variety of stimuli were effectively halted. This potent immunosuppressive effect suggests that localized infection will generate a "zone of inhibition" resulting from the diffusion of membrane blebs into the surrounding tissues. Moreover, it demonstrates that OMV-based vaccines must be developed from strains that lack CEACAM1-binding Opa variants.

  6. A new way to generate cytolytic tumor-specific T cells: electroporation of RNA coding for a T cell receptor into T lymphocytes.

    Science.gov (United States)

    Schaft, Niels; Dörrie, Jan; Müller, Ina; Beck, Verena; Baumann, Stefanie; Schunder, Tanja; Kämpgen, Eckhart; Schuler, Gerold

    2006-09-01

    Effective T cell receptor (TCR) transfer until now required stable retroviral transduction. However, retroviral transduction poses the threat of irreversible genetic manipulation of autologous cells. We, therefore, used optimized RNA transfection for transient manipulation. The transfection efficiency, using EGFP RNA, was >90%. The electroporation of primary T cells, isolated from blood, with TCR-coding RNA resulted in functional cytotoxic T lymphocytes (CTLs) (>60% killing at an effector to target ratio of 20:1) with the same HLA-A2/gp100-specificity as the parental CTL clone. The TCR-transfected T cells specifically recognized peptide-pulsed T2 cells, or dendritic cells electroporated with gp100-coding RNA, in an IFNgamma-secretion assay and retained this ability, even after cryopreservation, over 3 days. Most importantly, we show here for the first time that the electroporated T cells also displayed cytotoxicity, and specifically lysed peptide-loaded T2 cells and HLA-A2+/gp100+ melanoma cells over a period of at least 72 h. Peptide-titration studies showed that the lytic efficiency of the RNA-transfected T cells was similar to that of retrovirally transduced T cells, and approximated that of the parental CTL clone. Functional TCR transfer by RNA electroporation is now possible without the disadvantages of retroviral transduction, and forms a new strategy for the immunotherapy of cancer.

  7. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling.

    Science.gov (United States)

    Burger, Jan A; Montserrat, Emili

    2013-02-28

    Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy.

  8. Mite allergen Der-p2 triggers human B lymphocyte activation and Toll-like receptor-4 induction.

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    Jaw Ji Tsai

    Full Text Available BACKGROUND: Allergic disease can be characterized as manifestations of an exaggerated inflammatory response to environmental allergens triggers. Mite allergen Der-p2 is one of the major allergens of the house dust mite, which contributes to TLR4 expression and function in B cells in allergic patients. However, the precise mechanisms of Der-p2 on B cells remain obscure. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of Der-p2 on proinflammatory cytokines responses and Toll-like receptor-4 (TLR4-related signaling in human B cells activation. We demonstrated that Der-p2 activates pro-inflammatory cytokines, TLR4 and its co-receptor MD2. ERK inhibitor PD98059 significantly enhanced TLR4/MD2 expression in Der-p2-treated B cells. Der-p2 markedly activated mitogen-activated protein kinase (MAPK phosphatase-1 (MKP-1 and decreased p38 phosphorylation in B cells. MKP-1-siRNA downregulated TLR4/MD2 expression in Der-p2-treated B cells. In addition, Der-p2 significantly up-regulated expression of co-stimulatory molecules and increased B cell proliferation. Neutralizing Der-p2 antibody could effectively abrogate the Der-p2-induced B cell proliferation. Der-p2 could also markedly induce NF-κB activation in B cells, which could be counteracted by dexamethasone. CONCLUSIONS/SIGNIFICANCE: These results strongly suggest that Der-p2 is capable of triggering B cell activation and MKP-1-activated p38/MAPK dephosphorylation-regulated TLR4 induction, which subsequently enhances host immune, defense responses and development of effective allergic disease therapeutics in B cells.

  9. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.

    Science.gov (United States)

    Denkert, Carsten; von Minckwitz, Gunter; Brase, Jan C; Sinn, Bruno V; Gade, Stephan; Kronenwett, Ralf; Pfitzner, Berit M; Salat, Christoph; Loi, Sherene; Schmitt, Wolfgang D; Schem, Christian; Fisch, Karin; Darb-Esfahani, Silvia; Mehta, Keyur; Sotiriou, Christos; Wienert, Stephan; Klare, Peter; André, Fabrice; Klauschen, Frederick; Blohmer, Jens-Uwe; Krappmann, Kristin; Schmidt, Marcus; Tesch, Hans; Kümmel, Sherko; Sinn, Peter; Jackisch, Christian; Dietel, Manfred; Reimer, Toralf; Untch, Michael; Loibl, Sibylle

    2015-03-20

    Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rates ≥ 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2-positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P < .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P < .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P < .001). Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC. © 2014 by American Society of Clinical Oncology.

  10. Toll-Like Receptor 7 Agonist Therapy with Imidazoquinoline Enhances Cancer Cell Death and Increases Lymphocytic Infiltration and Proinflammatory Cytokine Production in Established Tumors of a Renal Cell Carcinoma Mouse Model

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    Eric C. Kauffman

    2012-01-01

    Full Text Available Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum levels of proinflammatory cytokines. In conclusion, imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for imidazoquinoline in RCC.

  11. Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Francesco Maura

    Full Text Available Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV genes and heavy-chain complementarity determining region-3 (HCDR3, are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL. We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT of patients with early stage disease (Binet A. Stereotyped HCDR3 sequences were found in 357 cases (31.7%, 231 of which (64.7% were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17(p13. Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

  12. TCR gamma delta cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells.

    Science.gov (United States)

    Dolstra, H; Fredrix, H; van der Meer, A; de Witte, T; Figdor, C; van de Wiel-van Kemenade, E

    2001-05-01

    Cytotoxic T lymphocytes (CTL) are thought to play an important role in the graft-versus-leukemia (GVL) response. Unfortunately, GVL reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Characterization of CTL that selectively attack leukemic cells but not normal cells may lead to the development of adjuvant immunotherapy that separates GVL from GVHD. Here, we describe TCR gamma delta (V gamma 9/V delta 1) CTL, isolated from the peripheral blood of an AML patient after stem cell transplantation (SCT), that very efficiently lysed freshly isolated acute myeloid leukemia (AML) cells and AML cell lines. Interestingly, HLA-matched non-malignant hematopoietic cells were not killed. We revealed that the killer cell-inhibitory receptor (KIR) p58.2 (CD158b) specific for group 2 HLA-C molecules negatively regulates the cytotoxic effector function displayed by these TCR gamma delta CTL. First, an antibody against HLA-C enhances lysis of non-malignant cells. Secondly, stable transfection of HLA-Cw*0304 into the class I-negative cell line 721.221 inhibited lysis. Finally, engagement of p58.2 by antibodies immobilized on Fc gamma R-expressing murine P815 cells inhibits CD3- and TCR gamma delta-directed lysis. Compared to non-malignant hematopoietic cells, AML cells express much lower levels of MHC class I molecules making them susceptible to lysis by p58.2(+) TCR gamma delta CTL. Such KIR-regulated CTL reactivity may have a role in the GVL response without affecting normal tissues of the host and leading to GVHD.

  13. Rearrangement and junctional-site sequence analyses of T-cell receptor gamma genes in intestinal intraepithelial lymphocytes from murine athymic chimeras.

    Science.gov (United States)

    Whetsell, M; Mosley, R L; Whetsell, L; Schaefer, F V; Miller, K S; Klein, J R

    1991-12-01

    The molecular organization of rearranged T-cell receptor (TCR) gamma genes intraepithelial lymphocytes (IEL) was studied in athymic radiation chimeras and was compared with the organization of gamma gene rearrangements in IEL from thymus-bearing animals by polymerase chain reaction and by sequence analyses of DNA spanning the junction of the variable (V) and joining (J) genes. In both thymus-bearing mice and athymic chimeras, IEL V-J gamma-gene rearrangements occurred for V gamma 1.2, V gamma 2, and V gamma 5 but not for V gamma 3 or V gamma 4. Sequence analyses of cloned V-J polymerase chain reaction-amplified products indicated that in both thymus-bearing mice and athymic chimeras, rearrangement of V gamma 1.2 and V gamma 5 resulted in in-frame as well as out-of-frame genes, whereas nearly all V gamma 2 rearrangements were out of frame from either type of animal. V-segment nucleotide removal occurred in most V gamma 1.2, V gamma 2, and V gamma 5 rearrangements; J-segment nucleotide removal was common in V gamma 1.2 but not in V gamma 2 or V gamma 5 rearrangements. N-segment nucleotide insertions were present in V gamma 1.2, V gamma 2, and V gamma 5 IEL rearrangements in both thymus-bearing mice and athymic chimeras, resulting in a predominant in-frame sequence for V gamma 5 and a predominant out-of-frame sequence for V gamma 2 genes. These findings demonstrate that (i) TCR gamma-gene rearrangement occurs extrathymically in IEL, (ii) rearrangements of TCR gamma genes involve the same V gene regardless of thymus influence; and (iii) the thymus does not determine the degree to which functional or nonfunctional rearrangements occur in IEL.

  14. Two forms of adaptive immunity in vertebrates: similarities and differences.

    Science.gov (United States)

    Kasahara, Masanori; Sutoh, Yoichi

    2014-01-01

    Unlike jawed vertebrates that use T-cell and B-cell receptors for antigen recognition, jawless vertebrates represented by lampreys and hagfish use variable lymphocyte receptors (VLRs) as antigen receptors. VLRs generate diversity comparable to that of gnathostome antigen receptors by assembling variable leucine-rich repeat modules. The discovery of VLR has revolutionized our understanding of how adaptive immunity emerged and highlighted the differences between the adaptive immune systems (AISs) of jawed and jawless vertebrates. However, emerging evidence also indicates that their AISs have much in common. Particularly striking is the conservation of lymphocyte lineages. The basic architecture of the AIS including the dichotomy of lymphocytes appears to have been established in a common ancestor of jawed and jawless vertebrates. We review here the current knowledge on the AIS of jawless vertebrates, emphasizing both the similarities to and differences from the AIS of jawed vertebrates.

  15. 嵌合抗原受体修饰淋巴细胞在多发性骨髓瘤中的研究进展%Advances in immunotherapy of multiple myeloma by using chimeric antigen receptor-modified lymphocytes

    Institute of Scientific and Technical Information of China (English)

    魏华萍; 赵小利; 高春记

    2015-01-01

    Chimeric antigen receptor-modified lymphocyte is a type of cancer immunotherapies. By re-engineering antigen receptor in vitro, it can be expressed on the membrane of lymphocytes and increase the function of killing cancer cells. It is now the most attractivefield of cancer immunotherapies in hematologic malignancies, especially in B-cell malignancies by its significant therapeutic effect. Multiple myeloma (MM) is the second common hematologic cancer in the elderly populations. Up to now, it is still incurable. Researchers have been exploring the applications of immunotherapy in MM. This review discusses the recent development of chimeric antigen receptor-modified lymphocytic cell technology and its application in multiple myeloma.%嵌合抗原受体修饰淋巴细胞是过继免疫治疗的一种类型,其通过体外改造细胞表面受体,使淋巴细胞过表达,从而促进淋巴细胞的抗肿瘤活性。这种技术是目前恶性肿瘤免疫治疗领域中的新疗方法之一,在恶性血液病尤其是B细胞系统恶性血液病中治疗效果令人振奋。多发性骨髓瘤是血液系统第二常见恶性肿瘤,好发于老年人,目前仍无法治愈,研究者们一直在探索该病的免疫治疗。本文对近年来嵌合抗原受体修饰淋巴细胞技术的发展及其在多发性骨髓瘤中的应用进行综述。

  16. Chronic lymphocytic leukaemia

    Science.gov (United States)

    Kipps, Thomas J.; Stevenson, Freda K.; Wu, Catherine J.; Croce, Carlo M.; Packham, Graham; Wierda, William G.; O’Brien, Susan; Gribben, John; Rai, Kanti

    2017-01-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer. PMID:28102226

  17. Adipose tissue lymphocytes: types and roles.

    Science.gov (United States)

    Caspar-Bauguil, S; Cousin, B; Bour, S; Casteilla, L; Castiella, L; Penicaud, L; Carpéné, C

    2009-12-01

    Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development.

  18. Heterogeneity in the properties of mutant secreted lymphocyte antigen 6/urokinase receptor-related protein 1 (SLURP1) in Mal de Meleda

    DEFF Research Database (Denmark)

    Adeyo, Oludotun; Oberer, Monika; Ploug, M

    2015-01-01

    Genetic defects in SLURP1, a "lymphocyte antigen 6" (Ly6)-like protein, cause mal de Meleda, a palmoplantar keratoderma (PPK). The hallmark of Ly6 proteins is an 80-amino acid domain containing 10 cysteines, all arranged in a characteristic spacing pattern and all disulfide-bonded, creating a thr...

  19. Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity.

    Science.gov (United States)

    Krönig, Holger; Hofer, Kathrin; Conrad, Heinke; Guilaume, Philippe; Müller, Julia; Schiemann, Matthias; Lennerz, Volker; Cosma, Antonio; Peschel, Christian; Busch, Dirk H; Romero, Pedro; Bernhard, Helga

    2009-08-01

    The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1-expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY-ESO-1-specific T lymphocytes displayed TCRs with the highest avidity and best anti-tumor recognition activity. TCRs derived from allorestricted, NY-ESO-1-specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of NY-ESO-1-expressing hematological malignancies and solid tumors.

  20. CTLA4Fcε, a novel soluble fusion protein that binds B7 molecules and the IgE receptors, and reduces human in vitro soluble CD23 production and lymphocyte proliferation.

    Science.gov (United States)

    Perez-Witzke, Daniel; Miranda-García, María Auxiliadora; Suárez, Nuris; Becerra, Raquel; Duque, Kharelys; Porras, Verónica; Fuenmayor, Jaheli; Montano, Ramon Fernando

    2016-05-01

    Immunoglobulin E-mediated allergy and certain autoimmune diseases are characterized by the presence of a T helper type 2 (Th2) immune response and allergen-specific or self-reactive IgE. Soluble CD23 (sCD23) is a B-cell factor that fosters IgE class-switching and synthesis, suggesting that sCD23 may be a therapeutic target for these pathologies. We produced a recombinant protein, CTLA4Fcε, by fusing the ectodomain of the immunoregulatory molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4) with a fragment of the IgE H-chain constant region. In SDS-PAGE/inmunoblot analyses, CTLA4Fcε appeared as a 70,000 MW polypeptide that forms homodimers. Flow cytometry showed that CTLA4Fcε binds to IgE receptors FcεRI and FcεRII/CD23, as well as to CTLA-4 counter-receptors CD80 and CD86. Binding of CTLA4Fcε to FcεRII/CD23 appeared stronger than that of IgE. Since the cells used to study CD23 binding express CD80 and CD86, simultaneous binding of CTLA4Fcε to CD23 and CD80/CD86 seems to occur and would explain this difference. As measured by a human CD23-specific ELISA, CTLA4Fcε - but not IgE - induced a concentration-dependent reduction of sCD23 in culture supernatants of RPMI-8866 cells. Our results suggest that the simultaneous binding of CTLA4Fcɛ to CD23-CD80/CD86 may cause the formation of multi-molecular complexes that are either internalized or pose a steric hindrance to enzymatic proteolysis, so blocking sCD23 generation. CTLA4Fcε caused a concentration-dependent reduction of lymphocyte proliferation in human peripheral blood mononuclear cell samples stimulated in vitro with concanavalin A. The ability to bind IgE receptors on effector cells, to regulate the production of sCD23 and to inhibit lymphocyte proliferation suggests that CTLA4Fcɛ has immunomodulatory properties on human Th2 responses.

  1. Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

    Science.gov (United States)

    Giannoni, Paolo; Pietra, Gabriella; Travaini, Giorgia; Quarto, Rodolfo; Shyti, Genti; Benelli, Roberto; Ottaggio, Laura; Mingari, Maria Cristina; Zupo, Simona; Cutrona, Giovanna; Pierri, Ivana; Balleari, Enrico; Pattarozzi, Alessandra; Calvaruso, Marco; Tripodo, Claudio; Ferrarini, Manlio; de Totero, Daniela

    2014-01-01

    Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3TYR705 phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients’ monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET+ and indoleamine 2,3-dioxygenase+ cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4+CD25high+/FOXP3+ T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of

  2. SECRETION OF IL-12, IL-27 BY MONONUCLEAR LEUKOCYTES AND EXPRESSION OF THEIR RECEPTORS ON T-LYMPHOCYTES IN CONDITIONS OF DIRECTED CELL INDUCTION IN VITRO IN PULMONARY TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    I. E. Esimova

    2014-01-01

    Full Text Available The article presents the results of studies concerning secretion of cytokines belonging to interleukin 12 family, i.e., IL-12р70, IL-12р40, IL-12р35 and IL-27 in mononuclear blood leukocytes, as well as expression of their specific receptors on T-lymphocytes from tuberculosis patients under the in vitro conditions of directed (resp., antigen- and cytokine-mediated cell induction. In patients with pulmonary TB, we have registered suppression of both spontaneous and BCG-induced secretion of IL-12р70 and IL- 12р35, along with overproduction of IL-12р40 and IL-27. Furthermore, a decrease in relative contents of СD3+gp130+,CD3+IL12Rβ2+ lymphocytes were revealed in the in vitro IL-12/IL-27 induction tests, as well as increased concentration of T-cells with high expression of the inhibitory molecule WSX-1 (CD3+WSX-1+hi. It was shown that the detectable changes are unidirectional in most cases, being dependent on clinical form of the disease and sensitivity of the etiological agent to anti-tuberculosis drugs.

  3. Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD

    NARCIS (Netherlands)

    Matic, Gordana; Milutinovic, Danijela Vojnovic; Nestorov, Jelena; Elakovic, Ivana; Jovanovic, Sanja Manitasevic; Perisic, Tatjana; Dunderski, Jadranka; Damjanovic, Svetozar; Knezevic, Goran; Spiric, Zeljko; Vermetten, Eric; Savic, Danka

    2013-01-01

    Objective: Posttraumatic stress disorder (PTSD) has been shown to be associated with altered glucocorticoid receptor (GR) activity. We studied the expression and functional properties of the receptor in peripheral blood mononuclear cells (PBMCs) from non-traumatized healthy individuals (healthy cont

  4. REARRANGEMENT AND EXPRESSION OF T CELL RECEPTOR β GENE IN HUMAN HEMOPOIETIC CELL LINES AND PRIMARY CELLS FROM ACUTE LYMPHOCYTIC LEUKEMIAS

    Institute of Scientific and Technical Information of China (English)

    仇一华; 陈诗书

    1992-01-01

    Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat, Daudi and Raji cells as well as lymphocytes from 17 acute lymphocytic leukemia (ALL) patients. The results showed. Ⅰ) Rearrangement of TCR βgene was seen in Jurkat cells. A germline pattern was observed in HL-60, Daudi and Raji cells. 2) Eight of 9 patients with T-ALL had cells with rearranged TCR βgene. But two of 3 patients with B-ALL and three of 5 patients with nonT, nonB-ALL also had cells with rearranged TCR βgene. 3) A 1.3 kb full-length transcript and a 1.0 kb truncated transcript were detected in Jurkat cells by probing with 32P-TCR βcDNA. But some leukemic B cells also expressed an incompleted transcript. 4) TCR βmRNA was detected in six of 8 patients with T-ALL, four of 5 patients with nonT, nonB-ALL and one of 3 patients with B-ALL. But the level of expression was quite differ ent. The dual-rearrangement and the abnormal expression may give us a new clue for researching leukemogenesis.

  5. Oropharyngeal malignant epithelial cell, lymphocyte and macrophage CD44 surface receptors for hyaluronate are expressed in sustained EBV infection: immunohistochemical data and EBV DNA tissue indices.

    Science.gov (United States)

    Groma, Valerija; Kazanceva, Anna; Nora-Krukle, Zaiga; Murovska, Modra

    2012-09-15

    The role of CD44 in Epstein-Barr virus (EBV)-related epithelial tumors is poorly understood. We studied the expression of CD44 in EBV infection in patients with oral squamous cell carcinoma (SCC) and nasopharyngeal carcinoma (NPC) and measured the EBV DNA. Whole blood, plasma and tissue samples from 8 male and 2 female patients with oral SCC, NPC, salivary gland lymphoepithelioma, normal salivary gland and buccal mucosa were assayed for EBV DNA. Expression of CD44, latent membrane protein (LMP), and labeling of lymphocytes, macrophages and dendritic cells were estimated by immunohistochemistry. Tissue EBV DNA was detected in 7 of 8 cases (87.5%) of oral malignant, benign and border-line lesions. LMP expression levels in tumors varied from absence and minimal to moderate - 50.3, 43.6, 6.0% and 91.1, 6.7, 2.2% for SCC and NPC, respectively. Levels of CD44 positivity in neoplasms were minimal (15.5 and 16.7%), moderate (30.3 and 47.8%), and diffuse (54.2 and 35.5%) for SCC and NPC, respectively, thus deviating from normal oral mucosa revealing heavily stained (100.0%) epithelial contours. CD19-positive B lymphocytes and S100-positive dendritic cells were intermixed with neoplastic cells. Collectively, CD44 mediated signaling may be implicated in EBV infection associated with the pathogenesis of oral SCC and NPC.

  6. [Evolution and phylogeny of B lymphocytes].

    Science.gov (United States)

    Claudio-Piedras, Fabiola; Lanz-Mendoza, Humberto

    2016-01-01

    B lymphocytes are one of the most important cell types involved in the immune response of mammals. The origin and evolution of this cellular type is unknown, but the B lymphocyte bona fide appeared first in fish. In this review we analize the principal components of the immune response of invertebrates, their phylogenetic distribution and the permancence of some properties that allowed the emergence of the B lymphocyte. We started from the idea that many of the components that characterize the B lymphocyte are found distributed among the invertebrates, however, it is in the B lymphocyte, where all these components that give this type of cell its identity, converged. The actual knowledge we have in regards of the lymphocytes comes, in the most part, from physiological studies in mammals, being the mice the more representative. The origin of the B lymphocyte, its alternative mechanisms for generating receptor diversity, its immune effector response, and the generation of memory, require an evolutionary and multidisiplinary approach for its study.

  7. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Herman, S E M; Niemann, C U; Farooqui, M

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further...

  8. Evolution of innate and adaptive immune systems in jawless vertebrates.

    Science.gov (United States)

    Kasamatsu, Jun

    2013-01-01

    Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates. Jawless vertebrates have developed lymphocyte-like cells that morphologically resemble the T and B cells of jawed vertebrates, but they express variable lymphocyte receptors (VLRs) instead of the T and B cell receptors that specifically recognize antigens in jawed vertebrates. These VLRs act as antigen receptors, diversity being generated in their antigen-binding sites by assembly of highly diverse leucine-rich repeat modules. Therefore, jawless vertebrates have developed adaptive immune systems based on the VLRs. Although pattern recognition receptors, including Toll-like receptors (TLRs) and Rig-like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates, some transcription factor and inflammatory cytokine genes in the TLR and RLR pathways are not present. However, like jawed vertebrates, the initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system. These observations imply that the innate immune systems of jawless vertebrates have a unique molecular basis that is distinct from that of jawed vertebrates. Altogether, although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, jawless vertebrates have developed versions of these immune systems that are similar to those of jawed vertebrates.

  9. Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2014-10-30

    Hematopoietic/Lymphoid Cancer; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  10. S1P(1) Receptor Modulation Preserves Vascular Function in Mesenteric and Coronary Arteries after CPB in the Rat Independent of Depletion of Lymphocytes

    NARCIS (Netherlands)

    Samarska, Iryna V.; Bouma, Hjalmar R.; Buikema, Hendrik; Mungroop, Hubert E.; Houwertjes, Martin C.; Absalom, Anthony R.; Epema, Anne H.; Henning, Robert H.

    2014-01-01

    Background: Cardiopulmonary bypass (CPB) may induce systemic inflammation and vascular dysfunction. Sphingosine 1-phosphate (S1P) modulates various vascular and immune responses. Here we explored whether agonists of the S1P receptors, FTY720 and SEW2871 improve vascular reactivity after CPB in the r

  11. The wild boar (Sus scrofa Lymphocyte function-associated antigen-1 (CD11a/CD18 receptor: cDNA sequencing, structure analysis and comparison with homologues

    Directory of Open Access Journals (Sweden)

    Bergh Philippe

    2007-10-01

    Full Text Available Abstract Background The most predominant beta2-integrin lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2, expressed on all leukocytes, is essential for many adhesive functions of the immune system. Interestingly, RTX toxin-producing bacteria specifically target this leukocyte beta2-integrin which exacerbates lesions and disease development. Results This study reports the sequencing of the wild boar beta2-integrin CD11a and CD18 cDNAs. Predicted CD11a and CD18 subunits share all the main structural characteristics of their mammalian homologues, with a larger interspecies conservation for the CD18 than the CD11a. Besides these strong overall similarities, wild boar and domestic pig LFA-1 differ by 2 (CD18 and 1 or 3 (CD11a substitutions, of which one is located in the crucial I-domain (CD11a, E168D. Conclusion As most wild boars are seropositive to the RTX toxin-producing bacterium Actinobacillus pleuropneumoniae and because they have sustained continuous natural selection, future studies addressing the functional impact of these polymorphisms could bring interesting new information on the physiopathology of Actinobacillus pleuropneumoniae-associated pneumonia in domestic pigs.

  12. Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia.

    Directory of Open Access Journals (Sweden)

    Francesco Maura

    Full Text Available IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540. High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM status (p<0.0001, high CD38 expression (p<0.0001, trisomy 12 (p<0.0001, and del(11(q23 (p=0.014. Interestingly, higher IGF1R expression (p=0.002 characterized patients with NOTCH1 mutation (c.7541_7542delCT, identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.

  13. Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

    Science.gov (United States)

    Maura, Francesco; Mosca, Laura; Fabris, Sonia; Cutrona, Giovanna; Matis, Serena; Lionetti, Marta; Agnelli, Luca; Barbieri, Marzia; D’Anca, Marianna; Manzoni, Martina; Colombo, Monica; Massucco, Carlotta; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Ilariucci, Fiorella; Musolino, Caterina; Di Raimondo, Francesco; Cortelezzi, Agostino; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation. PMID:25786252

  14. Prenatal ontogeny of lymphocyte subpopulations in pigs.

    Science.gov (United States)

    Sinkora, M; Sinkora, J; Reháková, Z; Splíchal, I; Yang, H; Parkhouse, R M; Trebichavsk, I

    1998-12-01

    Although porcine lymphocytes have been classified into numerous subpopulations in postnatal animals, little is known about the ontogeny of these complex cell subsets. Using double- and triple-colour flow cytometry (FCM), we investigated the surface phenotype of fetal lymphoid cells in the thymus, cord blood, spleen and mesenteric lymph nodes at different stages of gestation. It was found that the major lymphocyte subpopulations started to appear at the beginning of the second third of the gestation period, with B cells being the earliest lymphocyte subpopulation to appear in the periphery. The T-cell receptor (TCR) gamma delta+ cells were the earliest detectable T-cell subset, developing first in the thymus and subsequently arriving in the periphery. Later in ontogeny, however, the number of TCRalpha beta+ lymphocytes rapidly increased, becoming the predominant T cells both in the thymus and in the periphery. Cells with the phenotype of adult natural killer cells were also identified in pig fetuses, though their nature and functional roles remain to be investigated. In addition, CD2 was expressed on most B cells whilst very few CD4+ TCRalpha beta+ cells or CD2+ TCRgamma delta+ cells expressed CD8, suggesting that the expression of CD2 and CD8 may reflect the functional status of the cells in postnatal animals. Taken together, this study has provided a systematic analysis of fetal porcine lymphocyte subpopulations and may provide the base for studies to establish the physiological roles of these lymphocyte subsets.

  15. Flow cytometric analysis of lymphocytes and lymphocyte subpopulations in induced sputum from patients with asthma

    Directory of Open Access Journals (Sweden)

    Yutaro Shiota

    2000-01-01

    Full Text Available Study objectives were to compare the numbers of lymphocytes and lymphocyte subpopulations in induced sputum from asthmatic patients and from healthy subjects, and to determine the effect of inhaled anti-asthmatic steroid therapy on these cell numbers. Hypertonic saline inhalation was used to non-invasively induce sputum samples in 34 patients with bronchial asthma and 21 healthy subjects. The sputum samples were reduced with dithioerythritol and absolute numbers of lymphocytes and lymphocyte subpopulations were assessed by direct immunofluorescence and flow cytometry. To assess the effect of beclomethasone dipropionate (BDP on induced sputum, numbers of lymphocytes and lymphocyte subpopulations in sputum also were evaluated after 4 weeks of BDP inhalation treatment in seven asthmatic patients. An adequate sample was obtained in 85.3% of patients with asthma and in 79.2% of the healthy subjects. Induced sputum from patients with asthma had increased numbers of lymphocytes (P = 0.009; CD4+ cells (P = 0.044; CD4+ cells-bearing interleukin-2 receptor (CD25; P = 0.016; and CD4+ cells bearing human histocompatibility leukocyte antigen (HLA-DR (P = 0.033. CD8+ cells were not increased in asthmatic patients. In patients treated with inhaled steroids, numbers of lymphocytes, CD4+ cells, CD25-bearing CD4+ cells and HLA-DR-bearing CD4+ cells in sputum decreased from pretreatment numbers (P = 0.016, 0.002, 0.003 and 0.002, respectively. Analysis of lymphocytes in induced sputum by flow cytometry is useful in assessing bronchial inflammation, and activated CD4+ lymphocytes may play a key role in the pathogenesis of airway inflammation in bronchial asthma.

  16. NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development.

    Science.gov (United States)

    Berga-Bolaños, Rosa; Alberdi, Maria; Buxadé, Maria; Aramburu, José; López-Rodríguez, Cristina

    2013-10-01

    The Rel-like transcription factors nuclear factor kappa B (NF-κB) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKKβ regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor αβ thymocytes and the transition from the β-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in β-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKKβ/NF-κB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor.

  17. NFAT5 induction by the pre–T-cell receptor serves as a selective survival signal in T-lymphocyte development

    Science.gov (United States)

    Berga-Bolaños, Rosa; Alberdi, Maria; Buxadé, Maria; Aramburu, José; López-Rodríguez, Cristina

    2013-01-01

    The Rel-like transcription factors nuclear factor kappa B (NF-κB) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKKβ regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor αβ thymocytes and the transition from the β-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre–T-cell receptor but exhibited a partial defect in β-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKKβ/NF-κB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre–T-cell receptor. PMID:24043824

  18. An intrinsic GABAergic system in human lymphocytes.

    Science.gov (United States)

    Dionisio, Leonardo; José De Rosa, María; Bouzat, Cecilia; Esandi, María Del Carmen

    2011-01-01

    γ-amino butyric acid (GABA) is an ubiquitous neurotransmitter in the central nervous system and it is also present in non-neuronal cells. In this study we investigated the presence of neuronal components of the GABAergic system in lymphocytes and its functional significance. By using RT-PCR we detected mRNA expression of different components of the GABAergic system in resting and mitogen-activated lymphocytes: i) GAD67, an isoform of the enzyme that synthetizes GABA; ii) VIAAT, the vesicular protein involved in GABA storage; iii) GABA transporters (GAT-1 and GAT-2); iv) GABA-T, the enzyme that catabolizes GABA; and v) subunits that conform ionotropic GABA receptors. The presence of VIAAT protein in resting and activated cells was confirmed by immunocytochemistry. The functionality of GABA transporters was evaluated by measuring the uptake of radioactive GABA. The results show that [(3)H]GABA uptake is 5-fold higher in activated than in resting lymphocytes. To determine if GABA subunits assemble into functional channels, we performed whole-cell recordings in activated lymphocytes. GABA and muscimol, a specific agonist of ionotropic GABA receptors, elicit macroscopic currents in about 10-15% of the cells. Finally, by using [(3)H]thymidine incorporation assays, we determined that the presence of agonists of GABA receptor during activation inhibits lymphocyte proliferation. Our results reveal that lymphocytes have a functional GABAergic system, similar to the neuronal one, which may operate as a modulator of T-cell activation. Pharmacological modulation of this system may provide new approaches for regulation of T-cell response. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. Bendamustine Plus Alemtuzumab for Refractory Chronic Lymphocytic Leukemia (CLL)

    Science.gov (United States)

    2013-08-20

    Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  20. Novel Confocal Microscopic and Flow Cytometric Based Assays to Visualize and Detect the (Beta)2-Adrenergic Receptor in Human Lymphocyte and Mononuclear Cell Populations

    Science.gov (United States)

    Salicru, A. N.; Crucian, B. E.; Nelman, M. A.; Sams, C. F.; Actor, J. K.; Marshall, G. D.

    2006-01-01

    The data show that immunophenotyping of leukocyte populations with (beta)2AR is possible with the commercially available Ab, although the FC assay is limited to the IST as a result of the Ab binding site to the intracellular C-terminus of the 2AR. The FC assay has applications for measuring alterations in total (beta)2AR in human leukocyte populations as changes in fluorescence. In addition, CM confirms that both surface and intracellular compartments stain positively for the (beta)2AR and can be used for qualitative assays that screen for changes in receptor compartmentalization and localization.

  1. Transducción de señales generadas a partir del receptor antigénico de los linfocitos T Transduction of signal generated from the antigenic receptor of T lymphocytes

    Directory of Open Access Journals (Sweden)

    Carlos Julio Montoya Guarín

    1999-04-01

    Full Text Available A diferencia de lo observado para los linfocitos B, que reconocen antígenos libres en forma nativa, los linfocitos T han evolucionado para reconocer pequeños péptidos antigénicos presentados por moléculas de histocompatibilidad en la superficie de células presentadoras especializadas o de células diana. Para ello los linfocitos T maduros cuentan con un grupo de proteínas de membrana que en conjunto se denominan complejo TCR. Este grupo de cadenas polipeptídicas se expresan en la membrana de los linfocitos T y cumplen una función doble: reconocer los fragmentos antigénicos presentados por las moléculas de histocompatibilidad y transmitir las señales de ese reconocimiento al interior del linfocito. Las consecuencias de esta señalización pueden variar desde la activación funcional hasta la anergia o la apoptosis. Gracias a una intensa investigación en esta área, en los últimos años se han revelado muchas de las proteínas involucradas en la transducción de señales en los linfocitos T y sus mecanismos de acción. En esta revisión se examinan los modelos que explican la dinámica de la ligación del TCR, las principales vías de transducción de señales, los agentes farmacológicos que han permitido su estudio y dos modelos de enfermedades humanas que presentan entre sus mecanismos fisiopatológicos alteraciones en las vías de señalización a través del TCR. T lymphocytes, in contrast to B lymphocytes which bind free antigens in a native form, recognize little antigenic peptides displayed on histocompatibility molecules in the surface of specialized or target cells. For this, mature T lymphocytes have a group of membrane proteins that together are named TCR complex. This group of polypeptide chains expresses in the membrane and has a double function: to recognize the antigenic fragments bound to histocompatibility molecules and to transmit signals arisen from the recognition to the inner of the lymphocyte. The consequences

  2. What Is Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Chronic Lymphocytic Leukemia (CLL) About Chronic Lymphocytic Leukemia What Is Chronic Lymphocytic Leukemia? Cancer starts when cells ... body, including the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts ...

  3. Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2013-07-01

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  4. Domain analyses of the Runx1 transcription factor responsible for modulating T-cell receptor-β/CD4 and interleukin-4/interferon-γ expression in CD4+ peripheral T lymphocytes

    Science.gov (United States)

    Uchino, Ryuji

    2009-01-01

    The Runx1 transcription factor is one of the master regulators of T-lymphocyte differentiation. There have been several reports trying to assign a domain within the Runx1 protein that is responsible for gene expression in thymocytes. The Runx1 domains involved in regulating the expression of several genes in peripheral CD4+ T cells were analysed. It was observed that Runx1 over-expression enhanced the surface expression of CD4 and CD69 molecules via its activation domain and VWRPY domain, and decreased that of T-cell receptor-β via its activation domain. Runx1 over-expression enhanced interferon-γ expression via its activation and VWRPY domains, and abolished interleukin-4 expression through its activation domain. Transduction of Runx1 did not down-regulate CD4 expression until 72 hr of culture, but the repression of CD4 expression became evident after 96 hr. The main region responsible for repressing CD4 expression was the inhibitory domain of Runx1. Taken together, these results lead to a proposal that the regions in Runx1 responsible for modulating gene expression are distinct in thymocytes and in peripheral CD4+ T cells. PMID:19689732

  5. Cultured lymphocytes from alcoholic subjects have altered cAMP signal transduction.

    OpenAIRE

    Nagy, L E; Diamond, I; Gordon, A.

    1988-01-01

    Previous work has shown that freshly isolated lymphocytes from alcoholic subjects show significantly reduced basal and adenosine receptor-stimulated cAMP levels. This decrease could be due to ethanol-induced cellular adaptation or to a genetic difference in the regulation of cAMP signal transduction. Therefore, we cultured human lymphocytes in defined medium without ethanol for 7-8 days and then examined differences in receptor-dependent cAMP accumulation between lymphocytes from alcoholic an...

  6. T-cell receptor v-alpha and v-Beta gene usage in interleukin-2-cultured tumor-infiltrating lymphocytes from patients with breast-cancer

    DEFF Research Database (Denmark)

    Andersen, E; Scholler, J; Straten, P;

    1994-01-01

    surface through the T cell receptor (TCR) complex. We have studied the phenotype, cytotoxicity, and expression of TCR variable (V) alpha and beta chain on in vitro IL-2-cultured TIL isolated from primary malignant breast tumors from 11 patients. 10/11 cultures were dominated by CD4(+) (T-helper) cells....... The different TIL cultures exhibited varying levels of cytotoxicity against the natural killer (NK)-sensitive cell line K562 and breast cancer cell line T47D. The level of clonality, as measured by PCR-based analyses of usage of the different V segments was low, as only a few tumors showed patterns...... of restricted V gene expression. The mean number of V alpha segments per TIL culture was higher than the number of V beta segments per culture. A significant negative correlation was observed between the number of CD4+ cells and the number of V beta segments per culture, and no other correlations between...

  7. Production of two hemopoietic growth factors is differentially regulated in single T lymphocytes activated with an anti-T cell receptor antibody

    DEFF Research Database (Denmark)

    Kelso, A; Owens, T

    1988-01-01

    by micromanipulation into wells coated with the monoclonal anti-T cell receptor antibody F23.1, up to 90% of cells produced CSF as detected by CSF-dependent hemopoietic cell lines. Production occurred in the absence of proliferation and did not require the addition of accessory cells or IL-2. Both the frequency of CSF......-producing cells and the average production per positive cell depended on the density of the immobilized stimulating ligand, indicating that the response of each cell is not an all-or-none phenomenon but varies with the strength of stimulation. Individual cells of the clone varied over a 100-fold range...... based since such cells could give rise to progeny that synthesized multi-CSF. These results suggest that the synthesis of these two lymphokines can be differentially regulated at the level of the single cell....

  8. Histamine Regulates Actin Cytoskeleton in Human Toll-like Receptor 4-activated Monocyte-derived Dendritic Cells Tuning CD4+ T Lymphocyte Response.

    Science.gov (United States)

    Aldinucci, Alessandra; Bonechi, Elena; Manuelli, Cinzia; Nosi, Daniele; Masini, Emanuela; Passani, Maria Beatrice; Ballerini, Clara

    2016-07-08

    Histamine, a major mediator in allergic diseases, differentially regulates the polarizing ability of dendritic cells after Toll-like receptor (TLR) stimulation, by not completely explained mechanisms. In this study we investigated the effects of histamine on innate immune reaction during the response of human monocyte-derived DCs (mDCs) to different TLR stimuli: LPS, specific for TLR4, and Pam3Cys, specific for heterodimer molecule TLR1/TLR2. We investigated actin remodeling induced by histamine together with mDCs phenotype, cytokine production, and the stimulatory and polarizing ability of Th0. By confocal microscopy and RT-PCR expression of Rac1/CdC42 Rho GTPases, responsible for actin remodeling, we show that histamine selectively modifies actin cytoskeleton organization induced by TLR4, but not TLR2 and this correlates with increased IL4 production and decreased IFNγ by primed T cells. We also demonstrate that histamine-induced cytoskeleton organization is at least in part mediated by down-regulation of small Rho GTPase CdC42 and the protein target PAK1, but not by down-regulation of Rac1. The presence and relative expression of histamine receptors HR1-4 and TLRs were determined as well. Independently of actin remodeling, histamine down-regulates IL12p70 and CXCL10 production in mDCs after TLR2 and TLR4 stimulation. We also observed a trend of IL10 up-regulation that, despite previous reports, did not reach statistical significance.

  9. Retargeting of T lymphocytes to PSCA- or PSMA positive prostate cancer cells using the novel modular chimeric antigen receptor platform technology “UniCAR”

    Science.gov (United States)

    Feldmann, Anja; Arndt, Claudia; Bergmann, Ralf; Loff, Simon; Cartellieri, Marc; Bachmann, Dominik; Aliperta, Roberta; Hetzenecker, Mirjam; Ludwig, Florian; Albert, Susann; Ziller-Walter, Pauline; Kegler, Alexandra; Koristka, Stefanie; Gärtner, Sebastian; Schmitz, Marc; Ehninger, Armin; Ehninger, Gerhard; Pietzsch, Jens; Steinbach, Jörg; Bachmann, Michael

    2017-01-01

    New treatment options especially of solid tumors including for metastasized prostate cancer (PCa) are urgently needed. Recent treatments of leukemias with chimeric antigen receptors (CARs) underline their impressive therapeutic potential. However CARs currently applied in the clinics cannot be repeatedly turned on and off potentially leading to severe life threatening side effects. To overcome these problems, we recently described a modular CAR technology termed UniCAR: UniCAR T cells are inert but can be turned on by application of one or multiple target modules (TMs). Here we present preclinical data summarizing the retargeting of UniCAR T cells to PCa cells using TMs directed to prostate stem cell- (PSCA) or/and prostate specific membrane antigen (PSMA). In the presence of the respective TM(s), we see a highly efficient target-specific and target-dependent activation of UniCAR T cells, secretion of pro-inflammatory cytokines, and PCa cell lysis both in vitro and experimental mice. PMID:28404896

  10. Association of suboptimal health status with psychosocial stress, plasma cortisol and mRNA expression of glucocorticoid receptor α/β in lymphocyte.

    Science.gov (United States)

    Yan, Yu-Xiang; Dong, Jing; Liu, You-Qin; Zhang, Jie; Song, Man-Shu; He, Yan; Wang, Wei

    2015-01-01

    Suboptimal health status (SHS) has become a new public health challenge in China. This study investigated whether high SHS is associated with psychosocial stress, changes in cortisol level and/or glucocorticoid receptor (GR) isoform expression. Three-hundred eighty-six workers employed in three companies in Beijing were recruited. The SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. The mean value of the five scales of COPSOQ and distribution of plasma cortisol and mRNA expression of GRα/GRβ between the high level of SHS group and the low level of SHS group were compared using a general linear model procedure. Multiple linear regression analysis was used to analyze the effect of psychosocial stress on SHS. We identified three factors that were predictive of SHS, including "demands at work", "interpersonal relations and leadership" and "insecurity at work". Significantly higher levels of plasma cortisol and GRβ/GRα mRNA ratio were observed among the high SHS group. High level of SHS is associated with decreased mRNA expression of GRα. This study confirmed the association between chronic psychosocial stress and SHS, indicating that improving the psychosocial work environment may reduce SHS and then prevent chronic diseases effectively.

  11. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response.

    Science.gov (United States)

    Robbins, Paul F; Kassim, Sadik H; Tran, Thai L N; Crystal, Jessica S; Morgan, Richard A; Feldman, Steven A; Yang, James C; Dudley, Mark E; Wunderlich, John R; Sherry, Richard M; Kammula, Udai S; Hughes, Marybeth S; Restifo, Nicholas P; Raffeld, Mark; Lee, Chyi-Chia R; Li, Yong F; El-Gamil, Mona; Rosenberg, Steven A

    2015-03-01

    Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, the application of this approach to the treatment of other solid tumors has been limited. The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70% to 80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial using the adoptive transfer of autologous peripheral blood mononuclear cells that were retrovirally transduced with an NY-ESO-1-reactive T-cell receptor (TCR) to heavily pretreated patients bearing these metastatic cancers. HLA-*0201 patients with metastatic synovial cell sarcoma or melanoma refractory to standard treatments and whose cancers expressed NY-ESO-1 received autologous TCR-transduced T cells following a lymphodepleting preparative chemotherapy. Response rates using Response Evaluation Criteria in Solid Tumors (RECIST), as well as immunologic correlates of response, are presented in this report. Eleven of 18 patients with NY-ESO-1(+) synovial cell sarcomas (61%) and 11 of 20 patients with NY-ESO-1(+) melanomas (55%) who received autologous T cells transduced with an NY-ESO-1-reactive TCR demonstrated objective clinical responses. The estimated overall 3- and 5-year survival rates for patients with synovial cell sarcoma were 38% and 14%, respectively, whereas the corresponding estimated survival rates for patients with melanoma were both 33%. The adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope can be an effective therapy for some patients bearing synovial cell sarcomas and melanomas that are refractory to other treatments. ©2014 American Association for Cancer Research.

  12. Acute Lymphocytic Leukemia

    Science.gov (United States)

    ... for information in your local library and on the Internet. Good sources include the National Cancer Institute, the ... mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/CON-20042915 . Mayo Clinic Footer Legal Conditions and ...

  13. [Adoptive transfer of T lymphocytes].

    Science.gov (United States)

    Vié, H; Clémenceau, B

    2017-09-01

    Within a few years, the success of treatments based on the use of T-cells armed with a chimeric T-receptor for the CD19 molecule (CAR-T CD19) has revolutionized the perception of adoptive transfer approaches. The levels of responses observed in acute leukemias, of the order of 70-90 % are indeed unprecedented. The medical and financial enthusiasm aroused by these results has led to the current situation where more than 300 clinical trials are under way, against some thirty different antigens. This enthusiasm, well justified by the first successes, must however be tempered by the difficulties associated with the use of these cells. Indeed, the management of patients is made very complex both for medical reasons, because the toxicities associated with these treatments are important, and for technical reasons, because the preparation of T lymphocytes for therapeutic use requires dedicated structures. During this same period, knowledge of the mechanisms of regulation of T lymphocytes and the possibilities offered by synthetic biology and techniques of genome engineering have progressed considerably. Combined, they allow envisaging a true "programming" of the T lymphocytes, intended to improve the efficiency of the treatments and the safety of the patients. Medical and industrial perspectives and the role of these approaches in the arsenal of cancer therapies will depend largely on two conditions: the emergence of a robust demonstration of their effectiveness in solid tumors, and the establishment of an acceptable production and distribution model 1. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Ch(a)vez-Gal(a)n L; Arenas-Del Angel MC; Zenteno E; Ch(a)vez R; Lascurain R

    2009-01-01

    One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8+T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lyric molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis.

  15. Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes.

    Science.gov (United States)

    Papadakis, Konstantinos A; Krempski, James; Reiter, Jesse; Svingen, Phyllis; Xiong, Yuning; Sarmento, Olga F; Huseby, April; Johnson, Aaron J; Lomberk, Gwen A; Urrutia, Raul A; Faubion, William A

    2015-03-01

    KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4(+) T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8(+) T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10(-/-) CD8(+) T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8(+) T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8(+) T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8(+) T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8(+) T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10(-/-) CD8(+) T cells and a higher percentage of IFN-γ-producing CD8(+) T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8(+) T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial. Copyright © 2015 the American Physiological Society.

  16. Stress regulates the lymphocyte homing receptor CD62L (L-selectin Regulação do receptor de alojamento linfocitário CD62L (L-selectina pelo estresse

    Directory of Open Access Journals (Sweden)

    Gisele Gus Manfro

    2003-03-01

    Full Text Available Based on a previous study showing that panic disorder patients had increased expression of naïve phenotype lymphocytes (CD45RA+ and CD62L+, increased plasma cortisol, as well as decreased interleukin-2 (IL-2 producion, we hypothesized that changes in the percentage of expression of these lymphocyte surface molecules could be related to the substances released by the hypothalamic-pituitary-adrenal (HPA axis and possibly associated to panic disorder (cortisol, IL-2, serotonin and epinephrine. In order to study the altered expression, blood mononuclear cells of normal volunteers were stimulated with mitogen, in the presence of dexamethasone, IL-2, serotonin and epinephrin. CD62L is decreased by IL-2 in vitro. Serotonin and epinephrine did not promote changes in the expression of these surface molecules. The results of the ex vivo study are in agreement with a previous clinical study with panic patients. It could be suggested that stress is responsible for certain immunologic dysfunctions and new studies should be conducted.Baseado em estudo prévio que demonstrou que os pacientes com transtorno do pânico apresentavam aumento na porcentagem de expressão de linfócitos com fenótipo virgem (CD45RA+ e CD62L+, aumento no cortisol plasmático, assim como diminuição na produção de interleucinas, foi sugerido que as alterações na porcentagem de expressão dessas moléculas de superfície dos linfócitos poderia estar relacionada com a liberação de substâncias pelo eixo hipotálamo-hipófise-adrenal (HHA e possivelmente associada ao transtorno do pânico (cortisol, IL-2, serotonina e epinefrina. Com o objetivo de estudar essas alterações, células mononucleares do sangue periférico de voluntários normais foram estimuladas com mitógeno, na presença de dexametasona, IL-2, serotonina e epinefrina. A expressão de CD62L "in vitro" é diminuida com IL-2. Serotonina e epinefrina não promovem alterações na expressão dessas moléculas de

  17. Biophysical aspects of T lymphocyte activation at the immune synapse

    Directory of Open Access Journals (Sweden)

    Claire eHivroz

    2016-02-01

    Full Text Available T lymphocyte activation is a pivotal step of the adaptive immune response. It requires the recognition by T-cell receptors (TCR of peptides presented in the context of major histocompatibility complex molecules (pMHC present at the surface of antigen presenting cells (APCs. T lymphocyte activation also involves engagement of co-stimulatory receptors and adhesion molecules recognizing ligands on the APC. Integration of these different signals requires the formation of a specialized dynamic structure: the immune synapse. While the biochemical and molecular aspects of this cell-cell communication have been extensively studied, their mechanical features have only recently been addressed. Yet, the immune synapse is also the place of exchange of mechanical signals. Receptors engaged on the T lymphocyte surface are submitted to many tensile and traction forces. These forces are generated by various phenomena: membrane undulation/protrusion/retraction, cell mobility or spreading and dynamic remodeling of the actomyosin cytoskeleton inside the T lymphocyte. Moreover, the TCR can both induce force development, following triggering, and sense and convert forces into biochemical signals, as a bona fide mechanotransducer. Other co-stimulatory molecules such as LFA-1, engaged during immune synapse formation, also display these features. Moreover, T lymphocytes themselves are mechanosensitive, since substrate stiffness can modulate their response. In this review, we will summarize recent studies from a biophysical perspective to explain how mechanical cues can affect T lymphocyte activation. We will particularly discuss how forces are generated during immune synapse formation; how these forces affect various aspects of T lymphocyte biology; and what are the key features of T lymphocyte response to stiffness.

  18. Study on the expression of the IL-7 receptor on T lymphocytes in HIV infected Long-Term Non-Progressors%中国HIV感染长期不进展者T细胞表面IL-7受体表达研究

    Institute of Scientific and Technical Information of China (English)

    李革飞; 张子宁; 张旻; 刘静; 施万英; 金鑫; 姜拥军; 王亚男; 尚红

    2011-01-01

    Objective: To investigate the expression of Interleukin-7 (IL-7) receptor on T lymphocytes of Long-Term Non-Progressors (LTNP)and its association with disease progression. Methods: LTNP, HIV, AIDS patients and healthy controls (20 patients for each group)were enrolled and flow cytometry was used to detect the IL-7 receptor expression on T lymphocytes of whole blood samples taken from the patients and the controls. The association between IL-7 receptor expression on T lymphocytes and IL-7 level in plasma was analyzed. Results: The expression of IL-7 receptor on CD4 and CD8 + T lymphocytes and central memory T cells (Tcm), effector memory T cells (Tem) of LTNP group was significantly higher than that of AIDS and HIV groups ( P < 0.05) ;The expression of IL-7 receptor on Na(i)ve and Terminally differentiated effector memory T cells(Tem/td) of LTNP group was not statistically different from that of AIDS, HIV groups and healthy controls. The percentage of IL-7 receptor expression on CD4, CD8+ T cells of H1V/AIDS patients negatively correlated with IL-7 level in plasma and HIV virus load and positively correlated with CD4 absolute value ( P < 0.05) .Conclusion:The expression of the IL-7 receptor on T lymphocytes from peripheral blood is significantly correlated with HIV disease progression and higher level of IL-7 receptor expression on T cells of LTNPs may play a role in slowing down the disease progression.%目的:了解中国HIV感染长期不进展者(Long-Term Non-Progressor,LTNP)T细胞表面IL-7(Interleukin-7,IL-7)受体的表达,分析其与疾病进展的关系.方法:收集LTNP组、HIV组、AIDS组及健康对照组(每组各20例)的抗凝全血,用流式细胞仪检测IL-7受体的表达,并分析IL-7受体表达与血浆中IL-7水平的相关性.结果:LTNP组CD4+T、CD8+T、中枢记忆T细胞 (Central memory T cells,Tcm)、效应记忆性T细胞 (Effector memory T cells,Tem)表面IL-7受体表达水平明显高于无症

  19. Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2015-11-10

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  20. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  1. Slamf receptors : Modulators of Phagocyte Immune Responses

    NARCIS (Netherlands)

    Van Driel, Boaz Job

    2015-01-01

    Signaling Lymphocyte Activation Molecule family (Slamf) receptors can operate in three distinct modes. Slamf receptors can dictate the extent of immune responses, thereby maneuvering immunity to the optimal zone between immunopathology or autoimmunity and weak, ineffective immune responses. A second

  2. Carotenoids located in human lymphocyte subpopulations and Natural Killer cells by Raman microspectroscopy

    NARCIS (Netherlands)

    Puppels, G.J.; Puppels, G.J.; Garritsen, H.S.P.; Garritsen, H.S.P.; Kummer, J.A.; Greve, Jan

    1993-01-01

    The presence and subcellular location of carotenoids in human lymphocyte sub-populations (CD4+, CD8+, T-cell receptor-γδ+, and CD19+ ) and natural killer cells (CD16+ ) were studied by means of Raman microspectroscopy. In CD4+ lymphocytes a high concentration (10-3M) of carotenoids was found in the

  3. B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study

    DEFF Research Database (Denmark)

    El Fassi, Daniel; Nielsen, Claus H; Bonnema, Steen J

    2007-01-01

    Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might be of bene...

  4. Effect of thapsigargin on cytoplasmic Ca2+ and proliferation of human lymphocytes in relation to AIDS

    DEFF Research Database (Denmark)

    Scharff, O; Foder, B; Thastrup, Ole

    1988-01-01

    response at 100 nM. The effect of thapsigargin on [Ca2+]i exceeded that of phytohaemagglutinin (PHA) which raised [Ca2+]i to maximum 300 nM. In combination with phorbol 12-myristate 13-acetate (PMA), thapsigargin stimulated the proliferation of normal lymphocytes to the same extent as did PHA, whereas...... of the lymphocytes, which was much higher than that caused by the PHA treatment, even in AIDS lymphocytes. Moreover, the thapsigargin/PMA treatment stimulated the expression of the IL-2 receptors on both normal and AIDS lymphocytes, similar to the effect of PHA. It is concluded that thapsigargin exerts its effects...

  5. Recent advances in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    N Vyas

    2012-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL was largely considered to be a disease of slow progression, standard treatment with Chlorambucil and having almost similar prognosis. With the introduction of molecular methods for understanding the disease pathophysiology in CLL there has been a remarkable change in the approach towards the disease. The variation in B-cell receptor response and immunoglobulin heavy chain variable region (IGHV mutation, genetic aberration and defect in apoptosis and proliferation has had an impact on therapy initiation and prognosis. Early diagnosis of molecular variant is therefore necessary in CLL.

  6. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-10-04

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  7. Inhibition of human lymphocyte proliferation and cleavage of interleukin-2 by Pseudomonas aeruginosa proteases

    DEFF Research Database (Denmark)

    Theander, T G; Kharazmi, A; Pedersen, B K

    1988-01-01

    This study was undertaken to determine the effect of Pseudomonas aeruginosa alkaline protease (AP) and elastase (ELA) on human lymphocyte function. AP at 50 micrograms/ml and ELA at 12 micrograms/ml caused a 50% inhibition of phytohemagglutinin-induced proliferation. There was no difference......, the inhibition was partly reversed. ELA at 10 micrograms/ml cleaved IL-2, as judged by size chromatography of a reaction mixture containing 125I-labeled IL-2 and the proteases. The ELA-digested IL-2 exhibited a reduced binding capacity to IL-2 receptors on the lymphocytes. Furthermore, treatment...... of phytohemagglutinin-stimulated lymphocytes with AP and ELA resulted in inhibition of binding of intact IL-2 to IL-2 receptors on the stimulated lymphocytes. These results indicated that P. aeruginosa-derived enzymes are able to interfere with human lymphocyte function in vitro and that this effect might be due...

  8. [Changes in blood lymphocytes and their subpopulation in patients with myeloblastic leukemia treated with cytostatic agents].

    Science.gov (United States)

    Urasiński, I; Proniewska, M; Schumacher, K

    1979-01-01

    Quantitative determinations of lymphocytas were done in the active period of the disease, immediately after treatment by the COAP schedule and during remission. In 6 patients the determinations were done several times during 20 weeks of maintenance treatment. It was found that independently of the stage of the disease the absolute lymphocyte count and the counts of B and T populations were low, while that of lymphocyte O population was raised. It was observed that the reduced count concerned all 4 subclasses of lymphocytes B, that is those with surface receptors for IgA, IgM, IgG and IgE immunoglobulins. In remission the values of lymphocytes and their T and B subpopulations increased, failing, however, to reach the normal values. This rise was more pronounced in the case of lymphocytes T. Lymphocyte depression in these patients is explained by the authors as due mainly to intensive cytostatic treatment.

  9. Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology

    Science.gov (United States)

    Shi, Yufang; Devadas, Satish; Greeneltch, Kristy M.; Yin, Deling; Allan Mufson, R.; Zhou, Jian-nian

    2003-01-01

    Psychological and physical stressors best exemplify the intercommunication of the immune and the nervous systems. It has been shown that stress significantly impacts leukocyte cellularity and immune responses and alters susceptibility to various diseases. While acute stress has been shown to enhance immune responses, chronic stress often leads to immunosuppression. Among many criteria examined upon exposure to chronic stress, the reduction in lymphocyte mitogenic response and lymphocyte cellularity are commonly assessed. We have reported that chronic restraint stress could induce lymphocyte reduction, an effect dependent on endogenous opioids. Interestingly, the effect of endogenous opioids was found to be exerted through increasing the expression of a cell death receptor, Fas, and an increased sensitivity of lymphocytes to apoptosis. Stress-induced lymphocyte reduction was not affected by adrenalectomy. In this review, based on available literature and our recent data, we will discuss the role of the hypothalamic-pituitary-adrenal axis and endogenous opioids and examine the mechanisms by which chronic stress modulates lymphocyte apoptosis.

  10. Lymphocyte Trafficking to Mucosal Tissues

    DEFF Research Database (Denmark)

    Mikhak, Zamaneh; Agace, William Winston; Luster, Andrew D.

    2015-01-01

    Lymphocytes are the key cells of the adaptive immune system that provide antigen-specific responses tailored to the context of antigen exposure. Through cytokine release and antibody production, lymphocytes orchestrate and amplify the recruitment and function of other immune cells and contribute...... to host defense against invading pathogens and the pathogenesis of many inflammatory diseases. Lymphocyte function is critically dependent on their ability to traffic into the correct anatomic locations at the appropriate times. This process is highly regulated and requires that lymphocytes interact...

  11. Lymphocytic Interstitial Pneumonia.

    Science.gov (United States)

    Panchabhai, Tanmay S; Farver, Carol; Highland, Kristin B

    2016-09-01

    Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. LIP is frequently associated with connective tissue diseases or infections. Idiopathic LIP is rare; every attempt must be made to diagnose underlying conditions when LIP is diagnosed. Computed tomography of the chest in patients with LIP may reveal ground-glass opacities, centrilobular and subpleural nodules, and randomly distributed thin-walled cysts. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process.

  12. Syk Inhibition with Fostamatinib Leads to Transitional B Lymphocyte Depletion

    Science.gov (United States)

    Barr, Paul M.; Wei, Chungwen; Roger, James; Schaefer-Cutillo, Julia; Kelly, Jennifer L.; Rosenberg, Alexander F.; Jung, John; Sanz, Iñaki; Friedberg, Jonathan W.

    2012-01-01

    Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents. PMID:22284392

  13. Decreased deformability of lymphocytes in chronic lymphocytic leukemia

    Science.gov (United States)

    Zheng, Yi; Wen, Jun; Nguyen, John; Cachia, Mark A.; Wang, Chen; Sun, Yu

    2015-01-01

    This paper reports the first study of stiffness/deformability changes of lymphocytes in chronic lymphocytic leukemia (CLL) patients, demonstrating that at the single cell level, leukemic metastasis progresses are accompanied by biophysical property alterations. A microfluidic device was utilized to electrically measure cell volume and transit time of single lymphocytes from healthy and CLL patients. The results from testing thousands of cells reveal that lymphocytes from CLL patients have higher stiffness (i.e., lower deformability), as compared to lymphocytes in healthy samples, which was also confirmed by AFM indentation tests. This observation is in sharp contrast to the known knowledge on other types of metastatic cells (e.g., breast and lung cancer cells) whose stiffness becomes lower as metastasis progresses.

  14. 细粒棘球蚴感染中阻断TGF-β1受体对淋巴细胞的影响%Effect of inhibition of TGF-β1 receptors on lymphocytes during infection of Echi-nococcus granulosus

    Institute of Scientific and Technical Information of China (English)

    印双红; 杨文才; 张俊波; 陈小林; 徐芳洁; 侯隽; 吴向未; 陈雪玲; 姚元勇; 邢明明

    2015-01-01

    Objective:To investigate the effects of TGF-β1 on T lymphocytes of BALB/c mice infected with Echinococcus granulosus( E.granulosus ) in vitro.Methods: The inhibitor group:the spleen cells of BALB/c mouse were co-cultured with E.granulosus and SB525334.The control group:the spleen cells of BALB/c mouse were co-cultured with E.granulosus and PBS.The blank group:the spleen cells of BALB/c mouse were co-cultured with RPMI-1640 medium and SB525334.The lymphocytes were collected at 48 h post-infection.The T lymphocyte subsets, the number of CD4+CD25+T cells, the number of NK cells, and the expression of NKG2D receptor were detected by flow cytometry.The NK cell activity was determined with the lactate dehydrogenase leakage assay(LDH).Results:The inhibition the TGF-β1 receptors resulted in the increase of in the number of CD4+T cells,the decrease in the number of CD8+T cells,the increase of in the ratio CD4+/CD8+T cells,the decrease of in the number of CD4+CD25+T cells,the increase in the expression of the NKG2D receptors,the increase in the lysis rate of Yac-1 cells by NK cells,and a positive cor-relation between the expression of activity receptor NKG2D and killing activity of NK, which were mediated by E.granulosus.Conclusion: The inhibition of TGF-β1 receptors can enhance the immune response of T lymphocytes against E.granulosus infection in vitro.%目的:观察TGF-β1对细粒棘球蚴体外与BALB/c小鼠T淋巴细胞培养的影响。方法:阻断剂组:BALB/c小鼠脾细胞+细粒棘球蚴+SB525334共培养;对照组:BALB/c小鼠脾细胞+细粒棘球蚴+PBS共培养;空白对照:BALB/c小鼠脾细胞+RPMI-1640培养基+SB525334共培养。方法:48 h收集淋巴细胞,流式细胞仪检测T淋巴细胞亚群、CD4+CD25+T细胞的数量、NK细胞的数量及其活性受体NKG2D的表达;乳酸脱氢酶法检测NK细胞的杀伤活性。结果:体外阻断TGF-β1受体后,引起细粒棘球蚴介导的CD4

  15. Life and death of lymphocytes: a role in immunesenescence

    Directory of Open Access Journals (Sweden)

    Agrawal Sudhanshu

    2005-08-01

    Full Text Available Abstract Human aging is associated with progressive decline in immune functions, increased frequency of infections. Among immune functions, a decline in T cell functions during aging predominates. In this review, we will discuss the molecular signaling in two major pathways of apoptosis, namely death receptor pathway and mitochondrial pathway, and their alterations in both T and B lymphocytes in human aging with a special emphasis on naïve and different memory subsets of CD8+ T cells. We will also discuss a possible role of lymphocyte apoptosis in immune senescence.

  16. Obinutuzumab in chronic lymphocytic leukemia.

    Science.gov (United States)

    Dupuis, Jehan

    2015-09-01

    Obinutuzumab is the second next-generation monoclonal anti-CD20 antibody (after ofatumumab) to enter clinical practice in chronic lymphocytic leukemia. Its superiority in association with chlorambucil as compared with chlorambucil alone has led to its approval as a first-line treatment for chronic lymphocytic leukemia, for patients who are not candidates for a more intensive treatment.

  17. Chicken Ig-like receptor B2, a member of a multigene family, is mainly expressed on B lymphocytes, recruits both Src homology 2 domain containing protein tyrosine phosphatase (SHP)-1 and SHP-2, and inhibits proliferation

    NARCIS (Netherlands)

    Viertlboeck, B.C.; Crooijmans, R.P.M.A.; Groenen, M.A.M.; Gobel, T.W.

    2004-01-01

    Ig-like inhibitory receptors have been the focus of intensive research particularly in mouse and human. We report the cloning and characterization of three novel inhibitory chicken Ig-like receptors (CHIR) that display a two Ig-domain extracellular structure, a transmembrane region lacking charged

  18. Clonal expansion of renal cell carcinoma-infiltrating T lymphocytes

    DEFF Research Database (Denmark)

    Sittig, Simone; Køllgaard, Tania; Grønbæk, Kirsten

    2013-01-01

    T lymphocytes can mediate the destruction of cancer cells by virtue of their ability to recognize tumor-derived antigenic peptides that are presented on the cell surface in complex with HLA molecules and expand. Thus, the presence of clonally expanded T cells within neoplastic lesions...... is an indication of ongoing HLA-restricted T cell-mediated immune responses. Multiple tumors, including renal cell carcinomas (RCCs), are often infiltrated by significant amounts of T cells, the so-called tumor-infiltrating lymphocytes (TILs). In the present study, we analyzed RCC lesions (n = 13) for the presence...... of expanded T-cell clonotypes using T-cell receptor clonotype mapping. Surprisingly, we found that RCCs comprise relatively low numbers of distinct expanded T-cell clonotypes as compared with melanoma lesions. The numbers of different T-cell clonotypes detected among RCC-infiltrating lymphocytes were...

  19. Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes

    Science.gov (United States)

    Morgan, Richard A.; Dudley, Mark E.; Wunderlich, John R.; Hughes, Marybeth S.; Yang, James C.; Sherry, Richard M.; Royal, Richard E.; Topalian, Suzanne L.; Kammula, Udai S.; Restifo, Nicholas P.; Zheng, Zhili; Nahvi, Azam; de Vries, Christiaan R.; Rogers-Freezer, Linda J.; Mavroukakis, Sharon A.; Rosenberg, Steven A.

    2006-10-01

    Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

  20. Human lymphocyte sub-populations and K cells.

    Science.gov (United States)

    Sandilands, G; Gray, K; Cooney, A; Froebel, K; Anderson, J R

    1976-01-01

    Peripheral blood lymphocytes from 19 normal subjects were examined for surface Ig (SIg) and capacity to form rosettes with normal and neuraminidase-treated sheep erythrocytes and with chicken erythrocytes sensitised with IgG antibody. Information on the relationship between the presence of SIg and capacity to form rosettes was obtained by combined tests and depletion experiments. By these means, a population of lymphocytes with Fc receptors, but lacking SIg (mean 14.6%) was defined and shown to correlate closely with cytotoxic activity for antibody-sensitised target cells. Indirect evidence was also obtained that these lymphocytes, which are regarded as the major population of antibody-dependent cytotoxic cells, are capable of forming rosettes with normal and neuraminidase-treated sheep erythrocytes. The nature of these cells is briefly discussed.

  1. Immune Escape for Renal Cell Carcinoma: CD70 Mediates Apoptosis in Lymphocytes

    Directory of Open Access Journals (Sweden)

    Julia Diegmann

    2006-11-01

    Full Text Available Tumors can escape immune recognition and destruction through the induction of apoptosis in lymphocytes. Although renal cell carcinoma (RCC is able to prevent immune recognition, only a few genes (such as FasL that are relevant for RCC immune escape have been identified so far. We have previously shown that some apoptosis-inducing genes are overexpressed in RCC. We hypothesized that these genes could be part of the immune-escape strategy of these tumors. Here we report that CD70, a cytokine overexpressed in RCC, promotes lymphocyte apoptosis through interaction with its receptor CD27 and with the intracellular receptor-binding protein SIVA. Apoptosis increased after cocultivating lymphocytes with the RCC cell lines A498 and CAKI2. The addition of recombinant soluble CD70 to both native lymphocytes and a T-cell cell line resulted in increased lymphocyte apoptosis as well. Furthermore, induced apoptosis could be partially blocked with anti-CD27 and anti-CD70 antibodies. Our results strongly indicate a role for CD70 and CD27 receptor in lymphocyte apoptosis within the tumor environment. Apoptosis mediated by exposure to the CD70 secreted by tumor cells may contribute to the failure of RCC patients to develop an effective lymphocyte-mediated antitumor response.

  2. Laboratorial diagnosis of lymphocytic meningitis

    Directory of Open Access Journals (Sweden)

    Sérgio Monteiro de Almeida

    Full Text Available Meningitis is the main infectious central nervous system (CNS syndrome. Viruses or bacteria can cause acute meningitis of infectious etiology. The term "Aseptic Meningitis" denotes a clinical syndrome with a predominance of lymphocytes in the cerebrospinal fluid (CSF, with no common bacterial agents identified in the CSF. Viral meningitis is considered the main cause of lymphocyte meningitis. There are other etiologies of an infectious nature. CSF examination is essential to establish the diagnosis and to identify the etiological agent of lymphocytic meningitis. We examined CSF characteristics and the differential diagnosis of the main types of meningitis.

  3. Laboratorial diagnosis of lymphocytic meningitis

    Directory of Open Access Journals (Sweden)

    Sérgio Monteiro de Almeida

    2007-10-01

    Full Text Available Meningitis is the main infectious central nervous system (CNS syndrome. Viruses or bacteria can cause acute meningitis of infectious etiology. The term "Aseptic Meningitis" denotes a clinical syndrome with a predominance of lymphocytes in the cerebrospinal fluid (CSF, with no common bacterial agents identified in the CSF. Viral meningitis is considered the main cause of lymphocyte meningitis. There are other etiologies of an infectious nature. CSF examination is essential to establish the diagnosis and to identify the etiological agent of lymphocytic meningitis. We examined CSF characteristics and the differential diagnosis of the main types of meningitis.

  4. T lymphocyte insensitivity to corticosteroids in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Kaur Manminder

    2012-03-01

    Full Text Available Abstract Background There are increased numbers of activated lymphocytes in the lungs of chronic obstructive pulmonary disease (COPD patients. The clinical benefits of corticosteroids in COPD patients are limited. Our hypothesis is that lymphocytes play a role in this corticosteroid insensitivity. Objectives To investigate the effects of the corticosteroid dexamethasone on lung lymphocyte cytokine production from patients with COPD compared to controls. Methods Cultured airway lymphocytes obtained by bronchoscopy from healthy non-smokers (HNS, smokers (S and COPD patients were stimulated with phytohaemagglutinin (PHA & phorbol myristate acetate (PMA, +/- dexamethasone. Supernatants were assayed for interleukin (IL-2 and interferon (IFNγ. Immunofluoresence was used to analyse changes in CD8 glucocorticoid receptor (GRα and GRβ expression. Results The inhibition of PHA/PMA stimulated IFNγ production by dexamethasone was reduced in COPD patients compared to HNS (p p Conclusions IFNγ production from COPD airway lymphocytes is corticosteroid insensitive. This phenomenon may be important in the poor clinical response often observed with corticosteroids.

  5. Summary of workshop findings for porcine T-lymphocyte-specific monoclonal antibodies

    DEFF Research Database (Denmark)

    Saalmuller, A.; Kuebart, G.; Hollemweguer, E.;

    2001-01-01

    blood mononuclear cells, nylon-wool enriched T-lymphocytes, thymocytes, splenocytes, and lymphocytes derived from Peyer's patches. These second round analyses revealed 15 different data sets. Together with 22 pre-selected data sets from the first round analyses with the whole panel of monoclonal......Ab) directed against subsets of CD4(-)CD8(-) T-lymphocytes. These mAb seem to recognise antigens on porcine T-lymphocytes with T-cell receptor (TcR) gamma/delta chains. Three clusters (C8, C9, CIO, C13) seem to be artificial. They contain either mAb staining CD4(-)CD8(-) T-lymphocytes and low CD8+ cells (C8, C...

  6. Specific high-affinity binding sites for a synthetic gliadin heptapeptide of human peripheral blood lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Payan, D.G.; Horvath, K.; Graf, L.

    1987-03-23

    The synthetic peptide containing residues 43-49 of ..cap alpha..-gliadin, the major protein component of gluten, has previously been shown to inhibit the production of lymphokine activities by mononuclear leukocytes. The authors demonstrate using radiolabeled ..cap alpha..-gliadin(43-49) that human peripheral blood lymphocytes express approximately 20,000-25,000 surface receptors for this peptide, with a dissociation constant (K/sub D/) of 20 nM. In addition, binding is inhibited by naloxone and an enkephalin analog, thus confirming the functional correlate which demonstrates inhibition by these agents of ..cap alpha..-gliadin(43-49) functional effects. Furthermore, B-lymphocytes bind specifically a greater amount of (/sup 125/I)..cap alpha..-gliadin(43-49) than T-lymphocytes. The lymphocyte ..cap alpha..-gliadin(43-49) receptor may play an important role in mediating the immunological response to ..cap alpha..-gliadin. 16 references, 4 figures.

  7. Reduced binding of 3H-spiroperidol to lymphocyte in Wilson's disease.

    Science.gov (United States)

    Członkowski, A; Członkowska, A

    1984-05-01

    Biochemical studies of CSF from patients with Wilson's disease (WD) have increased that alterations in the state of dopaminergic and serotoninergic systems are similar to those manifested in Parkinson's disease. Recently, the density of dopaminergic receptors on lymphocytes has been found to be diminished in Parkinson's disease. In the present study, 3H-spiroperidol binding was evaluated in lymphocytes acquired from 12 patients suffering from WD, as compared to blood donors. A significant decrease in the number of binding sites (Bmax) was observed in the lymphocytes of the WD patients. There was no clear relationship between clinical status, age and duration of the disease and the alterations in receptor density. The mechanism underlying the decrease in lymphocyte 3H-spiroperidol binding sites in WD demands clarification.

  8. Initiation of lymphocyte DNA synthesis.

    Science.gov (United States)

    Coffman, F D; Fresa, K L; Cohen, S

    1991-01-01

    The initiation of DNA replication in T lymphocytes appears to be regulated by two distinct activities: one associated with proliferation which mediates initiation, and another associated with quiescence which blocks initiation. Activated lymphocytes and proliferating lymphoid cell lines produce an activity, termed ADR, which can initiate DNA replication in isolated, quiescent nuclei. ADR is heat-labile, has protease activity or interacts closely with a protease, and is distinct from the DNA polymerases. ADR activity is absent in quiescent lymphocytes and appears in mitogen-stimulated lymphocytes after IL-2 binding. The generation of active ADR appears to be mediated by phosphorylation of a precursor which is present in resting cells. Nuclei from mitogen-unresponsive lymphocytes fail to initiate DNA replication in response to ADR, of potential importance in the age-related decline of immunity. Quiescent lymphocytes lack ADR and synthesize an ADR-inhibitory activity. The ADR inhibitor is a heat-stable protein which suppresses the initiation of DNA synthesis, but is ineffective at suppressing elongation once DNA strand replication has begun. Nuclei from several neoplastic cell lines fail to respond to the ADR inhibitor, which may play a role in the continuous proliferation of these cells. At least one of these neoplastic cell lines produces both ADR and an inhibitory factor. These findings suggest that the regulation of proliferation is dependent on the balance between activating and inhibitory pathways.

  9. Reactivity of eleven anti-human leucocyte monoclonal antibodies with lymphocytes from several domestic animals

    DEFF Research Database (Denmark)

    Aasted, Bent; Blixenkrone-Møller, Merete; Larsen, Else Bang

    1988-01-01

    Nine commercially available monoclonal antibodies and two monoclonal antibodies from The American Type Culture Collection, raised against various human leucocyte surface antigens, were tested on lymphocytes from cow, sheep, goat, swine, horse, cat, dog, mink, and rabbit as well as man. Four...... antibodies bound to lymphocytes from some of the animals. These were the antibodies against CD8 and CD4 antigen, the antibody to C3b-receptor, and the antibody to the HLA-DR antigen. The CD8 antigen-reactive antibody reacted with lymphocytes from mink, cat, dog, and sheep, while the CD4 antigen...

  10. Analysis of IL-2-like factor in lymphocyte culture supernatant of olive flounder, Paralichthys oliveaceus

    Institute of Scientific and Technical Information of China (English)

    WU Riqin; ZHANG Peijun; LI Jun; XU Yongli

    2005-01-01

    To study immune mechanism of fish lymphocyte we performed a proliferation assay and ELISA using monoclonal antibody against human IL-2. The result showed that an interleukin-2 (IL-2)-like factor was detected in the supernatant of plant haemoglutinin (PHA)-stimulated lymphocyte culture from peripheral blood,spleen and head kidney of olive flounder, Paralichthys olivaceus. The quantities of IL-2-1ike factor in the supematant from different lymphoid tissues were quite different. The IL-2 like factor in the supernatant from cultured head kidney lymphocytes was much higher than those of peripheral blood lymphocytes and spleen lymphocytes (P<0.01). The IL-2 activity was found in either mouse thymocyte proliferation assay or flounder head kidney lymphocyte proliferation assay and shown to have obvious enhancing effect on proliferation of the above two types of cell. The recombinant human IL-2 (rhIL-2) was able to stimulate flounder thymocyte proliferation and used to detect the IL-2 receptor (IL-2R) on the surface of flounder lymphocyte. The cross-reaction between the lymphocytes of flounder peripheral blood and CD25(IL-2R) was detected with flow cytometry and shown that the percentage of CD25-positive cell in peripheral blood was 7.74± 0.67%.

  11. Lymphocytes prime activation is required for nicotine-induced calcium waves.

    Science.gov (United States)

    Landais, Emilie; Liautaud-Roger, Francoise; Antonicelli, Frank

    2010-06-01

    Lymphocytes are reported to express nicotinic acetylcholine receptors (nAChR). However, no data are available on the expression of these nAChR on activated lymphocyte relatively to resting lymphocytes. In this study, we examined nAChR subunits expression in PHA-stimulated versus un-stimulated lymphocytes, and four leukemic cell lines. Cell stimulation with nicotine triggered calcium responses only in some experiments conducted with PHA-stimulated lymphocytes. Likewise, only the Jurkat and HL-60 cell lines displayed calcium waves upon nicotine stimulation, whereas the Raji and CCRF-CEM did not. All responding cells displayed an active form of the nicotinic a-7 nAChR. Indeed, use of 2 different sets of primers for the corresponding mRNA showed that expression of the full-length a-7 subunit mRNA was only present in PHA-stimulated lymphocytes for which calcium waves had been evidenced. Microscopy analysis of lymphocytes structure showed a direct relationship between their size, their a-7 nAChR expression, and calcium release upon nicotine stimulation. Then, this relationship suggested that lymphocytes need a prime activation to express the a-7 nAChR, and therefore to release calcium in response to nicotine.

  12. T cell receptor (TCR-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ signaling mediate superior tumor regression in an animal model of adoptive cell therapy

    Directory of Open Access Journals (Sweden)

    Quatromoni Jon G

    2012-06-01

    Full Text Available Abstract Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFβ, which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFβ by transduction with a TGFβ dominant negative receptor II (DN, were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-γ in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer.

  13. No changes in lymphocyte muscarinic receptors and platelet monoamine oxidase-B examined as surrogate central nervous system biomarkers in a Faroese children cohort prenatally exposed to methylmercury and polychlorinated biphenyls

    DEFF Research Database (Denmark)

    Coccini, Teresa; Manzo, Luigi; Debes, Frodi

    2009-01-01

    Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet M....../or PCB exposure, whereas these markers are significantly altered in sustained exposure scenarios, as shown by clinical studies in drug addicts or patients treated with psychopharmacological agents....

  14. IAN family critically regulates survival and development of T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Takeshi Nitta

    2006-04-01

    Full Text Available The IAN (immune-associated nucleotide-binding protein family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins.

  15. Signaling lymphocyte activating molecule (SLAM) expression in subacute sclerosing panencephalitis.

    Science.gov (United States)

    Piskin, A Kevser; Akpinar, Pinar; Muftuoglu, Sevda; Anlar, Banu

    2007-08-01

    Signaling lymphocyte activating molecule (SLAM) is a receptor for measles virus which also has immunomodulatory activity. We analyzed SLAM expression in mononuclear cells (MNC) of patients with SSPE (n=7) and control subjects (n=7) from the same population. Native 10% PAGE analysis in cell and brain tissue extracts followed by Western blotting using monoclonal anti-human SLAM showed four types of bands. Differences in the type and amount of SLAM expression were observed between SSPE and control cases. Lymphocytes of SSPE patients showed two types of SLAM bands in comparison to only one in control lymphocytes. Stimulation of cells with lipopolysaccharide (80 u/ml) and concanavalin A (1 microg/ml) in vitro led to the appearance of a second isoform in both groups. Brain homogenates of SSPE patients (n=2) displayed all four types of SLAM isoforms at significantly higher levels than those of control brains (n=2). Our results show native PAGE enables the detection of all SLAM isotypes. The expression of SLAM is increased in lymphocytes, monocytes, and brain tissues of SSPE patients.

  16. Chicken NK cell receptors.

    Science.gov (United States)

    Straub, Christian; Neulen, Marie-Luise; Sperling, Beatrice; Windau, Katharina; Zechmann, Maria; Jansen, Christine A; Viertlboeck, Birgit C; Göbel, Thomas W

    2013-11-01

    Natural killer cells are innate immune cells that destroy virally infected or transformed cells. They recognize these altered cells by a plethora of diverse receptors and thereby differ from other lymphocytes that use clonally distributed antigen receptors. To date, several receptor families that play a role in either activating or inhibiting NK cells have been identified in mammals. In the chicken, NK cells have been functionally and morphologically defined, however, a conclusive analysis of receptors involved in NK cell mediated functions has not been available. This is partly due to the low frequencies of NK cells in blood or spleen that has hampered their intensive characterization. Here we will review recent progress regarding the diverse NK cell receptor families, with special emphasis on novel families identified in the chicken genome with potential as chicken NK cell receptors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Desensitization oft lymphocyte function by CXCR3 ligands in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yu-Qing Liu; Ronnie T. Poon; Jeremy Hughes; Qin-Yu Li; Wan-Ching Yu; Sheung-Tat Fan

    2005-01-01

    AIM: Despite the presence of lymphocyte infiltration, human hepatocellular carcinoma (HCC) is typically a rapidly progressive disease. The mechanism of regulation of lymphocyte migration is poorly understood. In this study,we investigated various factors regulating T cell migration in HCC patients. We examined serum CXC chemokine levels in HCC patients and demonstrated the production of CXC chemokines by HCC cell lines. We determined the effect of both HCC patient serum and tumor cell conditioned supernatant upon lymphocyte expression of chemokine receptor CXCR3 as well as lymphocyte migration. Lastly,we examined the chemotactic responses of lymphocytes derived from HCC patients.METHODS: The serum chemokines IP-10 (CXCL10) and Mig (CXCL9) levels were measured by cytometric bead array (CBA) and the tumor tissue IP-10 concentration was measured by ELISA. The surface expression of CXCR3 on lymphocytes was determined by flow cytometry. The migratory function of lymphocytes to the corresponding chemokines was assessed using an in vitro chemotactic assay. Phosphorylation of extracellular signal-regulated kinase (ERK) was determined by Western blot analysis.RESULTS: Increased levels of IP-10 and Mig were detected in HCC patient serum and culture supernatants of HCC cell lines. The IP-10 concentration in the tumor was significantly higher than that in the non-involved adjacent liver tissues.HCC cell lines secreted functional chemokines that induced a CXCR3-specific chemotactic response of lymphocytes.Furthermore, tumor-cell-derived chemokines induced initial rapid phosphorylation of lymphocyte ERK followed by later inhibition of ERK phosphorylation. The culture of normal lymphocytes with HCC cell line supernatants or medium containing serum from HCC patients resulted in a significant reduction in the proportion of lymphocytes exhibiting surface expression of CXCR3. The reduction in T cell expression of CXCR3 resulted in reduced migration toward the ligand IP-10, and both

  18. Interleukin-7 Receptor Signaling Network: An Integrated Systems Perspective

    Institute of Scientific and Technical Information of China (English)

    Megan J. Palmer; Vinay S. Mahajan; Lily C. Trajman; Darrell J. Irvine; Douglas A.Lauffenburger; Jianzhu Chen

    2008-01-01

    Interleukin-7 (IL-7) is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor (IL-7R), activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstaik, shared interaction domains, feedback loops, integrated gene regulation, muitimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology.

  19. Effects of cobalt and chromium ions on lymphocyte migration.

    Science.gov (United States)

    Baskey, Stephen J; Lehoux, Eric A; Catelas, Isabelle

    2017-04-01

    A T cell-mediated hypersensitivity reaction has been reported in some patients with CoCrMo-based implants. However, the role of cobalt and chromium ions in this reaction remains unclear. The objective of the present study was to analyze the effects of Co(2+) and Cr(3+) in culture medium, as well as the effects of culture supernatants of macrophages exposed to Co(2+) or Cr(3+) , on the migration of lymphocytes. The release of cytokines/chemokines by macrophages exposed to Co(2+) and Cr(3+) was also analyzed. The migration of murine lymphocytes was quantified using the Boyden chamber assay and flow cytometry, while cytokine/chemokine release by J774A.1 macrophages was measured by ELISA. Results showed an ion concentration-dependent increase in TNF-α and MIP-1α release and a decrease in MCP-1 and RANTES release. Migration analysis showed that the presence of Co(2+) (8 ppm) and Cr(3+) (100 ppm) in culture medium increased the migration of T lymphocytes, while it had little or no effect on the migration of B lymphocytes, suggesting that Co(2+) and Cr(3+) can stimulate the migration of T but not B lymphocytes. Levels of T lymphocyte migration in culture medium containing Co(2+) or Cr(3+) were not statistically different from those in culture supernatants of macrophages exposed to Co(2+) or Cr(3+) , suggesting that the effects of the ions and chemokines were not additive, possibly because of ion interference with the chemokines and/or their cognate receptors. Overall, results suggest that Co(2+) and Cr(3+) are capable of stimulating the migration of T (but not B) lymphocytes in the absence of cytokines/chemokines, and could thereby contribute to the accumulation of more T than B lymphocytes in periprosthetic tissues of some patients with CoCrMo-based implants. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:916-924, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  20. Consistency of T-cell receptor gene mutation between lymphocytes in rats after irradiation in vivo and in vitro%整体和离体照射致大鼠淋巴细胞T细胞受体基因突变的一致性研究

    Institute of Scientific and Technical Information of China (English)

    石燕; 刘伟; 侯殿俊; 马娅; 乔建维; 卢峰; 商希梅

    2010-01-01

    Objective To observe the consistency of T-cell receptor (TCR) genes mutation in lymphocytes in rats after irradiation in vivo and in vitro.Methods A total of 48 female rats were randomly divided into 6 equal groups.Peripheral blood samples from them were collected to separate the lymphocytes and then irradiated to X-ray irradiation with the dose rate of 200 cGy/min at the doses of 0,0.5,0.75,1.0,2.0,and 3.0 Gy,respectively.Then all the lymphocyte samples were cultured for 7 days.Flow cytometry with direct immunofluorescence was used to detect the TCR gene mutation.The levels of TCR gene mutant frequency (TCRMF) of different groups were calculated.Results The TCRMF levels of different groups after irradiation in vivo and in vitro all displayed a dose-dependent manner and there were no significant differences in the TCRMF between different dose irradiation groups(t = -1.1-0.3 ,P >0.05).Conclusions A consistency of TCRMF after irradiation in vivo and in vitro is proven.The results of TCRMF of peripheral blood lymphocytes irradiated in vitro by flow cytometry can precisely reflect the TCR genes mutation after whole-body irradiation.%目的 探讨整体和离体照射所致的大鼠淋巴细胞T细胞受体(TCR)基因突变的一致性.方法 48只雌性大鼠随机分为6组,每组8只,分别取外周静脉血标本,经0、0.5、0.75、1.0、2.0和3.0 Gy照射.用相同方法 照射各组大鼠,照后取外周血标本.所有淋巴细胞体外培养7 d后,用单克隆抗体直接免疫荧光标记流式细胞术检测TCR突变频率(TCRMF).结果 整体和离体照射组TCR基因突变频率均呈剂量依赖性增高,两组间TCRMF比较,差异无统计学意义(t=-1.1~0.3,P>0.05).结论 整体和离体照射所致的大鼠淋巴细胞TCR基因突变频率一致,即外周血淋巴细胞经X射线照射体外培养后,流式细胞术检测,可客观准确的反映全身照射的情况.

  1. Apicobasal Polarity Controls Lymphocyte Adhesion to Hepatic Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Natalia Reglero-Real

    2014-09-01

    Full Text Available Loss of apicobasal polarity is a hallmark of epithelial pathologies. Leukocyte infiltration and crosstalk with dysfunctional epithelial barriers are crucial for the inflammatory response. Here, we show that apicobasal architecture regulates the adhesion between hepatic epithelial cells and lymphocytes. Polarized hepatocytes and epithelium from bile ducts segregate the intercellular adhesion molecule 1 (ICAM-1 adhesion receptor onto their apical, microvilli-rich membranes, which are less accessible by circulating immune cells. Upon cell depolarization, hepatic ICAM-1 becomes exposed and increases lymphocyte binding. Polarized hepatic cells prevent ICAM-1 exposure to lymphocytes by redirecting basolateral ICAM-1 to apical domains. Loss of ICAM-1 polarity occurs in human inflammatory liver diseases and can be induced by the inflammatory cytokine tumor necrosis factor alpha (TNF-α. We propose that adhesion receptor polarization is a parenchymal immune checkpoint that allows functional epithelium to hamper leukocyte binding. This contributes to the haptotactic guidance of leukocytes toward neighboring damaged or chronically inflamed epithelial cells that expose their adhesion machinery.

  2. Studies on rabbit lymphocytes in vitro

    Science.gov (United States)

    Sell, S.; Gell, P. G. H.

    1969-01-01

    Anti-allotypic sera that have no known allotypic determinants other than those also present in the genotype of the lymphocyte donor are as able to induce lymphocyte `blast' transformation in vitro as are anti-allotypic sera that do have allotypic determinants that are not present in the lymphocyte donor. Therefore, anti-allotypic sera do not appear to function in the stimulation of blast transformation by providing access for any of the known allotypic determinants into lymphocytes. PMID:5769980

  3. In vitro generation of human cytotoxic lymphocytes by virus. Viral glycoproteins induce nonspecific cell-mediated cytotoxicity without release of interferon

    OpenAIRE

    1981-01-01

    Purified hemagglutinin and fusion glycoproteins of measles virus either in soluble form or inserted in artifical membranes bind to human peripheral blood lymphocytes and induce cell-mediated cytotoxicity (CMC) in a dose-response fashion. Both autologous and heterologous noninfected target cells are lysed in vitro. The expression of CMC is not inhibited by anti-measles virus antibody added to lymphocytes previously exposed to viral glycoproteins. THe killer lymphocytes are Fc receptor positive...

  4. Rapid exacerbation of lymphocytic infundibuloneurohypophysitis

    Science.gov (United States)

    Shibue, Kimitaka; Fujii, Toshihito; Goto, Hisanori; Yamashita, Yui; Sugimura, Yoshihisa; Tanji, Masahiro; Yasoda, Akihiro; Inagaki, Nobuya

    2017-01-01

    Abstract Rationale: Lymphocytic hypophysitis is a relatively rare autoimmune disease defined by lymphocytic infiltration to the pituitary. Its rarity and wide spectrum of clinical manifestations make clarification of the pathology difficult. Here, we describe a case we examined from the primary diagnosis to final discharge, showing the serial progression of lymphocytic infundibuloneurohypophysitis (LINH) to panhypopituitarism with extrapituitary inflammatory invasion in a short period, and responding favorably to high-dose glucocorticoid treatment. Patient concerns: Polyuria, General fatigue and Nausea/Vomiting. Diagnoses: Central diabetes insipidus (CDI), Lymphocytic infundibuloneurohypophysitis (LINH). Interventions: Desmopressin acetate, High-dose glucocorticoid (GC) treatment. Outcomes: He was prescribed desmopressin acetate and subsequently discharged. A month later, he revisited our hospital with general fatigue and nausea/vomiting. A screening test disclosed hypopituitarism with adrenal insufficiency. MRI revealed expanded contrast enhancement to the peripheral extrapituitary lesion. He received high-dose GC treatment and the affected lesion exhibited marked improvement on MRI, along with the recovery of the anterior pituitary function. Lessons: This case demonstrates the potential for classical LINH to develop into panhypopituitarsim. We consider this is the first documentation of approaching the cause of atypical LINH with progressive clinical course from the pathological viewpoint. PMID:28248860

  5. Treatment of chronic lymphocytic leukemia.

    Science.gov (United States)

    Ferrajoli, Alessandra; O'Brien, Susan M

    2004-04-01

    Treatment options for patients with chronic lymphocytic leukemia have changed over the past two decades. This article reviews the experience accumulated with the use of alkylating agents alone and in combination; purine analogues alone and in combination and monoclonal antibodies such as rituximab, and alemtuzumab alone and in combination. The results obtained with different treatment strategies are summarized, compared, and reviewed.

  6. Abnormal lipid rafts related ganglioside expression and signaling in T lymphocytes in immune thrombocytopenia patients.

    Science.gov (United States)

    Zhang, Xian; Zhang, Donglei; Liu, Wenjie; Li, Huiyuan; Fu, Rongfeng; Liu, Xiaofan; Xue, Feng; Yang, Renchi

    2016-01-01

    Aberrant T lymphocytes signaling is considered to play a crucial role in the abnormal immune state of primary immune thrombocytopenia (ITP). Lipid raft has been verified to engage in the T cell receptor (TCR)-mediated T lymphocytes signal transduction. Whether lipid raft-associated T cells signal transduction has impact on the pathogenesis of ITP is still unconfirmed. In this study, we aimed to reveal the abnormality in structure and function of lipid rafts (LRs) in CD4(+) and CD8(+) T lymphocytes of patients with ITP. Our results showed that there was an increased lipid raft aggregation in ITP patients, while this kind of increase would not be influenced by platelet counts or therapeutic regimes. Stimulation by anti-CD3/CD28 monoclonal antibodies promoted enhanced lipid raft clustering in T lymphocytes of ITP patients compared with negative controls. Methyl-β-cyclodextrin (MβCD) could block the abnormal lipid raft aggregation and disrupt the TCR-mediated T cells proliferation and cytokines secretion, including both proinflammatory cytokines and anti-inflammatory cytokines. The spontaneous activation of T lymphocytes from ITP patients might be due to the elevated co-localization of protein tyrosine phosphatase (PTP) CD45 and lipid rafts in patients' CD4(+) and CD8(+) T lymphocytes. These findings suggest that the autoactivation of T lymphocytes from ITP patients may lead to the abnormality in lipid raft structure and raft-anchored proteins, and the changes conversely promote the TCR-mediated T cells activation of ITP patients.

  7. TRPML cation channels regulate the specialized lysosomal compartment of vertebrate B-lymphocytes.

    Science.gov (United States)

    Song, Yumei; Dayalu, Rashmi; Matthews, Sharon A; Scharenberg, Andrew M

    2006-12-01

    B-lymphocytes possess a specialized lysosomal compartment, the regulated transformation of which has been implicated in B-cell antigen presentation. Members of the mucolipin (TRPML) family of cation channels have been implicated in regulated vesicular transport in several tissues, but a role for TRPML function in lymphocyte vesicular transport physiology has not been previously described. To address the role of TRPML proteins in lymphocyte vesicular transport, we analyzed the lysosomal compartment in cultured B-lymphocytes engineered to lack TRPML1 or after expression of N- or C-terminal GFP fusion proteins of TRPML1 or TRPML2. Consistent with previous analyses of lymphocytes derived from human patients with mutations in TRPML1, we were not able to detect abnormalities in the lysosomes of TRPML1-deficient DT40 B-lymphocytes. However, while N-terminal GFP fusions of TRPML2 localized to normal appearing lysosomes, C-terminal GFP fusions of either TRPML1 or TRPML2 acted to antagonize endogenous TRPML function, localizing to large vesicular structures, the histological properties of which were indistinguishable from the enlarged lysosomes observed in affected tissues of TRPML1-deficient humans. Endocytosed B-cell receptors were delivered to these enlarged lysosomes, demonstrating that a TRPML-dependent process is required for normal regulation of the specialized lysosome compartment of vertebrate B-lymphocytes.

  8. Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2017-03-27

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia

  9. The fourth dimension in immunological space: how the struggle for nutrients selects high-affinity lymphocytes.

    Science.gov (United States)

    Wensveen, Felix M; van Gisbergen, Klaas P J M; Eldering, Eric

    2012-09-01

    Lymphocyte activation via the antigen receptor is associated with radical shifts in metabolism and changes in requirements for nutrients and cytokines. Concomitantly, drastic changes occur in the expression of pro-and anti-apoptotic proteins that alter the sensitivity of lymphocytes to limiting concentrations of key survival factors. Antigen affinity is a primary determinant for the capacity of activated lymphocytes to access these vital resources. The shift in metabolic needs and the variable access to key survival factors is used by the immune system to eliminate activated low-affinity cells and to generate an optimal high-affinity response. In this review, we focus on the control of apoptosis regulators in activated lymphocytes by nutrients, cytokines, and costimulation. We propose that the struggle among individual clones that leads to the formation of high-affinity effector cell populations is in effect an 'invisible' fourth signal required for effective immune responses.

  10. A high-content analysis toolbox permits dissection of diverse signaling pathways for T lymphocyte polarization.

    Science.gov (United States)

    Freeley, Michael; Bakos, Gabor; Davies, Anthony; Kelleher, Dermot; Long, Aideen; Dunican, Dara J

    2010-06-01

    RNA interfering (RNAi) screening strategies offer the potential to elucidate the signaling pathways that regulate integrin and adhesion receptor-mediated changes in T lymphocyte morphology. Of crucial importance, however, is the definition of key sets of parameters that will provide accurate, quantitative, and nonredundant information to flag relevant hits in such assays. In this study, the authors have used an image-based high-content analysis (HCA) technology platform and a panel of 24 pharmacological inhibitors, at a range of concentrations, to define key sets of parameters that enables sensitive and quantitative effects on integrin (LFA-1)-mediated lymphocyte morphology to be evaluated. In particular, multiparametric analysis of lymphocyte morphology that was based on intracellular staining of both the F-actin and alpha-tubulin cytoskeleton resulted in improved ability to discriminate morphological behavior compared to F-actin staining alone. Morphological and fluorescence intensity/distribution profiling of pharmacologically treated lymphocytes stimulated with integrin (LFA-1) and adhesion receptors (CD44) also revealed notable differences in their sensitivity to inhibitors. The assay described here may be used in HCA strategies such as RNAi screening assays to elucidate the signaling pathways and molecules that regulate integrin/adhesion receptor-mediated T lymphocyte polarization.

  11. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    Science.gov (United States)

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  12. 淋巴细胞清除剂与IL-2受体拮抗剂诱导疗法在活体肾移植中的安全性比较%Comparison of the effectiveness and safety between lymphocytes scavenger and IL-2 receptor blocking agent induction in living kidney transplantation

    Institute of Scientific and Technical Information of China (English)

    秦宁波; 蔡明; 许亮; 李州利; 金海龙; 王强; 詹胜利; 崔瀚文

    2013-01-01

    Objective To compare the safety of two antibody inductors, namely lymphocytes scavenger and IL-2 receptor blocking agent, in living kidney transplantation. Methods The data of 191 patients, who received living kidney transplant in our hospital from Feb. 2007 to Jul. 2012, were retrospectively analyzed, and grouped according to the inductors they received as: a) lymphocytes scavenger group (n=56), with rabbit antithymocyte immunoglobulin (rATG, 4 cases) and porcine antihuman T-lymphocyte immunoglobulin (pATG, 52 cases) served as the inductor; b) IL-2 receptor blocking agent group (n=54), with basiliximab (40 cases) and daclizumab (14 cases) served as the inductor; and c) control group (n=8l). The incidence of rejection and infection, and the survival rate of patient/allograft within one year were then compared among the three groups. Results Within one year after the transplantation, the incidence of acute rejection in lymphocytes scavenger group, IL-2 receptor blocking agent group and control group was 12.5%, 11.1% and 28.4%, respectively. There was a significant difference between the two inductor groups and control group (P=0.003), but no significant difference was found between the two inductor groups (P>0.05). The incidence of delayed graft function (DGF) in the three groups was 8.9%, 7.4% and 13.6%, respectively, with no statistical significance (P>0.05). Also there was no significant difference among the three groups in the incidence of infection and the survival rate of patient/allograft within one year after transplantation (P>0.05). Conclusion Both inductors may significantly reduce the incidence of acute rejection within one year without increasing the incidence of infection and other adverse events, nor affect the postoperative patient/graft survival, so they are both safe and effective.%目的 比较两种抗体诱导剂(淋巴细胞清除剂和IL-2受体拮抗剂)在活体肾移植中的安全性.方法 回顾性分析2007年2月-2012年4

  13. Platelet-Activating Factor Antagonists Decrease Follicular Dendritic-Cell Stimulation of Human B Lymphocytes

    Directory of Open Access Journals (Sweden)

    Halickman Isaac

    2005-06-01

    Full Text Available Abstract Both B-lymphoblastoid cell lines and tonsillar B lymphocytes express receptors for platelet-activating factor (PAF. In lymph node germinal centres, B lymphocytes interact with follicular dendritic cells (FDCs, which present antigen-containing immune complexes to B lymphocytes. FDCs have phenotypic features that are similar to those of stromal cells and monocytes and may therefore be a source of lipid mediators. In this study, we evaluated the effects of the PAF antagonist WEB 2170 on the activation of tonsillar B lymphocytes by FDCs. FDCs were isolated from tonsils by Bovine Serum Albumin (BSA gradient centrifugation. After being cultured for 6 to 10 days, they were incubated with freshly isolated B cells in the presence or absence of the specific PAF receptor antagonist WEB 2170. B-lymphocyte proliferation was assessed by [3H]-thymidine incorporation, and immunoglobulin (Ig G and IgM secretion was assessed by enzyme-linked immunosorbent assay (ELISA. WEB 2170 (10-6 to 10-8 M inhibited [3H]-thymidine incorporation by up to 35% ± 3%. Moreover, the secretion of IgG and IgM was inhibited by up to 50% by WEB 2170 concentrations ranging from 10-6 to 10-8 M. There was no evidence of toxicity by trypan blue staining, and the addition of WEB 2170 to B cells in the absence of FDCs did not inhibit the spontaneous production of IgG or IgM. The effect of the PAF antagonist is primarily on B lymphocytes, as reverse transcription polymerase chain reaction detected little PAF receptor messenger ribonucleic acid (mRNA from FDCs. These data suggest that endogenous production of PAF may be important in the interaction of B lymphocytes with FDCs.

  14. Growing B Lymphocytes in a Three-Dimensional Culture System

    Science.gov (United States)

    Wu, J. H. David; Bottaro, Andrea

    2010-01-01

    A three-dimensional (3D) culture system for growing long-lived B lymphocytes has been invented. The capabilities afforded by the system can be expected to expand the range of options for immunological research and related activities, including testing of immunogenicity of vaccine candidates in vitro, generation of human monoclonal antibodies, and immunotherapy. Mature lymphocytes, which are the effectors of adaptive immune responses in vertebrates, are extremely susceptible to apoptotic death, and depend on continuous reception of survival-inducing stimulation (in the forms of cytokines, cell-to-cell contacts, and antigen receptor signaling) from the microenvironment. For this reason, efforts to develop systems for long-term culture of functional, non-transformed and non-activated mature lymphocytes have been unsuccessful until now. The bone-marrow microenvironment supports the growth and differentiation of many hematopoietic lineages, in addition to B-lymphocytes. Primary bone-marrow cell cultures designed to promote the development of specific cell types in vitro are highly desirable experimental systems, amenable to manipulation under controlled conditions. However, the dynamic and complex network of stromal cells and insoluble matrix proteins is disrupted in prior plate- and flask-based culture systems, wherein the microenvironments have a predominantly two-dimensional (2D) character. In 2D bone-marrow cultures, normal B-lymphoid cells become progressively skewed toward precursor B-cell populations that do not retain a normal immunophenotype, and such mature B-lymphocytes as those harvested from the spleen or lymph nodes do not survive beyond several days ex vivo in the absence of mitogenic stimulation. The present 3D culture system is a bioreactor that contains highly porous artificial scaffolding that supports the long-term culture of bone marrow, spleen, and lymph-node samples. In this system, unlike in 2D culture systems, B-cell subpopulations developing

  15. Curcuma longa attenuates carbon tetrachloride-induced oxidative stress in T-lymphocyte subpopulations.

    Science.gov (United States)

    Abu-Rizq, H A; Mansour, Mohamed H; Afzal, Mohammad

    2015-01-01

    A comparison of crude curcuminoid extract and purified curcumin was made to evaluate the immunoprotective effect of Curcuma longa (turmeric) Zingiberaceae. Carbon tetrachloride (CCl4) induced selective cytolytic effects among immature (PNA(+)) thymocytes and peripheral helper (CD4(+)) T lymphocytes in the spleen were paralleled by a significant reduction in CD25, CD71, and Con A receptor expression. Treatment with curcumanoid crude extract, at two different doses, showed a significant restoration of lymphocyte viability and CD25, CD71, and Con A receptor expression in both immature (PNA+) thymocytes and splenic helper (CD4(+)) T lymphocytes. Turmeric crude extract, at both low and high dose, was found to be more efficient as compared to purified curcumin, suggesting synergistic effect of curcumin with other components of the crude extract.

  16. FcgammaRIIb expression on human germinal center B lymphocytes.

    Science.gov (United States)

    Macardle, Peter J; Mardell, Carolyn; Bailey, Sheree; Wheatland, Loretta; Ho, Alice; Jessup, Claire; Roberton, Donal M; Zola, Heddy

    2002-12-01

    IgG antibody can specifically suppress the antibody response to antigen. This has been explained by the hypothesis that signaling through the B cell antigen receptor is negatively modulated by the co-ligation of immunoglobulin with the receptor for IgG, FcgammaRIIb. We hypothesized that inhibitory signaling through FcgammaRIIb would be counter-productive in germinal center cells undergoing selection by affinity maturation, since these cells are thought to receive a survival/proliferative signal by interacting with antigen displayed on follicular dendritic cells. We have identified and characterized a population of B lymphocytes with low/negative FcgammaRIIb expression that are present in human tonsil. Phenotypically these cells correspond to germinal center B cells and comprise both centroblast and centrocyte populations. In examining expression at the molecular level we determined that these B cells do not express detectable mRNA for FcgammaRIIb. We examined several culture conditions to induce expression of FcgammaRIIb on germinal center cells but could not determine conditions that altered expression. We then examined the functional consequence of cross-linking membrane immunoglobulin and the receptor for IgG on human B lymphocytes. Our results cast some doubt on the value of anti-IgG as a model for antigen-antibody complexes in studying human B cell regulation.

  17. Crosstalk between medulloblastoma cells and endothelium triggers a strong chemotactic signal recruiting T lymphocytes to the tumor microenvironment.

    Directory of Open Access Journals (Sweden)

    Vita S Salsman

    Full Text Available Cancer cells can live and grow if they succeed in creating a favorable niche that often includes elements from the immune system. While T lymphocytes play an important role in the host response to tumor growth, the mechanism of their trafficking to the tumor remains poorly understood. We show here that T lymphocytes consistently infiltrate the primary brain cancer, medulloblastoma. We demonstrate, both in vitro and in vivo, that these T lymphocytes are attracted to tumor deposits only after the tumor cells have interacted with tumor vascular endothelium. Macrophage Migration Inhibitory Factor (MIF" is the key chemokine molecule secreted by tumor cells which induces the tumor vascular endothelial cells to secrete the potent T lymphocyte attractant "Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES." This in turn creates a chemotactic gradient for RANTES-receptor bearing T lymphocytes. Manipulation of this pathway could have important therapeutic implications.

  18. Not all IGHV3-21 chronic lymphocytic leukemias are equal

    DEFF Research Database (Denmark)

    Baliakas, Panagiotis; Agathangelidis, Andreas; Hadzidimitriou, Anastasia

    2015-01-01

    An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue...

  19. Not all IGHV3-21 chronic lymphocytic leukemias are equal: Prognostic considerations

    NARCIS (Netherlands)

    P. Baliakas (P.); A. Agathangelidis (Andreas); A. Hadzidimitriou (A.); L.-A. Sutton (L.); E. Minga (Evangelia); A. Tsanousa (Athina); L. Scarfó (L.); Z. Davis (Zadie); X.-J. Yan (Xiao-Jie); T. Shanafelt (Tait); K. Plevova (K.); Y. Sandberg (Yorick); F.J. Vojdeman (Fie Juhl); M. Boudjogra (Myriam); T. Tzenou (T.); M. Chatzouli (Maria); C.C. Chu (Charles C.); S. Veronese (Silvio); A. Gardiner (Anne); A. Mansouri (Ahmed); O. Smedby; L.B. Pedersen (Lone Bredo); D. Moreno (Denis); K. van Lom (Kirsten); V. Giudicelli (Veronique); H.S. Francova (Hana Skuhrova); F. Nguyen-Khac (Florence); P. Panagiotidis (P.); G. Juliusson (Gunnar); L. Angelis (Lefteris); C. Anagnostopoulos (Constantinos); M.-P. Lefranc (Marie-Paule); M. Facco (Monica); L. Trentin (Livio); M. Catherwood (M.); M. Montillo (Marco); C.H. Geisler (Christian); A.W. Langerak (Ton); D. Pospisilova (Dagmar); N. Chiorazzi (Nicholas); D.G. Oscier (David Graham); D.F. Jelinek (Diane F.); N. Darzentas (N.); C. Belessi (C.); F. Davi; P. Ghia (Paolo); R. Rosenquist (R.); K. Stamatopoulos (K.)

    2015-01-01

    textabstractAn unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised thi

  20. N-(4-F-18-Fluorobenzoyl)Interleukin-2 for PET of Human-Activated T Lymphocytes

    NARCIS (Netherlands)

    Di Gialleonardo, Valentina; Signore, Alberto; Glaudemans, Andor W. J. M.; Dierckx, Rudi A. J. O.; De Vries, Erik F. J.

    2012-01-01

    Interleukin-2 (IL2) binds with high affinity to the IL2 receptors overexpressed on activated T lymphocytes in various pathologic conditions. Radiolabeling of IL2 with a positron-emitting isotope could provide a tool for noninvasive PET of activated T cells in immune-mediated diseases. We report the

  1. The immunoglobulin genes: structure and specificity in chronic lymphocytic leukemia.

    Science.gov (United States)

    Tobin, Gerard

    2007-06-01

    The rearrangement of the immunoglobulin genes (IG) provides a large diversity of B-cell receptors conformations and allows the immune system to respond differently to foreign antigens. In chronic lymphocytic leukemia (CLL), there are a restricted number of stereotyped B-cell receptors rearranged by the tumor B-cells between CLL patients. These subsets with stereotyped receptors appear to have clinical implications, for example cases that rearrange the IGHV3-21 gene display poor clinical prognosis. The number of subsets with stereotyped receptors has been reported at a frequency of over 20% of CLL cases; however, the specificities of these receptors are still not clearly defined. Reactivity to epitopes from bacterial antigen, cytoskeleton components such as vimentin, and antigens on viable and apoptotic T-cell have been proposed. The role of antigen in CLL development is currently being more clearly defined with identification of stereotyped receptors, and their antigen specificity and the continued role antigen stimulation plays in CLL disease will be an important question in the future.

  2. Lymphocyte homing antagonists in the treatment of inflammatory bowel diseases.

    Science.gov (United States)

    Saruta, Masayuki; Papadakis, Konstantinos A

    2014-09-01

    Lymphocyte homing antagonists represent promising therapeutic agents for the treatment of idiopathic inflammatory bowel disease (IBD). Several critical molecules involved in the recruitment of inflammatory cells in the intestine, including integrins and chemokine receptors, have been successfully targeted for the treatment of IBD. These agents have shown great promise for the induction and maintenance of remission for both Crohn disease and ulcerative colitis. This article discusses currently approved prototypic agents for the treatment of IBD (natalizumab, anti-α4 integrin; vedolizumab, anti-α4β7 integrin), and several other agents in the same class currently under development. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. On the horizon: flexible immune recognition outside lymphocytes.

    Science.gov (United States)

    Kaminski, Wolfgang E; Beham, Alexander W; Kzhyshkowska, Julia; Gratchev, Alexei; Puellmann, Kerstin

    2013-03-01

    Since decades there is consensus among immunologists that in jawless and jawed vertebrates flexible immune recognition is strictly confined to the lymphoid lineage. In jawed vertebrates the adaptive immune system is represented by two lineages of lymphocytes, B cells and T cells that express recombinatorial antigen receptors of enormous diversity known as immunoglobulins and the T cell receptor (TCR). The recent identification of recombined immune receptors that are structurally based on the TCR in subpopulations of neutrophils and eosinophils (referred to here as TCR-like immunoreceptors, "TCRL") provides unexpected evidence for the existence of flexible host defense mechanisms beyond the realm of lymphocytes. Consistent with this, subpopulations of monocytes and macrophages from humans and mice now have also been shown to constitutively express recombined TCR-like immunoreceptors. Available in vitro evidence suggests that the TCRL in macrophages may exert functions as facilitators of phagocytosis and self-recruitment. More importantly, our recent findings that the macrophage-TCRL is implicated in granuloma formation in tuberculosis and the neutrophil-TCRL is associated with autoimmune hemolytic anemia establish for the first time a link between myeloid recombinatorial immune receptors and clinical disease. The discovery of recombined TCR-like immune receptors in granulocytes and macrophages extends the principle of combinatorial immune recognition to phagocytic cells. Conceptually, this unifies the two hitherto disparate cardinal features of innate and adaptive immunity, phagocytic capacity and recombinatorial immune recognition on a common cellular platform. Moreover, it strongly suggests that flexible host defense in vertebrates may operate on a broader cellular basis than currently thought. Copyright © 2012. Published by Elsevier GmbH.

  4. Targeting CD20 in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Nahas MR

    2015-03-01

    Full Text Available Myrna R Nahas, Jon E ArnasonBeth Israel Deaconess Medical Center, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL, the most common leukemia in adults, is standardly managed with chemotherapy in combination with the anti-CD20 antibody rituximab. In this review, we discuss the history, use, and evolution of rituximab in the treatment of CLL and explore the next generation CD20 antibodies ofatumumab and obinutuzumab with a focus on recent clinical trials. Increased understanding of the importance of B cell receptor (BCR signaling in CLL has resulted in the development of several drugs with significant clinical activity that are ideally suited for combination with CD20 therapy as is being currently explored. Moving forward, these developments have the potential to result in treatment regimens that do not include traditional chemotherapeutic agents, which is of particular importance in CLL given the late onset of diagnosis and potential frailty of the patients.Keywords: CLL, monoclonal antibody, rituximab, ofatumumab, obinutuzumab

  5. Opinion: Interactions of innate and adaptive lymphocytes

    Science.gov (United States)

    Gasteiger, Georg; Rudensky, Alexander Y.

    2015-01-01

    Innate lymphocytes, including natural killer (NK) cells and the recently discovered innate lymphoid cells (ILCs) have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. Less well understood is the contribution of the adaptive immune system to the orchestration of innate lymphocyte responses. We review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which adaptive T cells function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential role of regulatory and helper T cells in these processes and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes. PMID:25132095

  6. Effect of Xuebijing injection on the number of T lymphocytes and Toll-like receptors as adjuvant therapy of severe abdominal infections%血必净注射液辅助治疗重症腹腔感染时对T淋巴细胞数量和Toll样受体的影响

    Institute of Scientific and Technical Information of China (English)

    林泽辉; 陈国宁; 杜永明

    2016-01-01

    ObjectiveTo examine the effect of Xuebijing Injection on the number of T lymphocytes and Toll-like receptors as adjuvant therapy of severe abdominal infections.MethodsA total of 78 patients with severe abdominal infection who were hospitalized in the intensive care unit were divided into control group and treatment group. The patients in control group received conventional therapy alone, while the patients in treatment group received Xuebijing Injection (50 mL twice daily for 2 weeks) in addition to conventional therapy. Blood sample was drawn before and after 2-week treatment to determine T lymphocytes. The peripheral blood mononuclear cells were separated to determine the expression of Toll-like receptors (TLR) 2 and TLR4. The Acute Physiology and Chronic Health Evaluation (APACHE) II score and gastrointestinal function score were recorded before and after treatment.ResultsThe levels of CD3+, CD4+ and CD4+/CD8+ of peripheral blood in the Xuebijing-treated patients were signiifcantly higher than those in control group (P<0.01), but the levels of CD8+ was signiifcantly lower than that in control group (P<0.01). The levels of TLR2 and TLR4 mRNA of the peripheral blood mononuclear cells in the treatment group were signiifcantly lower than those in control group (P<0.01). The APACHE II score and gastrointestinal function score in treatment group were signiifcantly lower than those in control group (P<0.01).ConclusionXuebijing Injection as adjuvant therapy of severe abdominal infection can improve the number of T lymphocytes, and reduce the expression of Toll-like receptors.%目的:观察血必净注射液辅助治疗重症腹腔感染时对T淋巴细胞数量和Toll样受体(TLR)的作用。方法选取2013年1月—2014年12月重症腹腔感染患者78例,随机分为对照组和观察组(每组39例),两组患者均接受常规基础治疗,观察组患者在常规治疗基础上静脉滴注血必净注射液,50 mL/次,2次/d,连用2

  7. Virally encoded 7TM receptors

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Waldhoer, M; Lüttichau, H R

    2001-01-01

    A number of herpes- and poxviruses encode 7TM G-protein coupled receptors most of which clearly are derived from their host chemokine system as well as induce high expression of certain 7TM receptors in the infected cells. The receptors appear to be exploited by the virus for either immune evasion...... in various parts of the viral life cyclus. Most of the receptors encoded by human pathogenic virus are still orphan receptors, i.e. the endogenous ligand is unknown. In the few cases where it has been possible to characterize these receptors pharmacologically, they have been found to bind a broad spectrum...... expression of this single gene in certain lymphocyte cell lineages leads to the development of lesions which are remarkably similar to Kaposi's sarcoma, a human herpesvirus 8 associated disease. Thus, this and other virally encoded 7TM receptors appear to be attractive future drug targets....

  8. Impaired removal of Vβ8(+) lymphocytes aggravates colitis in mice deficient for B cell lymphoma-2-interacting mediator of cell death (Bim).

    Science.gov (United States)

    Leucht, K; Caj, M; Fried, M; Rogler, G; Hausmann, M

    2013-09-01

    We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim(-/-) ) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim(-/-) mice compared to wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)-induced colitis, Bim(-/-) animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild-type mice. The number of autoreactive T cell receptor (TCR) Vβ8(+) lymphocytes was significantly higher in Bim(-/-) mice compared to wild-type controls. Impaired removal of autoreactive lymphocytes in Bim(-/-) mice upon chronic DSS-induced colitis may therefore contribute to aggravated mucosal inflammation.

  9. Lymphocyte subpopulations in Sheehan's syndrome.

    Science.gov (United States)

    Atmaca, Hulusi; Araslı, Mehmet; Yazıcı, Zihni Acar; Armutçu, Ferah; Tekin, Ishak Özel

    2013-06-01

    The role of autoimmunity in the development of Sheehan's syndrome is obscure. There are a limited number of studies investigating the immunological alterations accompanying Sheehan's Syndrome. Our objective was to evaluate lymphocyte subsets in these patients. We conducted a cross-sectional clinical study. Cytofluorometry was used for the immunophenotyping of peripheral blood leukocytes from patients with Sheehan's syndrome followed up in the endocrine clinic during 2005-2009. Fifteen consecutive patients (mean age 61.6 ± 11.3, range 34-75 years) and 25 healthy controls (mean age 56.7 ± 10.6, range 34-80 years) were included. There was no statistically significant difference between the groups in terms of mean age. The percentages of CD19(+), CD16(+)/56(+), CD8(+)28(-), γδTCR(+), CD8(+); the total lymphocyte counts; and the ratio of CD8(+)28(-)/CD8(+)28(+) were similar (p > 0.05) between patients and controls. Whereas the leucocyte counts (p = 0.003), the percentage of CD3 (+) DR (+) (p Sheehan's syndrome compared to healthy controls. There was a positive correlation between the duration of illness and the percentage of CD3(+)DR(+) (r = 0.53, p = 0.03) expression. Some peripheral lymphocyte cell subsets show marked variation in patients with Sheehan's syndrome in comparison to matched healthy subjects, which may have implications for altered immune regulation in these patients. High CD3 (+) DR (+) expression that correlates with the duration of illness in Sheehan's patients is suggestive of an ongoing inflammation accompanying the slow progression of pituitary dysfunction in Sheehan's syndrome. It is not clear if these cellular alterations contribute to the cause or consequence of pituitary deficiency in Sheehan's syndrome.

  10. The Importance of the Nurse Cells and Regulatory Cells in the Control of T Lymphocyte Responses

    Directory of Open Access Journals (Sweden)

    María Guadalupe Reyes García

    2013-01-01

    Full Text Available T lymphocytes from the immune system are bone marrow-derived cells whose development and activities are carefully supervised by two sets of accessory cells. In the thymus, the immature young T lymphocytes are engulfed by epithelial “nurse cells” and retained in vacuoles, where most of them (95% are negatively selected and removed when they have an incomplete development or express high affinity autoreactive receptors. The mature T lymphocytes that survive to this selection process leave the thymus and are controlled in the periphery by another subpopulation of accessory cells called “regulatory cells,” which reduce any excessive immune response and the risk of collateral injuries to healthy tissues. By different times and procedures, nurse cells and regulatory cells control both the development and the functions of T lymphocyte subpopulations. Disorders in the T lymphocytes development and migration have been observed in some parasitic diseases, which disrupt the thymic microenvironment of nurse cells. In other cases, parasites stimulate rather than depress the functions of regulatory T cells decreasing T-mediated host damages. This paper is a short review regarding some features of these accessory cells and their main interactions with T immature and mature lymphocytes. The modulatory role that neurotransmitters and hormones play in these interactions is also revised.

  11. Lymphocytes and the Dap12 adaptor are key regulators of osteoclast activation associated with gonadal failure.

    Directory of Open Access Journals (Sweden)

    Adrienne Anginot

    Full Text Available Bone resorption by osteoclasts is necessary to maintain bone homeostasis. Osteoclast differentiation from hematopoietic progenitors and their activation depend on M-CSF and RANKL, but also requires co-stimulatory signals acting through receptors associated with DAP12 and FcRgamma adaptors. Dap12 mutant mice (KDelta75 are osteopetrotic due to inactive osteoclasts but, surprisingly, these mice are more sensitive than WT mice to bone loss following an ovariectomy. Because estrogen withdrawal is known to disturb bone mass, at least in part, through lymphocyte interaction, we looked at the role of mature lymphocytes on osteoclastogenesis and bone mass in the absence of functional DAP12. Lymphocytes were found to stimulate an early osteoclast differentiation response from Dap12-deficient progenitors in vitro. In vivo, Rag1-/- mice lacking mature lymphocytes did not exhibit any bone phenotype, but lost their bone mass after ovariectomy like KDelta75 mice. KDelta75;Rag1-/- double mutant female mice exhibited a more severe osteopetrosis than Dap12-deficient animals but lost their bone mass after ovariectomy, like single mutants. These results suggest that both DAP12 and mature lymphocytes act synergistically to maintain bone mass under physiological conditions, while playing similar but not synergistic co-stimulatory roles in protecting bone loss after gonadal failure. Thus, our data support a role for lymphocytes during osteoclast differentiation and suggest that they may function as accessory cells when regular osteoclast function is compromised.

  12. An Efficient Low Cost Method for Gene Transfer to T Lymphocytes

    Science.gov (United States)

    Chicaybam, Leonardo; Sodre, Andressa Laino; Curzio, Bianca Azevedo; Bonamino, Martin Hernan

    2013-01-01

    Gene transfer to T lymphocytes has historically relied on retro and lentivirus, but recently transposon-based gene transfer is rising as a simpler and straight forward approach to achieve stable transgene expression. Transfer of expression cassettes to T lymphocytes remains challenging, being based mainly on commercial kits. Aims We herein report a convenient and affordable method based on in house made buffers, generic cuvettes and utilization of the widely available Lonza nucleofector II device to promote efficient gene transfer to T lymphocytes. Results This approach renders high transgene expression levels in primary human T lymphocytes (mean 45%, 41–59%), the hard to transfect murine T cells (mean 38%, 36–42% for C57/BL6 strain) and human Jurkat T cell line. Cell viability levels after electroporation allowed further manipulations such as in vitro expansion and Chimeric Antigen Receptor (CAR) mediated gain of function for target cell lysis. Conclusions We describe here an efficient general protocol for electroporation based modification of T lymphocytes. By opening access to this protocol, we expect that efficient gene transfer to T lymphocytes, for transient or stable expression, may be achieved by an increased number of laboratories at lower and affordable costs. PMID:23555950

  13. An efficient low cost method for gene transfer to T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Leonardo Chicaybam

    Full Text Available UNLABELLED: Gene transfer to T lymphocytes has historically relied on retro and lentivirus, but recently transposon-based gene transfer is rising as a simpler and straight forward approach to achieve stable transgene expression. Transfer of expression cassettes to T lymphocytes remains challenging, being based mainly on commercial kits. AIMS: We herein report a convenient and affordable method based on in house made buffers, generic cuvettes and utilization of the widely available Lonza nucleofector II device to promote efficient gene transfer to T lymphocytes. RESULTS: This approach renders high transgene expression levels in primary human T lymphocytes (mean 45%, 41-59%, the hard to transfect murine T cells (mean 38%, 36-42% for C57/BL6 strain and human Jurkat T cell line. Cell viability levels after electroporation allowed further manipulations such as in vitro expansion and Chimeric Antigen Receptor (CAR mediated gain of function for target cell lysis. CONCLUSIONS: We describe here an efficient general protocol for electroporation based modification of T lymphocytes. By opening access to this protocol, we expect that efficient gene transfer to T lymphocytes, for transient or stable expression, may be achieved by an increased number of laboratories at lower and affordable costs.

  14. Autoimmune hepatitis in association with lymphocytic colitis.

    LENUS (Irish Health Repository)

    Cronin, Edmond M

    2012-02-03

    Autoimmune hepatitis is a rare, chronic inflammatory disorder which has been associated with a number of other auto-immune conditions. However, there are no reports in the medical literature of an association with microscopic (lymphocytic) colitis. We report the case of a 53-year-old woman with several autoimmune conditions, including lymphocytic colitis, who presented with an acute hepatitis. On the basis of the clinical features, serology, and histopathology, we diagnosed autoimmune hepatitis. To our knowledge, this is the first report of autoimmune hepatitis in association with lymphocytic colitis, and lends support to the theory of an autoimmune etiology for lymphocytic colitis.

  15. Lymphocyte-platelet crosstalk in Graves' disease.

    Science.gov (United States)

    Kuznik, Boris I; Vitkovsky, Yuri A; Gvozdeva, Olga V; Solpov, Alexey V; Magen, Eli

    2014-03-01

    Platelets can modulate lymphocytes' role in the pathophysiology of thyroid autoimmune diseases. The present study was performed to clarify the status of platelet-lymphocyte subpopulations aggregation in circulating blood in patients with Graves' disease (GD). One hundred and fifty patients with GD (GD group) and 45 hyperthyroid patients with toxic multinodular goiter (TMG group) were recruited in the study. Control group consisted 150 healthy subjects. Immunophenotyping of lymphocytes was performed by flow cytometry. Detection of lymphocyte-platelet aggregates (LPAs) was done using light microscope after Ficoll-gradient centrifugation. The group of GD patients exhibited reduced CD8 lymphocyte and higher CD19 cell counts compared with TMG group and healthy controls. A greater number of activated CD3, HLA-DR+ lymphocytes were observed in GD than in TMG group and control group. GD group was characterized by lower blood platelet count (232 ± 89 × 10 cells/µL) than TMG group (251 ± 97 × 10 cells/µL; P < 0.05) and control group (262 ± 95 × 10 cells/µL; P < 0.05). In GD group, more platelet-bound lymphocytes (332 ± 91 /µL) were found than that in TMG group (116 ± 67/µL, P < 0.005) and control group (104 ± 58 /µL; P < 0.001). GD is associated with higher levels of activated lymphocytes and lymphocyte-platelet aggregates.

  16. Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

    Directory of Open Access Journals (Sweden)

    Madanat YF

    2016-03-01

    Full Text Available Yazan F Madanat,1 Mitchell R Smith,2 Alexandru Almasan,3 Brian T Hill2 1Department of Internal Medicine, 2Department of Hematology and Medical Oncology, Taussig Cancer Institute, 3Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Abstract: Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies. Keywords: idelalisib, PI3Kδ inhibitors, chronic lymphocytic leukemia, follicular lymphoma

  17. Changes of lymphocyte kinetics in the normal rat, induced by the lymphocyte mobilizing agent polymethacrylic acid

    NARCIS (Netherlands)

    Ormai, S.; Hagenbeek, A.; Palkovits, M.; Bekkum, D.W. van

    1973-01-01

    The changes in lymphocyte kinetics induced by the lymphocyte mobilizing agent polymethacrylic acid (PMAA) were studied in the normal rat. Quantitative data are presented concerning the degree of lymphocyte mobilization in the spleen and in various lymph nodes at different times after PMAA administra

  18. Signaling in Human and Murine Lymphocytes in Microgravity: Parallels and Contrasts

    Science.gov (United States)

    Neal, Pellis; Alamelu, Sundaresan; Kulkarni, A. D.; Yamauchi, K.

    2006-01-01

    Immune function in space undergoes dramatic changes, some of which are detrimental to lymphocyte function. These changes may lead to significant immune suppression. Studies with human lymphocytes both in space flight and with ground-based models (NASA in vitro ground-based microgravity analog) indicate that T cell activation is inhibited in microgravity. Other lymphocyte functions, such as locomotion, are also inhibited. There is about an 80 percent homology in the immune response of mice to that of humans. A murine model was investigated because of its ability to parallel some microgravity using hind limb suspension. In in vivo antiorthostatically (AOS)-suspended mice, T cell activation is greatly suppressed, with the majority of activation related cytokines being inhibited. PHA activation in lymphocytes derived from AOS mice (in vivo ground-based microgravity analog) is also suppressed. Calcium ionophore studies in human lymphocytes exposed to modeled microgravity indicate that the calcium pathways are probably unaffected in microgravity. IP3 (inositol triphosphate) receptor expression in both human and mouse lymphocytes cultured in modeled microgravity indicate no suppression of calcium signaling. In the human system, microgravity seems to inhibit signaling cascades either at the level of, or up-stream of, Protein Kinase C (PKC). In particular, a membrane event, such as phospholipase C gamma 1 activity in human lymphocytes is affected, with its direct upstream effector, LAT, being deficiently expressed. In the mouse pathway, LAT is undiminished while another critical intermediate, SLP-76, is diminished significantly. This study identifies critical stages in the human and mouse immune systems and in lymphocytes as a function of microgravity.

  19. Interpretation of NCCN Guideline: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 1, 2017

    Directory of Open Access Journals (Sweden)

    Lei XIA

    2016-12-01

    Full Text Available Chronic lymphocytic leukemia (CLL is a kind of chronic lymphocyte proliferative disease with corresponding clinical symptoms caused by the accumulation of mature B lymphocytes in peripheral blood, bone marrow and lymphatic tissues. In recent years, great achievements have been reached on the basic research, new prognostic markers, diagnostic criteria and therapeutic methods in CLL. This study mainly interpreted the corresponding diagnosis and treatment of CLL in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 1, 2017.

  20. Genetics Home Reference: bare lymphocyte syndrome type I

    Science.gov (United States)

    ... Home Health Conditions bare lymphocyte syndrome type I bare lymphocyte syndrome type I Enable Javascript to view ... boxes. Download PDF Open All Close All Description Bare lymphocyte syndrome type I (BLS I) is an ...

  1. The Danish National Chronic Lymphocytic Leukemia Registry

    DEFF Research Database (Denmark)

    da Cunha-Bang, Caspar; Geisler, Christian Hartmann; Enggaard, Lisbeth

    2016-01-01

    AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate...

  2. Metformin and insulin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.

  3. Lenalidomide and Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ana Pilar González-Rodríguez

    2013-01-01

    Full Text Available Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS and tumor flare reaction (TFR, that make its management different from other hematologic malignancies.

  4. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

    Science.gov (United States)

    Zouggari, Yasmine; Ait-Oufella, Hafid; Bonnin, Philippe; Simon, Tabassome; Sage, Andrew P; Guérin, Coralie; Vilar, José; Caligiuri, Giuseppina; Tsiantoulas, Dimitrios; Laurans, Ludivine; Dumeau, Edouard; Kotti, Salma; Bruneval, Patrick; Charo, Israel F; Binder, Christoph J; Danchin, Nicolas; Tedgui, Alain; Tedder, Thomas F; Silvestre, Jean-Sébastien; Mallat, Ziad

    2014-01-01

    Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6Chi monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell–selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction. PMID:24037091

  5. Effect of endogenous catecholamines on apoptosis of Con A-activated lymphocytes of rats.

    Science.gov (United States)

    Jiang, Jian-Lan; Peng, Yu-Ping; Qiu, Yi-Hua; Wang, Jian-Jun

    2007-12-01

    of Bax, Fas, FasL and caspase-3 mRNAs and proteins in the Con A-stimulated lymphocytes was remarkably enhanced by the treatment with pargyline of 10(-6) M and 10(-5) M, but the expression of Bcl-2 mRNA and protein was notably attenuated by the pargyline treatment. These results imply that endogenous CAs synthesized and secreted by lymphocytes accelerate lymphocyte apoptosis by altering fine balance between the expression of antiapoptotic and proapoptotic markers at transcriptional and translational levels, and suggest that both the death receptor pathway and the mitochondrial pathway are involved in the endogenous CAs-induced apoptosis.

  6. Reprogramming T cell Lymphocytes to Induced Pluripotent Stem Cells

    Science.gov (United States)

    Bared, Kalia

    The discovery of induced pluripotent stem cells (iPSC) provided a novel technology for the study of development and pharmacology and complement embryonic stem cells (ES) for cell therapy applications. Though iPSC are derived from adult tissue they are comparable to ES cells in their behavior; multi-lineage differentiation and self-renewal. This makes iPSC research appealing because they can be studied in great detail and expanded in culture broadly. Fibroblasts were the first cell type reprogrammed to an iPSC using a retrovirus vector, since then alternative cell types including lymphocytes have been used to generate iPSC. Different types of vectors have also been developed to enhance iPSC formation and quality. However, specific T lymphocyte subsets have not been shown to reprogram to a pluripotent state to date. Here, we proposed to derive iPSC from peripheral blood effector and central memory T cells, reasoning that the resultant iPSC will maintain the epigenetic memory of a T lymphocyte, including the T cell receptor (TCR) gene rearrangement. This epigenetic memory will enable the differentiation and expansion of T cell iPSC into professional T cells containing a specific TCR. These could then be used for cell therapy to target specific antigens, as well as to improve culture techniques to expand T cells in vitro. We studied different gene delivery methods to derive iPSC from different types of T lymphocytes. We assessed the viability of viral transduction using flow cytometry to detect green fluorescent marker contained in the viral construct and quantitative real time polymerase chain reaction (qRT-PCR) to detect Oct4, Klf4, Sox2, and c-Myc gene expression. Our results demonstrate that the Sendai virus construct is the most feasible platform to reprogram T lymphocytes. We anticipate that this platform will provide an efficient and safe approach to derive iPSC from different T cell subsets, including memory T cells.

  7. Fluoxetine suppresses calcium signaling in human T lymphocytes through depletion of intracellular calcium stores.

    Science.gov (United States)

    Gobin, V; De Bock, M; Broeckx, B J G; Kiselinova, M; De Spiegelaere, W; Vandekerckhove, L; Van Steendam, K; Leybaert, L; Deforce, D

    2015-09-01

    Selective serotonin reuptake inhibitors, such as fluoxetine, have recently been shown to exert anti-inflammatory and immunosuppressive effects. Although the effects on cytokine secretion, proliferation and viability of T lymphocytes have been extensively characterized, little is known about the mechanism behind these effects. It is well known that Ca(2+) signaling is an important step in the signaling transduction pathway following T cell receptor activation. Therefore, we investigated if fluoxetine interferes with Ca(2+) signaling in Jurkat T lymphocytes. Fluoxetine was found to suppress Ca(2+) signaling in response to T cell receptor activation. Moreover, fluoxetine was found to deplete intracellular Ca(2+) stores, thereby leaving less Ca(2+) available for release upon IP3- and ryanodine-receptor activation. The Ca(2+)-modifying effects of fluoxetine are not related to its capability to block the serotonin transporter, as even a large excess of 5HT did not abolish the effects. In conclusion, these data show that fluoxetine decreases IP3- and ryanodine-receptor mediated Ca(2+) release in Jurkat T lymphocytes, an effect likely to be at the basis of the observed immunosuppression.

  8. Metabolism of peripheral lymphocytes, interleukin-2-activated lymphocytes and tumor-infiltrating lymphocytes from sup 31 P NMR studies

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, O.; Cohen, J.S.; Aebersold, P.

    1989-11-20

    {sup 31}O NMR spectra of tumor-infiltrating lymphocytes (TILs) were found to be significantly diefferent form those of normal peripheral lymphocytes. The greatest difference was in the phosphodiester (PDE) region, mainly in the glycerophosphocholine (GPC) signal. Short-term activation of peripheral lymphocytes with interleukin-2 induced a small increase in ATP levels. In all lumphocytes the phosphomonoester (PME) region is dominated by phosphoethanolamine (PE), while there is an unusual absence of phosphocholine (PC). Perfusion of these cells with high concentrations of choline caused only a minimal increase in PC, indicating that choline kinase is not the rate limiting step of lecithin synthesis in lymphocytes. (author). 13 refs.; 3 figs.; 1 tab.

  9. Ubiquitylation of the chemokine receptor CCR7 enables efficient receptor recycling and cell migration

    OpenAIRE

    Schäuble, Karin; Hauser, Mark A.; Rippl, Alexandra; Bruderer, Roland; Otero, Carolina; Gröttrup, Marcus; Legler, Daniel F.

    2012-01-01

    The chemokine receptor CCR7 is essential for lymphocyte and dendritic cell homing to secondary lymphoid organs. Owing to the ability to induce directional migration, CCR7 and its ligands CCL19 and CCL21 are pivotal for the regulation of the immune system. Here, we identify a novel function for receptor ubiquitylation in the regulation of the trafficking process of this G-protein-coupled seven transmembrane receptor. We discovered that CCR7 is ubiquitylated in a constitutive, ligand-independen...

  10. 大豆异黄酮对大鼠肠道上皮内淋巴细胞、杯状细胞及瘦素长型受体的影响%Effect of soy isoflavones on intraepithelial lymphocytes, goblet cells and long leptin receptor in intestinal of rats

    Institute of Scientific and Technical Information of China (English)

    唐秀莹; 陈正礼; 罗启慧; 张小龙

    2013-01-01

    leptin levels in ovariectomized rats was lower than that in estradiol‐treated animals . Moreover , there was a tissue‐specific regulation of the leptin receptor ( OB‐Rb) , with less sensitivity to leptin in adipose tissue when the time of treatment or the dose of estradiol administered increased . The metabolites of soy isoflavones showed structural and functional similarities to estradiol . Available data indicated that soy isoflavones inhibited the leptin secretion , and thus influenced the expression of OB‐Rb . The study was divided into two steps . In the first experiment , male Sprague‐Dawley rats were fed with a high sugar and fat diet ( HSF) or basal diet for eight weeks . Food intake and animal mass were recorded weekly . In the second experiment , 40 selected obese rats were randomly divided into four groups with 10 rats in each group and were fed with soy isoflavones ( group Ⅰ 0 mg/kg , group Ⅱ 50 mg/kg , group Ⅲ 150 mg/kg and group IV 450 mg/kg) and 10 control rats ( group V) were fed with basal diet for four weeks . Soy isoflavones was gavaged with 0 .5%sodium carboxymethyl cellulose solutions respectively . At the end of the second experiment , rats were slightly anesthetized with sodium pentobarbital ip ( 40 mg/kg) , and intestinal was taken and fixed in 10% neutral buffered formalin , processed and trimmed , embedded in paraffin . IEL and GC in the villus epithelium were evaluated in these rats , as well as the OB‐Rb expression by immunohistochemistry staining . In the first experiment , the body mass of the HSF‐fed animals were significantly increased after eight weeks and the obesity module was succeeded . In the second experiment , the results showed that the structure of mucous epithelium , intraepithelial lymphocyte and the goblet cells were normal in the intestinal . The intraepithelial lymphocytes of rats were mainly small lymphocytes and located around the epithelial basement membrane . Goblet cells distributed in the

  11. Stages of Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... also called biotherapy or immunotherapy. Chimeric antigen receptor (CAR) T-cell therapy CAR T-cell therapy is ... of Health FOLLOW US Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp ...

  12. Microfluidics for T- lymphocyte cell separation and inflammation monitoring in burn patients.

    Science.gov (United States)

    Rosenbach, Alan E; Koria, Piyush; Goverman, Jeremy; Kotz, Kenneth T; Gupta, Amit; Yu, Ming; Fagan, Shawn P; Irimia, Daniel; Tompkins, Ronald G

    2011-02-01

    Severe burns result in T lymphocyte specific immunologic changes. In addition to decreased levels of circulating lymphocytes, changes in cytokine secretion and receptor expression also take place. Our finer understanding of the inflammatory response has led to the development of immune-targeted therapeutics, requiring specialized gene-expression monitoring. The emerging field of bio-micro-electromechanical systems can be used to isolate highly pure T lymphocytes in a clinically relevant and timely manner for downstream genomic analysis. Blood samples from healthy volunteers and burn-injured patients were introduced into microfluidic devices developed in our laboratory. Utilizing cell-affinity chromatography for positive selection of T lymphocytes, the devices served as a platform for RNA extraction and downstream cytokine analysis via quantitative real-time polymerase chain reaction (PCR). From a 0.5-mL whole blood sample, the microfluidic devices captured highly pure T lymphocytes from healthy volunteers and burn-injured patients. Cell capture was of sufficient quantity, and extracted RNA was of sufficient quality, for evaluating the gene expression of cytokines: interferon-gamma, interleukin-2, interleukin-4, and interleukin-10. Microfluidics is a useful tool in processing blood from burn-injured patients. Though in its very early stages of development, cell-specific information obtained by this platform/technology will likely be an important component of near-patient molecular diagnostics and personalized medicine.

  13. Glutamate decreases the secretion of IL-10 by peripheral blood lymphocytes in persons with autoimmune thyroiditis.

    Science.gov (United States)

    Kvaratskhelia, E; Dabrundashvili, N; Gagua, M; Maisuradze, E; Mikeladze, D

    2008-11-01

    Human T lymphocytes expose ionotropic and metabotropic glutamate receptors, which control immune responses, cell activation, maturation, and death. Several cytokines release during inflammation which identification may have important physiological and clinical implications. Main biological function of IL-10 is limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells. Various inflammatory molecules regulated the secretion of IL-8 and IL-10, but the action of glutamate on the biosynthesis of cytokines is unknown. We have found that in peripheral blood lymphocytes glutamate at the concentrations within normal plasma levels (1 x 10(-5) M), as well as at lower concentration (0.3 x 10(-6) M) changes the secretion of immunosuppressive cytokine IL-10, whereas synthesis of proinflammatory chemokine, IL-8 did not changed significantly. Moreover, our results have shown that peripheral blood lymphocytes from patients with autoimmune thyroiditis release less IL-10 at both concentration of glutamate than peripheral blood lymphocytes from healthy persons. These data suggest that glutamate decrease the secretion of IL-10 by peripheral blood lymphocytes, especially in patients with autoimmune thyroiditis that may be responsible for prolongation of inflammation.

  14. Emerging roles of L-type voltage gated and other calcium channels in T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Abdallah eBadou

    2013-08-01

    Full Text Available In T lymphocytes, calcium ion controls a variety of biological processes including development, survival, proliferation, and effector functions. These distinct and specific roles are regulated by different calcium signals, which are generated by various plasma membrane calcium channels. The repertoire of calcium-conducting proteins in T lymphocytes includes store-operated CRAC channels, transient receptor potential (TRP channels, P2X channels, and L-type voltage-gated calcium (Cav1 channels. In this paper, we will focus mainly on the role of the Cav1 channels found expressed by T lymphocytes, where these channels appear to operate in a TCR stimulation-dependent and voltage-sensor independent manner. We will review their expression profile at various differentiation stages of CD4 and CD8 T lymphocytes. Then, we will present crucial genetic evidence in favor of a role of these Cav1 channels and related regulatory proteins in both CD4 and CD8 T cell functions such as proliferation, survival, cytokine production and cytolysis. Finally, we will provide evidence and speculate on how these voltage-gated channels might function in the T lymphocyte, a non-excitable cell.

  15. Monoclonal antibodies in chronic lymphocytic leukemia.

    Science.gov (United States)

    Ferrajoli, Alessandra; Faderl, Stefan; Keating, Michael J

    2006-09-01

    Multiple options are now available for the treatment of chronic lymphocytic leukemia. Over the last 10 years, monoclonal antibodies have become an integral part of the management of this disease. Alemtuzumab has received approval for use in patients with fludarabine-refractory chronic lymphocytic leukemia. Rituximab has been investigated extensively in chronic lymphocytic leukemia both as a single agent and in combination with chemotherapy and other monoclonal antibodies. Epratuzumab and lumiliximab are newer monoclonal antibodies in the early phase of clinical development. This article will review the monoclonal antibodies more commonly used to treat chronic lymphocytic leukemia, the results obtained with monoclonal antibodies as single agents and in combination with chemotherapy, and other biological agents and newer compounds undergoing clinical trials.

  16. Chronic lymphocytic leukemia: present status.

    Science.gov (United States)

    Montserrat, E; Rozman, C

    1995-03-01

    Chronic lymphocytic leukemia (CLL) is the form of leukemia which occurs most frequently in Western countries. Its etiology is unknown, and no relationship with viruses or genes has been demonstrated. Epidemiological data suggest that genetic and ambiental factors might be of some significance. Clinical features of CLL are due to the accumulation of leukemic cells in bone marrow and lymphoid organs as well as the immune disturbances that accompany the disease. The prognosis of patients with CLL varies. Treatment is usually indicated by the risk of the individual patient, which is clearly reflected by the stage of the disease. In the early stage (Binet A, Rai O) it is reasonable to defer therapy until disease progression is observed. By contrast, because their median survival is less than five years, patients with more advanced stages require therapy. For almost 50 years, no major advances in the management of CLL, which has revolved around the use of alkylating agents, have been made. In recent years, the therapeutic approach in patients with CLL has changed as a result of the introduction of combination chemotherapy regimens and, in particular, purine analogues. The latter are already the treatment of choice for patients not responding to standard therapies, and their role as front-line therapy is being investigated. Bone marrow transplants are also being increasingly used. It is to be hoped that in years to come the outcome of patients with CLL will be improved by these advances.

  17. Lymphocyte subsets in pediatric migraine.

    Science.gov (United States)

    Cseh, Aron; Farkas, Kristof Mark; Derzbach, Laszlo; Muller, Katalin; Vasarhelyi, Barna; Szalay, Balazs; Treszl, Andras; Farkas, Viktor

    2013-07-01

    Aseptic inflammation due to activated immune cells has been implicated in the pathomechanism of migraine. We measured the prevalence of regulatory T cells (Tregs), along with that of CD4(+)/CD8(+) lymphocytes and their Th1/Th2 commitment in pediatric migraine. Children and adolescents suffering from migraine without aura, migraine with aura and hemiplegic migraine ictally (n = 53, 27, and 20, respectively), also interictally (n = 33) were recruited and compared to 24 healthy children. Our results indicated comparable prevalence of Tregs, CD4(+) and Th1/Th2 committed cells. CD8(+) prevalence was lower, and CD4(+)/CD8(+) ratio was higher in ictal phase irrespective of the subtype of migraine. No association between CD8(+) prevalence and gender, body weight, disease onset and attack duration in migraine subtypes was found. CD8(+) prevalence was normal in patients in interictal phase. These results suggest the absence of major systemic alteration of adaptive immunity in children and adolescents suffering from migraine; however, a transient decrease of CD8(+) prevalence during the ictal phase was detected irrespective of the subtype of migraine.

  18. Obinutuzumab for chronic lymphocytic leukemia.

    Science.gov (United States)

    Rioufol, Catherine; Salles, Gilles

    2014-10-01

    Chronic lymphocytic leukemia (CLL) is a frequent hematological malignancy that is incurable using standard approaches. Two anti-CD20 monoclonal antibodies (mAb), rituximab and ofatumumab, have been approved for CLL treatment. A new glycoengineered type II humanized anti-CD20 mAb, obinutuzumab (GA101), has been developed and demonstrates increased activity against B-cell malignancies by inducing direct cell death and better antibody-dependent cellular cytotoxicity. In a recent randomized Phase III study in patients with newly diagnosed CLL and coexisting conditions, obinutuzumab plus chlorambucil demonstrated significant improvement in progression-free survival and several other outcome parameters, in contrast to rituximab plus chlorambucil. Grade 3-4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Obinutuzumab represents a promising new option for patients with CLL and must be investigated with other chemotherapy regimens or with new targeted agents.

  19. How T lymphocytes see antigen

    Science.gov (United States)

    Chakraborty, Arup K.

    2009-03-01

    Complex organisms, like humans, have an adaptive immune system that enables us to do battle with diverse pathogens. This flexible system can also go awry, and many diseases are the direct consequence of the adaptive immune system failing to discriminate between markers of self and non-self. The orchestrators of adaptive immunity are a class of cells called T lymphocytes (T cells). T cells recognize minute numbers of molecular signatures of pathogens, and T cell recognition of these molecular markers of non-self is both specific and degenerate. The specific (yet, cross-reactive), diverse, and self-tolerant T cell repertoire is designed in the thymus. I will describe how an approach that brings together theoretical and computational studies (rooted in statistical physics) with experiments (carried out by key collaborators) has allowed us to shed light on the mechanistic principles underlying how T cells respond to pathogens in a digital fashion (``on'' or ``off''), and how this molecular machinery coupled with frustration (a la spin glasses) plays a key role in designing the special properties of the T cell repertoire during development in the thymus.

  20. Analysis of the mobility of signaling molecules in lymphocytes using fluorescence photobleaching techniques.

    Science.gov (United States)

    Tanimura, Natsuko; Nagafuku, Masakazu; Liddicoat, Douglas R; Hamaoka, Toshiyuki; Kosugi, Atsushi

    2003-06-03

    The earliest biochemical events at the plasma membrane that lead to gene activation appear to depend not only on the local concentration of signaling molecules, but also on the mobility of these molecules at the site of signaling. To elucidate the process of signal transduction after receptor engagement in the immune system, it is important to analyze the mobility of signaling molecules in living lymphocytes. Current knowledge of the changes in intracellular localization and dynamic movements of signaling molecules during lymphocyte activation is limited. Here, we describe a method for known as fluorescence recovery after photobleaching, used to measure the diffusion mobility of a signaling molecule in a T cell line after T cell receptor stimulation. This method is a useful tool in studies of spatiotemporal regulation in immunoreceptor signaling.

  1. Bilateral dacryoadenitis complicated by lymphocytic hypophysitis.

    Science.gov (United States)

    Baoke, Hou; Shihui, Wei; Maonian, Zhang; Zhaohui, Li; Zhitong, Zou; Zhigang, Song; Yan, Hei

    2009-09-01

    Three patients developed dacryoadenitis (DA) or lymphocytic pneumonitis before the diagnosis of lymphocytic hypophysitis (LyH). There were two previous reports of concurrence of DA and LyH. Our patients add support to the idea that DA and LyH are manifestations of a systemic autoimmune disease. We suggest that the discovery of DA should prompt imaging and endocrine investigation of LyH.

  2. Expression of tenascin in lymphocytic autoimmune thyroiditis.

    OpenAIRE

    Back, W; Heubner, C; Winter, J.; Bleyl, U

    1997-01-01

    AIMS: To study the distribution of tenascin by immunocytochemistry in autoimmune diseases of the thyroid. METHODS: Thyroids from patients with inflammatory lesions of the thyroid (lymphocytic thyroiditis Hashimoto, Grave's disease, thyroiditis DeQuervain) were studied by immunocytochemistry using antibodies against tenascin, collagen III, and collagen IV. RESULTS: In autoimmune lymphocytic thyroiditis Hashimoto there was a characteristic corona-like staining pattern of tenascin around all act...

  3. The Dopaminergic System in Peripheral Blood Lymphocytes: From Physiology to Pharmacology and Potential Applications to Neuropsychiatric Disorders

    OpenAIRE

    Buttarelli, Francesca R.; Fanciulli, Alessandra; Pellicano, Clelia; Pontieri, Francesco E.

    2011-01-01

    Besides its action on the nervous system, dopamine (DA) plays a role on neural-immune interactions. Here we review the current evidence on the dopaminergic system in human peripheral blood lymphocytes (PBL). PBL synthesize DA through the tyrosine-hydroxylase/DOPA-decarboxylase pathway, and express DA receptors and DA transporter (DAT) on their plasma membrane. Stimulation of DA receptors on PBL membrane contributes to modulate the development and initiation of immune responses under physiolog...

  4. Lymphocyte migration into syngeneic implanted lymph nodes

    Energy Technology Data Exchange (ETDEWEB)

    Gordeeva, M.S.

    1986-03-01

    To judge the functional activity of lymphocytes of an implanted lymph node (LN), the proliferative response of lymphocytes of the implanted organ in the blast-transformation reaction in vitro and their ability to induce a local graft versus host reaction (GVHR) were determined. The lymphocyte suspension for labeling with /sup 51/Cr was obtained from peripheral LN in different situations from syngeneic mice. The resulting lymphocyte suspension was labeled with a solution of sodium chromate-/sup 51/Cr in a concentration of 20-40 microCi/100.10/sup 6/ cells in 1 ml for 40 min at 37/sup 0/C. The proliferative activity of a suspension of lymphocytes was estimated as incorporation of /sup 3/H-thymidine into DNA during incubation of the cell suspension for 3 days. Data on migration of /sup 51/Cr-labeled cells and the results of the morphological observations revealed marked ability of lymphocytes of the peripheral pool to colonize the regenerating stroma.

  5. SHARPIN Regulates Uropod Detachment in Migrating Lymphocytes

    Directory of Open Access Journals (Sweden)

    Jeroen Pouwels

    2013-11-01

    Full Text Available SHARPIN-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization, and migration. We found that SHARPIN localizes to the trailing edges (uropods of both mouse and human chemokine-activated lymphocytes migrating on intercellular adhesion molecule-1 (ICAM-1, which is one of the major endothelial ligands for migrating leukocytes. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration, and uropod defects in SHARPIN-deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically, we show that SHARPIN interacts directly with lymphocyte-function-associated antigen-1 (LFA-1, a leukocyte counterreceptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus, SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.

  6. Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2017-07-24

    Anemia; B-Cell Prolymphocytic Leukemia; Fatigue; Fever; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Hairy Cell Leukemia; Lymphadenopathy; Lymphocytosis; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Richter Syndrome; Splenomegaly; Thrombocytopenia; Weight Loss

  7. Clonal dominance among T-lymphocyte infiltrates in arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Stamenkovic, I.; Stegagno, M.; Wright, K.A.; Krane, S.M.; Amento, E.P.; Colvin, R.B.; Duquesnoy, R.J.; Kurnick, J.T.

    1988-02-01

    Synovial membranes in patients with rheumatoid arthritis as well as other types of chronic destructive inflammatory arthritis contain infiltrates of activated T lymphocytes that probably contribute to the pathogenesis of the disease. In an effort to elucidate the nature of these infiltrates, interleukin 2 (IL-2)-responsive T lymphocytes were grown out of synovial fragments from 14 patients undergoing surgery for advanced destructive inflammatory joint disease. Eleven of the samples examined were from patients with classical rheumatoid arthritis, while three others were obtained from individuals with clinical osteoarthritis. Southern blot analysis of T-cell receptor (TCR) ..beta..-chain genes in 13 of 14 cultures showed distinct rearrangements, indicating that each culture was characterized by the predominance of a limited number of clones. T-cell populations from peripheral blood stimulated with a variety of activators and expanded with IL-2 did not demonstrate evidence of similar clonality in long-term culture. These results suggest that a limited number of activated T-cell clones predominate at the site of tissue injury in rheumatoid synovial membranes as well as in other types of destructive inflammatory joint disease. Further characterization of these T-cell clones may aid our understanding of the pathogenesis of these rheumatic disorders.

  8. Cell entry of lymphocytic choriomeningitis virus is restricted in myotubes.

    Science.gov (United States)

    Iwasaki, Masaharu; Urata, Shuzo; Cho, Yoshitake; Ngo, Nhi; de la Torre, Juan C

    2014-06-01

    In mice persistently infected since birth with the prototypic arenavirus lymphocytic choriomeningitis viurs, viral antigen and RNA are readily detected in most organs and cell types but remarkably absent in skeletal muscle. Here we report that mouse C2C12 myoblasts that are readily infected by LCMV, become highly refractory to LCMV infection upon their differentiation into myotubes. Myotube's resistance to LCMV was not due to an intracellular restriction of virus replication but rather an impaired cell entry mediated by the LCMV surface glycoprotein. Our findings provide an explanation for the observation that in LCMV carrier mice myotubes, which are constantly exposed to blood-containing virus, remain free of viral antigen and RNA despite myotubes express high levels of the LCMV receptor alpha dystroglycan and do not pose an intracellular blockade to LCMV multiplication.

  9. Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

    Science.gov (United States)

    Heikenwalder, Mathias; Zeller, Nicolas; Seeger, Harald; Prinz, Marco; Klöhn, Peter-Christian; Schwarz, Petra; Ruddle, Nancy H.; Weissmann, Charles; Aguzzi, Adriano

    2005-02-01

    Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-α or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.

  10. Activation-induced cell death in B lymphocytes

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Upon encountering the antigen (Ag), the immune system can either develop a specific immune response or enter a specific state of unresponsiveness, tolerance. The response of B cells to their specific Ag can be activation and proliferation, leading to the immune response, or anergy and activation-induced cell death (AICD), leading to tolerance. AICD in B lymphocytes is a highly regulated event initiated by crosslinking of the B cell receptor (BCR). BCR engagement initiates several signaling events such as activation of PLCγ, Ras, and PI3K, which generally speaking, lead to survival However, in the absence of survival signals (CD40 or IL-4R engagement), BCR crosslinking can also promote apoptotic signal transduction pathways such as activation of effector caspases, expression of pro-apoptotic genes, and inhibition of pro-survival genes. The complex interplay between survival and death signals determines the B cell fate and, consequently, the immune response.

  11. Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

    Science.gov (United States)

    2013-06-03

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

  12. Selective effects of alpha interferon on human T-lymphocyte subsets during mixed lymphocyte cultures

    DEFF Research Database (Denmark)

    Hokland, M; Hokland, P; Heron, I

    1983-01-01

    Mixed lymphocyte reaction (MLR) cultures of human lymphocyte subsets with or without the addition of physiological doses of human alpha interferon (IFN-alpha) were compared with respect to surface marker phenotypes and proliferative capacities of the responder cells. A selective depression on the T...

  13. 精神分裂症患者外周多巴胺D2受体及转运体mRNA的表达%Expression of dopamine receptor D2 and transporter mRNA in peripheral blood lymphocytes of schizophrenics

    Institute of Scientific and Technical Information of China (English)

    张会芳; 袁国桢; 刘新民

    2011-01-01

    Objective: To investigate the protein level of dopamine receptor D2 ( DRD2) and dopamine transporter( DAT) in peripheral blood lymphocytes ( PBL) in patients with schizophrenia and clinical symptom demonstration. Methods: By case-controls study, we included 25 schizophrenics experiencing their first episode and seeking for hospitalization in Wuxi Mental Health Center between Dec. 2009 and Sept. 2010 and another 28 healthy adults who underwent physical examination in the corresponding period. All subjects were subjected to fasting venous blood taking of 2 ml for detecting mRNA expression of DRD2 and DAT by reverse transcription polymerase chain reaction( RT-PCR). Positive and Negative Symptom Scale( PANSS) was used to estimate the clinical symptoms and severity for patients with schizophrenia. Results .The levels of DKD2 and DAT were significantly higher in PBL of schizophrenic as compared with the controls( F<0. 05 ) ,and DRD2 expression was positively associated with positive symptom in PANSS(r=0. 536.P =0. 006;r =0. 604.P = 0.001 ). Yet,DAT mRNA levels revealed no statistical difference (P> 0.05). Conclusion: Elevated DRD2 mKNA expression was found in PBL in patients with schizophrenia, suggesting that the protein level can be used as a peripheral marker for early diagnosis and screening of this disorder.%目的:探讨精神分裂症患者外周血淋巴细胞多巴胺D2受体(DRD2)与转运体(DAT)的mRNA表达水平及其与临床症状的关系.方法:研究对象为2009年12月~2010年10月间在无锡市精神卫生中心住院的首发精神分裂症患者25例及同期在该医院体检的健康成人28例.所有被试者空腹抽取肘静脉血2 ml,采用病例对照研究,RT-PCR技术检测精神分裂症患者及正常人外周血淋巴细胞DRD2、DAT的mRNA表达情况.用阳性阴性症状评定量表(PANSS)评定精神分裂症患者的临床症状和严重程度.结果:精神分裂症患者外周血淋巴细胞DRD2、DAT表

  14. Tweeters and Woofers: The Complex Orchestra of Calcium Currents in T Lymphocytes

    Directory of Open Access Journals (Sweden)

    Lilian L Nohara

    2015-05-01

    Full Text Available Elevation of intracellular calcium ion (Ca2+ levels is a vital event that regulates T lymphocyte homeostasis, activation, proliferation, differentiation, and apoptosis. The mechanisms that regulate intracellular Ca2+ signalling in lymphocytes involve tightly controlled orchestration of multiple ion channels, membrane receptors, and signalling molecules. T cell receptor (TCR engagement results in depletion of endoplasmic reticulum (ER Ca2+ stores and subsequent sustained influx of extracellular Ca2+ through Ca2+ release-activated Ca2+ (CRAC channels in the plasma membrane. This process termed store-operated Ca2+ entry (SOCE involves the ER Ca2+ sensing molecule, stromal interaction molecule 1 (STIM1, and a pore-forming plasma membrane protein, ORAI1. However, several other important Ca2+ channels that are instrumental in T cell function also exist. In this review, we discuss the role of additional Ca2+ channel families expressed on the plasma membrane of T cells that likely contribute to Ca2+ influx following TCR engagement, which include the IP3 receptors, the P2X receptors, the NMDA receptors, and the TRP channels, with a focus on the voltage-dependent Ca2+ (CaV channels.

  15. GTPase of the Immune-Associated Nucleotide Protein 5 Regulates the Lysosomal Calcium Compartment in T Lymphocytes

    Science.gov (United States)

    Serrano, Daniel; Ghobadi, Farnaz; Boulay, Guylain; Ilangumaran, Subburaj; Lavoie, Christine; Ramanathan, Sheela

    2017-01-01

    T lymphocytes from Gimap5lyp/lyp rats carrying a recessive mutation in the GTPase of immune-associated protein 5 (Gimap5) gene undergo spontaneous apoptosis. Molecular mechanisms underlying this survival defect are not yet clear. We have shown that Gimap5lyp/lyp T lymphocytes display reduced calcium influx following T cell antigen receptor (TCR) stimulation that was associated with impaired buffering of calcium by mitochondria. Here, we investigated the subcellular localization of GIMAP5 and its influence on Ca2+ response in HEK293T cells and T lymphocytes. The more abundantly expressed GIMAP5v2 localizes to the lysosome and certain endosomal vesicles. Gimap5lyp/lyp T lymphocytes showed increased accumulation of calcium in the lysosomes as evidenced by Gly-Phe β-naphthylamide (GPN) triggered Ca2+ release. As a corollary, GPN-induced Ca2+ flux was decreased in HEK293T cells expressing GIMAP5v2. Strikingly, TCR stimulation of rat, mouse, and human T lymphocytes increased lysosomal calcium content. Overall, our findings show that lysosomes modulate cellular Ca2+ response during T cell activation and that GIMAP5 regulates the lysosomal Ca2+ compartment in T lymphocytes. PMID:28223986

  16. Signal Transduction in Primary Human T Lymphocytes in Altered Gravity During Parabolic Flight and Clinostat Experiments

    Directory of Open Access Journals (Sweden)

    Svantje Tauber

    2015-02-01

    Full Text Available Background/Aims: Several limiting factors for human health and performance in microgravity have been clearly identified arising from the immune system, and substantial research activities are required in order to provide the basic information for appropriate integrated risk management. The gravity-sensitive nature of cells of the immune system renders them an ideal biological model in search for general gravity-sensitive mechanisms and to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to life on Earth. Methods: We investigated the influence of altered gravity in parabolic flight and 2D clinostat experiments on key proteins of activation and signaling in primary T lymphocytes. We quantified components of the signaling cascade 1. in non-activated T lymphocytes to assess the “basal status” of the cascade and 2. in the process of activation to assess the signal transduction. Results: We found a rapid decrease of CD3 and IL-2R surface expression and reduced p-LAT after 20 seconds of altered gravity in non-activated primary T lymphocytes during parabolic flight. Furthermore, we observed decreased CD3 surface expression, reduced ZAP-70 abundance and increased histone H3-acetylation in activated T lymphocytes after 5 minutes of clinorotation and a transient downregulation of CD3 and stable downregulation of IL-2R during 60 minutes of clinorotation. Conclusion: CD3 and IL-2R are downregulated in primary T lymphocytes in altered gravity. We assume that a gravity condition around 1g is required for the expression of key surface receptors and appropriate regulation of signal molecules in T lymphocytes.

  17. Molybdate modulates mitogen and cyclosporin responses of human peripheral blood lymphocytes.

    Science.gov (United States)

    Michelis, Fotios V; Delitheos, Andreas; Tiligada, Ekaterini

    2011-07-01

    The trace element molybdenum (Mo) is an essential component of key physiological systems in animals, plants and microorganisms. The molybdate oxoanion MoO(4)(2-) has been demonstrated to cause diverse yet poorly understood biochemical and pharmacological effects, such as non-specific inhibition of phosphatases and stabilization of steroid receptors. This study aimed to investigate the effects of molybdate on the activation of human peripheral blood lymphocytes (hPBLs) ex vivo and its potential interaction with the widely used immunosuppressant drug cyclosporin A (CsA). Lymphocyte activation was evaluated by performing multiple experiments determining blastogenesis in cultured peripheral blood lymphocytes obtained from 5 healthy volunteers, following stimulation induced by phytohemagglutinin (PHA), in the absence or presence of 0.05-10 mM sodium molybdate or/and 2.5-30 μg/mL CsA. Blastogenesis was assessed by a morphometric assay based on the relative proportions of unactivated lymphocytes, activated lymphoblasts and cells with aberrant morphology after PHA-induced activation. Molybdate concentrations up to 1 mM showed no effect on lymphocyte blastogenesis, while higher concentrations exerted immunosuppressive actions on cultured hPBLs. Co-administration of 0.1 mM sodium molybdate with CsA, at doses up to 20 μg/mL, induced no alteration in the response of cultured hPBLs to CsA. However, molybdate potentiated the immunosuppressive action of higher CsA concentrations, implying a likely dose-related synergistic interaction of the two agents in PHA-stimulated blood lymphocytes. These observations are indicative of the possible biological importance of molybdate oxoanions in the modulation of hPBL activation that may have pharmacological consequences during the therapeutic application of immunomodulatory drugs.

  18. Signal transduction in primary human T lymphocytes in altered gravity during parabolic flight and clinostat experiments.

    Science.gov (United States)

    Tauber, Svantje; Hauschild, Swantje; Paulsen, Katrin; Gutewort, Annett; Raig, Christiane; Hürlimann, Eva; Biskup, Josefine; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Pantaleo, Antonella; Cogoli, Augusto; Pippia, Proto; Layer, Liliana E; Thiel, Cora S; Ullrich, Oliver

    2015-01-01

    Several limiting factors for human health and performance in microgravity have been clearly identified arising from the immune system, and substantial research activities are required in order to provide the basic information for appropriate integrated risk management. The gravity-sensitive nature of cells of the immune system renders them an ideal biological model in search for general gravity-sensitive mechanisms and to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to life on Earth. We investigated the influence of altered gravity in parabolic flight and 2D clinostat experiments on key proteins of activation and signaling in primary T lymphocytes. We quantified components of the signaling cascade 1.) in non-activated T lymphocytes to assess the "basal status" of the cascade and 2.) in the process of activation to assess the signal transduction. We found a rapid decrease of CD3 and IL-2R surface expression and reduced p-LAT after 20 seconds of altered gravity in non-activated primary T lymphocytes during parabolic flight. Furthermore, we observed decreased CD3 surface expression, reduced ZAP-70 abundance and increased histone H3-acetylation in activated T lymphocytes after 5 minutes of clinorotation and a transient downregulation of CD3 and stable downregulation of IL-2R during 60 minutes of clinorotation. CD3 and IL-2R are downregulated in primary T lymphocytes in altered gravity. We assume that a gravity condition around 1g is required for the expression of key surface receptors and appropriate regulation of signal molecules in T lymphocytes. © 2015 S. Karger AG, Basel.

  19. Characterization of the atypical lymphocytes in African swine fever

    Directory of Open Access Journals (Sweden)

    Z. A. Karalyan

    2016-07-01

    Full Text Available Aim: Atypical lymphocytes usually described as lymphocytes with altered shape, increased DNA amount, and larger size. For analysis of cause of genesis and source of atypical lymphocytes during African swine fever virus (ASFV infection, bone marrow, peripheral blood, and in vitro model were investigated. Materials and Methods: Atypical lymphocytes under the influence of ASFV were studied for morphologic, cytophotometric, and membrane surface marker characteristics and were used in vivo and in vitro models. Results: This study indicated the increased size, high metabolic activity, and the presence of additional DNA amount in atypical lymphocytes caused by ASFV infection. Furthermore, in atypical lymphocytes, nuclear-cytoplasmic ratio usually decreased, compared to normal lymphocytes. In morphology, they looking like lymphocytes transformed into blasts by exposure to mitogens or antigens in vitro. They vary in morphologic detail, but most of them are CD2 positive. Conclusions: Our data suggest that atypical lymphocytes may represent an unusual and specific cellular response to ASFV infection.

  20. Characterization of the atypical lymphocytes in African swine fever

    Science.gov (United States)

    Karalyan, Z. A.; Ter-Pogossyan, Z. R.; Abroyan, L. O.; Hakobyan, L. H.; Avetisyan, A. S.; Karalyan, N. Yu; Karalova, E. M.

    2016-01-01

    Aim: Atypical lymphocytes usually described as lymphocytes with altered shape, increased DNA amount, and larger size. For analysis of cause of genesis and source of atypical lymphocytes during African swine fever virus (ASFV) infection, bone marrow, peripheral blood, and in vitro model were investigated. Materials and Methods: Atypical lymphocytes under the influence of ASFV were studied for morphologic, cytophotometric, and membrane surface marker characteristics and were used in vivo and in vitro models. Results: This study indicated the increased size, high metabolic activity, and the presence of additional DNA amount in atypical lymphocytes caused by ASFV infection. Furthermore, in atypical lymphocytes, nuclear-cytoplasmic ratio usually decreased, compared to normal lymphocytes. In morphology, they looking like lymphocytes transformed into blasts by exposure to mitogens or antigens in vitro. They vary in morphologic detail, but most of them are CD2 positive. Conclusions: Our data suggest that atypical lymphocytes may represent an unusual and specific cellular response to ASFV infection. PMID:27536044

  1. The role of the prostaglandin D2 receptor, DP, in eosinophil trafficking

    DEFF Research Database (Denmark)

    Schratl, Petra; Royer, Julia F; Kostenis, Evi

    2007-01-01

    Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role...

  2. Nodular lymphocyte-predominant Hodgkin lymphoma.

    Science.gov (United States)

    Savage, Kerry J; Mottok, Anja; Fanale, Michelle

    2016-07-01

    Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma with distinct clinicopathologic features. It is typified by the presence of lymphocyte predominant (LP) cells, which are CD20(+) but CD15(-) and CD30(-) and are found scattered amongst small B lymphocytes arranged in a nodular pattern. Despite frequent and often late or multiple relapses, the prognosis of NLPHL is very favorable. There is an inherent risk of secondary aggressive non-Hodgkin lymphoma (NHL) and studies support that risk is highest in those with splenic involvement at presentation. Given disease rarity, the optimal management is unclear and opinions differ as to whether treatment paradigms should be similar to or differ from those for classical Hodgkin lymphoma (CHL). This review provides an overview of the existing literature describing pathological subtypes, outcome and treatment approaches for NLPHL.

  3. T cell immunity using transgenic B lymphocytes

    Science.gov (United States)

    Gerloni, Mara; Rizzi, Marta; Castiglioni, Paola; Zanetti, Maurizio

    2004-03-01

    Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes. Here, we show that mature naïve B lymphocytes can be genetically programmed by using nonviral DNA and turned into powerful antigen-presenting cells with a dual capacity of synthesis and presentation of antigen to T cells in vivo. A single i.v. injection of transgenic lymphocytes activates T cell responses reproducibly and specifically even at very low cell doses (102). We also demonstrate that T cell priming can occur in the absence of dendritic cells and results in immunological memory with protective effector functions. These findings disclose aspects in the regulation of adaptive immunity and indicate possibilities for vaccination against viruses and cancer in humans.

  4. HIV/AIDS患者外周血B细胞数量以及TLR9 mRNA表达水平的研究%B lymphocyte counts and Toil-like receptor 9 mRNA expression on cell from HIV-1 infected patients

    Institute of Scientific and Technical Information of China (English)

    孙宏; 姜拥军; 尚红; 耿文清; 崔华露; 赵敏; 韩晓旭; 张子宁; 刘静; 代娣; 王亚男

    2010-01-01

    目的 探讨HIV-1感染后外周血B细胞数量的变化,以及B细胞TLR9 mRNA表达水平与HIV-1感染疾病进展的关系.方法 采集HIV/AIDS患者EDTA抗凝静脉血,荧光抗体染色后用流式细胞仪检测HIV/AIDS患者B细胞数量.密度梯度离心法分离外周血单个核细胞,应用MACS磁珠分选系统分选CD19+B细胞,并采用荧光定量实时PCR技术检测B细胞TLR9 mRNA水平.结果 HIV/AIDS患者B细胞数量显著低于健康对照组(P<0.01),与CD4+T细胞数量呈正相关(r=0.534,P=0.006).HIV/AIDS患者外周血B细胞TIR9 mRNA的表达明显低于健康对照组(P=0.023),与CD4+T细胞数量呈正相关(r=0.390,P=0.040).结论 HIV感染可降低HIV/AIDS患者外周血B细胞数量以及B细胞TLR9 mRNA的表达量,B细胞数量和B细胞TLR9 mRNA的表达量均可能与疾病进展相关.%Objective To study the B lymphocytes counts and the expression of TLR9 mRNA on B lymphocytes in peripheral blood from Chinese HIV-infected patients.Methods The cells from peripheral blood were stained with antibodies labeled with fluorescence and B lymphocytes were counted with flow cytometry.Using the method of magnetic activated cell sorting and real-time PCR,the expression of TLR9 mRNA was measured.Results The B lymphocytes counts in HIV/AIDS patients was significantly lower than that of healthy controls(P <0.01).The B lymphocytes counts in HIV/AIDS patients positively correlated with the CD4 +T cells counts(r =0.534,P = 0.006).The expression of TLR9 mRNA on B lymphocytes in HIV/AIDS patients was significantly lower than that of healthy controls(P =0.023),and positively correlated with the CD4 + T cells counts(r = 0.390,P = 0.040).Conclusion The B lymphocytes counts and the expression of TLR9 mRNA on B lymphocytes in Chinese HIV/AIDS patients were decreased due to HIV infection,which may correlate with disease progression.

  5. Epidermal growth factor receptor expression in triple negative and nontriple negative breast carcinomas

    Directory of Open Access Journals (Sweden)

    Arathi A Changavi

    2015-01-01

    Conclusion: EGFR is an important marker to stratify patients with breast cancer according to molecular classification. Its expression correlated positively with young age, higher SBR grade, necrosis, lymphocytic infiltrate and inversely with hormonal receptor expression.

  6. Lymphocytic adenohypophysitis: skull radiographs and MRI

    Energy Technology Data Exchange (ETDEWEB)

    Saiwai, S.; Miyamoto, T. [Department of Radiology, Kobe Central Municipal Hospital, Hyogo (Japan); Inoue, Y.; Nemoto, Y.; Tashiro, T. [Department of Radiology, Osaka City University Medical School (Japan); Ishihara, T. [Department of Endocrinology, Kobe Central Municipal Hospital, Hyogo (Japan); Matsumoto, S. [Department of Neurosurgery, Kobe Central Municipal Hospital, Hyogo (Japan); Hakuba, A. [Department of Neurosurgery, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno, Osaka, 545 (Japan)

    1998-02-01

    We report the skull radiograph, CT and MRI findings in three patients with lymphocytic adenohypophysitis mimicking pituitary adenoma. All cases were associated with pregnancy. CT demonstrated a pituitary mass but did not differentiate lymphocytic adenohypophysitis from pituitary adenoma. The skull radiographs showed either a normal sella turcica or minimal abnormalities; they did not show ballooning or destruction. The MRI appearances were distinctive: relatively low signal on T1-weighted images; preservation of the bright posterior pituitary lobe despite the presence of a relatively large pituitary mass, less common in macroadenomas; marked contrast enhancement compared with pituitary macroadenomas; and dural enhancement adjacent to a pituitary mass. (orig.) With 3 figs., 1 tab., 40 refs.

  7. Local glucocorticoid production in lymphoid organs of mice and birds: Functions in lymphocyte development.

    Science.gov (United States)

    Taves, Matthew D; Hamden, Jordan E; Soma, Kiran K

    2017-02-01

    Circulating glucocorticoids (GCs) are powerful regulators of immunity. Stress-induced GC secretion by the adrenal glands initially enhances and later suppresses the immune response. GC targets include lymphocytes of the adaptive immune system, which are well known for their sensitivity to GCs. Less appreciated, however, is that GCs are locally produced in lymphoid organs, such as the thymus, where GCs play a critical role in selection of the T cell antigen receptor (TCR) repertoire. Here, we review the roles of systemic and locally-produced GCs in T lymphocyte development, which has been studied primarily in laboratory mice. By antagonizing TCR signaling in developing T cells, thymus-derived GCs promote selection of T cells with stronger TCR signaling. This results in increased T cell-mediated immune responses to a range of antigens. We then compare local and systemic GC patterns in mice to those in several bird species. Taken together, these studies suggest that a combination of adrenal and lymphoid GC production might function to adaptively regulate lymphocyte development and selection, and thus antigen-specific immune reactivity, to optimize survival under different environmental conditions. Future studies should examine how lymphoid GC patterns vary across other vertebrates, how GCs function in B lymphocyte development in the bone marrow, spleen, and the avian bursa of Fabricius, and whether GCs adaptively program immunity in free-living animals.

  8. Human malignant melanoma-derived progestagen-associated endometrial protein immunosuppresses T lymphocytes in vitro.

    Directory of Open Access Journals (Sweden)

    Suping Ren

    Full Text Available Progestagen-associated endometrial protein (PAEP is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow's 2.5mm or greater and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment.

  9. Lymphocyte-based model systems for allergy research: a historic overview.

    Science.gov (United States)

    Neunkirchner, Alina; Schmetterer, Klaus G; Pickl, Winfried F

    2014-01-01

    During the last decades, a multitude of studies applying distinct in vitro and in vivo model systems have contributed greatly to our better understanding of the initiation and regulation of inflammatory processes leading to allergic diseases. Over the years, it has become evident that among lymphocytes, not only IgE-producing B cells and allergy-orchestrating CD4(+) helper cells but also cytotoxic CD8(+) T cells, γδ-T cells and innate lymphoid cells, as well as regulatory lymphocytes, might critically shape the immune response towards usually innocuous allergens. In this review, we provide a historic overview of pioneering work leading to the establishment of important lymphocyte-based model systems for allergy research. Moreover, we contrast the original findings with our currently more refined knowledge to appreciate the actual validity of the respective models and to reassess the conclusions obtained from them. Conflicting studies and interpretations are identified and discussed. The tables are intended to provide an easy overview of the field not only for scientists newly entering the field but also for the broader readership interested in updating their knowledge. Along those lines, herein we discuss in vitro and in vivo approaches to the investigation of lymphocyte effector cell activation, polarization and regulation, and describe depletion and adoptive transfer models along with gene knockout and transgenic (tg) methodologies. In addition, novel attempts to establish humanized T cell antigen receptor tg mouse models for allergy research are described and discussed.

  10. Effect of melatonin on monochromatic light-induced T-lymphocyte proliferation in the thymus of chickens.

    Science.gov (United States)

    Chen, Fuju; Reheman, Aikebaier; Cao, Jing; Wang, Zixu; Dong, Yulan; Zhang, Yuxian; Chen, Yaoxing

    2016-08-01

    A total of 360 post-hatching day 0 (P0) Arbor Acre male broilers, including intact, sham operation and pinealectomy groups, were exposed to white light (WL), red light (RL), green light (GL) and blue light (BL) from a light-emitting diode (LED) system until for P14. We studied the effects of melatonin and its receptors on monochromatic light-induced T-lymphocyte proliferation in the thymus of broilers. The density of proliferating cell nuclear antigen (PCNA) cells and the proliferation of T-lymphocytes in response to Concanavalin A (ConA) in GL significantly increased both in vivo and in vitro (from 9.57% to 32.03% and from 34.30% to 50.53%, respectively) compared with other lights (plights (p<0.005). However, exogenous melatonin (10(-9)M) significantly increased the proliferative activity of T-lymphocyte by 9.64% (p=0.002). In addition, GL significantly increased mRNA expression levels of Mel1a, Mel1b and Mel1c receptors from 21.09% to 32.57%, and protein expression levels from 24.43% to 42.92% compared with RL (p<0.05). However, these effects were blocked after pinealectomy. Furthermore, 4P-PDOT (a selective Mel1b antagonist) and prazosin (a selective Mel1c antagonist) attenuated GL-induced T-lymphocyte proliferation in response to ConA (p=0.000). Luzindole (a nonselective Mel1a/Mel1b antagonist), however, did not induce these effects (p=0.334). These results suggest that melatonin may mediate GL-induced T-lymphocyte proliferation via the Mel1b and Mel1c receptors but not via the Mel1a receptor.

  11. The Uptake and Utilization of Chlorambucil by Lymphocytes from Patients with Chronic Lymphocytic Leukaemia

    Science.gov (United States)

    Hill, Bridget T.; Harrap, K. R.

    1972-01-01

    It has been shown that lymphocytes isolated from the peripheral blood of patients with chronic lymphocytic leukaemia do not modify the mustard group of chlorambucil, as has been demonstrated previously in Yoshida ascites cells. However, lymphocytes from patients with an unsatisfactory clinical course or poor response to treatment were able to modify the aromatic region of the drug molecule; little change occurred in the aromatic absorption of intracellular chlorambucil in patients who responded to treatment. This simple test may provide a rapid assessment of a patient's potential response to chemotherapy. PMID:4647395

  12. Lymphocytic adrenal medullitis and lymphocytic thyroiditis in a laboratory beagle dog.

    Science.gov (United States)

    Doi, Takuya; Tomonari, Yuki; Kawasako, Kazufumi; Yamada, Naoaki; Tsuchitani, Minoru

    2017-02-04

    Lymphocytic adrenal medullitis characterized by inflammation and atrophy in the medulla of the bilateral adrenal glands was observed in an 18-month-old male laboratory beagle dog. It might be that the present lymphocytic adrenal medullitis is an autoimmune-mediated disease as the histological characteristics are consistent with an autoimmune pathogenesis. However, the actual cause remains unclear as the existence of serum autoantibodies against the adrenal medulla could not be confirmed. Although this dog also contracted lymphocytic thyroiditis along with serum thyroglobulin autoantibodies, indicating that the thyroiditis occurred with an autoimmune basis; the relation between the adrenal medullitis and thyroiditis is unknown.

  13. Impact of the Functional CD5 Polymorphism A471V on the Response of Chronic Lymphocytic Leukaemia to Conventional Chemotherapy Regimens

    Science.gov (United States)

    Delgado, Julio; Bielig, Torsten; Bonet, Lizette; Carnero-Montoro, Elena; Puente, Xose S.; Colomer, Dolors; Bosch, Elena; Campo, Elias; Lozano, Francisco

    2016-01-01

    Summary The CD5 lymphocyte receptor -a bona fide immunohistochemical marker of chronic lymphocytic leukaemia (CLL) cells- is a negative regulator of activation signals from the antigen-specific B-cell receptor (BCR). Given that signalling components of the BCR are important contributors to the variable clinical behaviour of CLL, the relevance of functional variants of CD5 on CLL prognosis was explored. The results show that germline-encoded CD5 variants influence the survival to conventional chemotherapies from CLL patients with unmutated IGVH genes. This result supports the notion that CD5 is not only a phenotypic marker but a relevant player in CLL cell biology. PMID:26991857

  14. Altered lymphocyte proliferation and innate immune function in scrapie 139A- and ME7-infected mice.

    Science.gov (United States)

    Cho, In Soo; Spinner, Daryl S; Kascsak, Richard J; Meeker, H Cliff; Kim, Bo Sook; Park, Seung Yong; Schuller-Levis, Georgia; Park, Eunkyue

    2013-06-01

    Lymphoid organs play an important role in prion disease development and progression. While the role of lymphoid organs and changes in immune-related genes have been extensively investigated in scrapie-infected animals, innate immunity has not. Previous studies examined lymphocyte function in scrapie-infected C3H/HeJ mice, which exhibit defects in lipopolysaccharide (LPS) response now known to result from a mutation in Toll-like receptor (TLR) 4. We examined immune function in scrapie-infected CD1 mice, which are LPS responders. Lymphocyte proliferation from CD1 mice infected with either 139A or ME7 scrapie was measured in response to concanavalin (Con) A or LPS at 1 and 3 months after infection. Following LPS exposure, mice infected 3 months with ME7, but not 139A, demonstrated significantly decreased lymphocyte proliferation compared to controls. After Con A exposure, lymphocyte proliferation in scrapie-infected mice did not differ from controls. Gender-specific comparison of lymphocyte proliferation showed significant decreases in mitogenic responses in females infected 3 months with either 139A or ME7, compared to controls. Males infected for 3 months with ME7, but not 139A, showed significantly decreased proliferation after lymphocyte exposure to LPS, but not Con A. Neither gender showed changes in lymphocyte proliferation after 1 month of scrapie infection. Innate immune activation of peritoneal macrophages was determined via production of nitric oxide (NO), IL-6, and TNF-α after exposure to TLR ligands. TNF-α and IL-6 production were reduced in macrophages from females infected with either scrapie strain for 3 months, while NO production after TLR agonist plus IFN-γ exposure was decreased in both females and males infected for 3 months with 139A, compared to ME7. These data demonstrated altered innate immunity, suggesting hormonal and/or other gender-specific regulation may contribute to gender differences in some immune functions. Our data demonstrate

  15. Re-evaluation of the immunological Big Bang.

    Science.gov (United States)

    Flajnik, Martin F

    2014-11-03

    Classically the immunological 'Big Bang' of adaptive immunity was believed to have resulted from the insertion of a transposon into an immunoglobulin superfamily gene member, initiating antigen receptor gene rearrangement via the RAG recombinase in an ancestor of jawed vertebrates. However, the discovery of a second, convergent adaptive immune system in jawless fish, focused on the so-called variable lymphocyte receptors (VLRs), was arguably the most exciting finding of the past decade in immunology and has drastically changed the view of immune origins. The recent report of a new lymphocyte lineage in lampreys, defined by the antigen receptor VLRC, suggests that there were three lymphocyte lineages in the common ancestor of jawless and jawed vertebrates that co-opted different antigen receptor supertypes. The transcriptional control of these lineages during development is predicted to be remarkably similar in both the jawless (agnathan) and jawed (gnathostome) vertebrates, suggesting that an early 'division of labor' among lymphocytes was a driving force in the emergence of adaptive immunity. The recent cartilaginous fish genome project suggests that most effector cytokines and chemokines were also present in these fish, and further studies of the lamprey and hagfish genomes will determine just how explosive the Big Bang actually was.

  16. Physiological crosstalk between the AC/PKA and PLC/PKC pathways modulates melatonin-mediated, monochromatic-light-induced proliferation of T-lymphocytes in chickens.

    Science.gov (United States)

    Guo, Qingyun; Wang, Zixu; Dong, Yulan; Cao, Jing; Chen, Yaoxing

    2017-06-28

    Previous study has demonstrated that melatonin plays a critical role in monochromatic-light-induced lymphocyte proliferation in response to T cell mitogen concanavalin A (ConA). However, its intracellular mechanism is still unclear. In this study, we investigate the intracellular signal pathways of melatonin receptor-mediated T-lymphocyte proliferation in the spleens of chicks exposed to different light wavelengths. Results showed that green light enhanced T-lymphocyte proliferation by 2.46-6.83% and increased splenic mRNA and protein expressions of melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) by 16.05-40.43% compared with the white, red and blue light groups. However, pinealectomy resulted in a decrease in T-lymphocyte proliferation and melatonin receptor expression with no statistically significant differences between the different light groups. In vitro experiments showed that the Mel1b selective antagonist 4P-PDOT, the Mel1c selective antagonist prazosin and the mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor PD98059 suppressed both melatonin-induced lymphocyte proliferation in response to ConA and melatonin- and ConA-stimulated extracellular signal-regulated kinase 1/2 (ERK1/2) activity but that the Mel1a/Mel1b non-selective antagonist luzindole did not. In addition, pretreatment with forskolin (FSK, the adenylyl cyclase activator), H89 (the PKA inhibitor), U73122 (the PLC inhibitor) or Go6983 (the broad spectrum PKC inhibitor) markedly attenuated melatonin- and ConA-stimulated T-lymphocyte proliferation and ERK1/2 activity. These results demonstrate that melatonin mediates green-light-induced T-lymphocyte proliferation via the Mel1b and Mel1c receptors by triggering crosstalk between the cAMP/PKA and PLC/PKC signal pathways followed by ERK1/2 activation.

  17. Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome.

    Science.gov (United States)

    Meininger, Isabel; Krappmann, Daniel

    2016-12-01

    The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigen-receptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated 'chronic' CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.

  18. Dual character of interaction between lymphocytes and allogeneic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Petrov, R.V.; Dozmorov, I.M.; Kochetkova, M.O.; Nikolaeva, I.S.

    1986-10-01

    The mechanisms of stimulation of colony formation by small doses of allogeneic lymphocytes were studied in mice. When interaction of lymphocytes with allogeneic stem cells was studied, bone marrow cells of mice were injected into lethally irradiated recipients in the control, and mixtures of bone marrow cells with varied numbers of lymphocytes were injected in the experiment. Dependence of the inactivation indices on the number of lymphocytes injected, based on the results of counting macro- and microcolonies in the spleen, is shown.

  19. Morphometric Characterization of Small Cell Lymphocytic Lymphoma

    Directory of Open Access Journals (Sweden)

    Chisoi Anca

    2014-11-01

    Full Text Available The morphometry in histopathology is used to characterize cell populations belonging to different tissues and to identify differences in their parameters with prognostic implications. To achieve morphometric examination were selected 6 of 24 cases identified as small cell lymphocytic lymphoma. For each case analysis was done on five fields, for each field measuring the parameters of 20 cells. The studied parameters were for cytoplasm: cytoplasmic area, maximum and minimum cytoplasmic diameter, cytoplasmic perimeter; for nucleus were measured: nuclear area, minimum and maximum nuclear diameter, nuclear perimeter, nuclear contour index, nuclear ellipticity index, nuclear irregularity index. Also the nucleocytoplasmic ratio was calculated in all studied cases. Small cell lymphocytic lymphoma is characterized in morphometric terms having a small cytoplasmic area (average 29.206 and also a small nuclear area (mean 28.939 having a nucleo-cytoplasmic ratio appearance suggestive for adult lymphocyte. A nuclear contour index small value (3.946, ellipticity index value also small (3.521 and small nuclear irregularity index (3.965. Standard deviations, in any of the studied morphometric categories, is around or below 1 suggesting monomorphic cell appearance. These morphometric and microscopic features characterized mainly by a small population of adult lymphocytes, monomorphic, with rounded hipercromic nuclei, dense chromatin, support the framing into indolent lymphoma group in terms of clinical outcome.

  20. Targeting cytotoxic T lymphocytes for cancer immunotherapy

    OpenAIRE

    Maher, J; Davies, E. T.

    2004-01-01

    In light of their preeminent role in cellular immunity, there is considerable interest in targeting of cytotoxic T-lymphocytes to cancer. This review summarises the active and passive immunotherapeutic approaches under development to achieve this goal, emphasising how recent advances in tumour immunology and gene transfer have impacted upon this field.

  1. Immunophenotypic lymphocyte profiles in human african trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Caroline Boda

    Full Text Available Human African trypanosomiasis (HAT is a deadly vector-born disease caused by an extracellular parasite, the trypanosome. Little is known about the cellular immune responses elicited by this parasite in humans. We used multiparameter flow cytometry to characterize leukocyte immunophenotypes in the blood and cerebrospinal fluid (CSF of 33 HAT patients and 27 healthy controls identified during a screening campaign in Angola and Gabon. We evaluated the subsets and activation markers of B and T lymphocytes. Patients had a higher percentage of CD19+ B lymphocytes and activated B lymphocytes in the blood than did controls, but lacked activated CD4+ T lymphocytes (CD25+. Patients displayed no increase in the percentage of activated CD8+ T cells (HLA-DR+, CD69+ or CD25+, but memory CD8 T-cell levels (CD8+CD45RA2 were significantly lower in patients than in controls, as were effector CD8 T-cell levels (CD8+CD45RA+CD62L2. No relationship was found between these blood immunophenotypes and disease severity (stage 1 vs 2. However, CD19+ B-cell levels in the CSF increased with disease severity. The patterns of T and B cell activation in HAT patients suggest that immunomodulatory mechanisms may operate during infection. Determinations of CD19+ B-cell levels in the CSF could improve disease staging.

  2. SnapShot: chronic lymphocytic leukemia.

    Science.gov (United States)

    Ciccone, Maria; Ferrajoli, Alessandra; Keating, Michael J; Calin, George A

    2014-11-10

    Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in western countries. This SnapShot depicts the origins and evolution of this B cell malignancy, describes prognostic factors and CLL animal models, and illustrates therapies in preclinical and clinical development against CLL.

  3. Regulatory T-lymphocytes in asthma

    NARCIS (Netherlands)

    van Oosterhout, AJM; Bloksma, N

    2005-01-01

    T-helper cell type (Th)2 lymphocytes play an important role in the initiation, progression and persistence of allergic diseases, including asthma. However, little is known about immunoregulatory mechanisms that determine susceptibility to, severity of, or persistence of asthma. The concept of a dist

  4. Lymphocyte dynamics in health and disease

    NARCIS (Netherlands)

    van Gent, R.

    2009-01-01

    Following immune depletion, it is vital that the immune system recovers rapidly to avoid severe or life-threatening infections. In adults, full recovery of CD4+ and CD8+ T-cell counts, important cell types of the immune system, may take years. Similar to other lymphocytes, T cells start their develo

  5. Peripheral lymphocyte subpopulations in recurrent aphthous ulceration

    DEFF Research Database (Denmark)

    Pedersen, A; Klausen, B; Hougen, H P

    1991-01-01

    Peripheral lymphocyte subsets--T-helper (CD4+), T-suppressor/cytotoxic (CD8+), and naive/virgin T cells/natural killer cells (CD45RA)--were studied quantitatively in 30 patients with recurrent aphthous ulceration (RAU) and 29 sex- and age-matched RAU-free control donors. The CD4+ percentage was s...

  6. Effect of chloroquine on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    the response to pokeweed mitogen. The response to concanavalin A and to various antigens was suppressed, especially the response to large particulate antigens. Oral intake of 300 mg of chloroquine base/week did not affect the lymphocyte proliferative responses. 600 mg of base/week decreased the response...

  7. Rosette formation of pig T lymphocytes with sheep erythrocytes.

    Science.gov (United States)

    Escajadillo, C; Binns, R M

    1975-01-01

    The relationship of sheep RBC rosette formation to density of thymus and blood lymphocytes was investigated. Thymocyte density was unimodal and cells of all densities rosetted equally. Blood lymphocyte density was bimodal with most rosette-forming cells in the denser ficoll layers. Papain treatment of SRBC increases rosette formation with blood lymphocytes while apparently maintaining specificity of T cells.

  8. 21 CFR 864.8500 - Lymphocyte separation medium.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Lymphocyte separation medium. 864.8500 Section 864.8500 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... medium. (a) Identification. A lymphocyte separation medium is a device used to isolate lymphocytes from...

  9. DMPD: Developmental plasticity of lymphocytes. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18472258 Developmental plasticity of lymphocytes. Cobaleda C, Busslinger M. Curr Op...in Immunol. 2008 Apr;20(2):139-48. Epub 2008 May 9. (.png) (.svg) (.html) (.csml) Show Developmental plastic...ity of lymphocytes. PubmedID 18472258 Title Developmental plasticity of lymphocytes. Authors Cobaleda C, Bus

  10. Flow cytometric analyses of the viability, surface marker expression and function of lymphocytes from children following cryopreservation.

    Science.gov (United States)

    Chen, Xi; Zhang, Hui; Mou, Wenjun; Qi, Zhan; Ren, Xiaoya; Wang, Guoliang; Jiao, Hong; Kong, Xiaohui; Gui, Jingang

    2016-11-01

    Flow cytometric analysis is important for the investigation and clinical preparation of lymphocytes from children. However, the strict requirement of cell freshness and inter‑assay variability limits the application of this methodology for pediatric investigations. Therefore, it is necessary to identify a reliable cryopreservative method capable of maintaining high cell viability and proper cell function in lymphocytes from children. In the present study, eight commonly‑used cell cyropreservative methods were used, and their effects on cell viability, surface marker expression and cell function were examined. In addition, how these methods affect the distribution of T‑cell receptor Vβ subfamilies were also determined. The results of the present study provided valuable experimental evidence, based on which the optimal method for the cryopreservation of lymphocytes from children in pediatric investigations and clinical applications can be selected.

  11. The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity.

    Science.gov (United States)

    Finetti, Francesca; Pellegrini, Michela; Ulivieri, Cristina; Savino, Maria Teresa; Paccagnini, Eugenio; Ginanneschi, Chiara; Lanfrancone, Luisa; Pelicci, Pier Giuseppe; Baldari, Cosima T

    2008-05-15

    The ShcA locus encodes 3 protein isoforms that differ in tissue specificity, subcellular localization, and function. Among these, p66Shc inhibits TCR coupling to the Ras/MAPK pathway and primes T cells to undergo apoptotic death. We have investigated the outcome of p66Shc deficiency on lymphocyte development and homeostasis. We show that p66Shc(-/-) mice develop an age-related lupus-like autoimmune disease characterized by spontaneous peripheral T- and B-cell activation and proliferation, autoantibody production, and immune complex deposition in kidney and skin, resulting in autoimmune glomerulonephritis and alopecia. p66Shc(-/-) lymphocytes display enhanced proliferation in response to antigen receptor engagement in vitro and more robust immune responses both to vaccination and to allergen sensitization in vivo. The data identify p66Shc as a negative regulator of lymphocyte activation and show that loss of this protein results in breaking of immunologic tolerance and development of systemic autoimmunity.

  12. Detection of CD4+ and CD8 + T-lymphocytes with the optofluidic ring resonator (OFRR) biosensor

    Science.gov (United States)

    Gohring, John T.; Fan, Xudong

    2009-05-01

    We have demonstrated the use of the Opto-Fluidic ring resonator (OFRR) to achieve the label-free detection of CD4+ and CD8+ T-Lymphocytes. The OFRR sensing technology combines microfluidics and optical sensing in a small platform that achieves rapid detection. In this work, white blood cells were obtained from healthy blood and the concentration altered to reflect CD4 and CD8 concentrations of HIV infected individuals. The OFRR was modified to effectively capture these receptors located on T-Lymphocytes and obtain a sensing signal through interaction with an evanescent field. Results show isolation of CD4+ and CD8+ T-Lymphocytes at medically significant levels. This work will lead to a device that can provide a CD4 and CD8 count to measure HIV progression in a low cost sensing setup.

  13. Chronic lymphocytic leukemia/small lymphocytic lymphoma presenting as septic arthritis of the shoulder

    Energy Technology Data Exchange (ETDEWEB)

    Donovan, Andrea; Schweitzer, Mark E.; Nomikos, George [NYU Hospital for Joint Diseases, New York, NY (United States); Garcia, Roberto A. [Bellevue Hospital Center, New York, NY (United States)

    2008-11-15

    We report a case of a 53-year-old man presenting with shoulder pain mimicking septic arthritis. Laboratory findings were atypical. Biopsy performed to assess for possible osteomyelitis demonstrated chronic lymphocytic leukemia/small lymphocytic lymphoma. Intra-articular lymphoma is a rare but important consideration in patients with atypical clinical presentation. Imaging alone may be insufficient to render diagnosis as lymphoma can mimic infection, synovial hypertrophic processes, and depositional arthropathy. (orig.)

  14. NEUTROPHIL/LYMPHOCYTE RATIO AND PLATELET/LYMPHOCYTE RATIO IN PATIENTS WITH NSCLC

    OpenAIRE

    Cukic, Vesna

    2016-01-01

    Objective: to compare neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in patients with NSCLC (Non- Small- Cell Lung Cancer): with and without metastases at the time of diagnosis to find out if there is the importance of these cell ratios in the assessment of severity NSCLC. Material and Methods: this is the retrospective analysis of NRL and PRL in patients with NSCLC at the time of the diagnosis of disease before any anti tumor treatment (chemotherapy, radiotherapy, surg...

  15. Lymphocytic colitis: A clue to bacterial etiology

    Institute of Scientific and Technical Information of China (English)

    Thanaa EA Helal; Naglaa S Ahmed; Osama Abo El Fotoh

    2005-01-01

    AIM: To find out the role of bacteria as a possible etiological factor in lymphocytic colitis.METHODS: Twenty patients with histopathological diagnosis of lymphocytic colitis and 10 normal controls were included in this study. Colonoscopic biopsies were obtained from three sites (hepatic and splenic flexures and rectosigmoid region). Each biopsy was divided into two parts. A fresh part was incubated on special cultures for bacterial growth. The other part was used for the preparation of histologic tissue sections that were examined for the presence of bacteria with the help of Giemsa stain.RESULTS: Culture of tissue biopsies revealed bacterial growth in 18 out of 20 patients with lymphocytic colitis mostly Escherichia coli(14/18), which was found in all rectosigmoid specimens (14/14), but only in 8/14 and 6/14 of splenic and hepatic flexure specimens respectively. In two of these cases, E coliwas associated with proteus. Proteus was found only in one case, Klebsiella in two cases, and Staphylococcus aureus in one case. In the control group, only 2 out of 10 controls showed the growth of E coliin their biopsy cultures.Histopathology showed rod-shaped bacilli in the tissue sections of 12 out of 14 cases with positive E coliin their specimen's culture. None of the controls showed these bacteria in histopathological sections.CONCLUSION: This preliminary study reports an association between E coliand lymphocytic colitis, based on histological and culture observations. Serotyping and molecular studies are in process to assess the role of E coliin the pathogenesis of lymphocytic colitis.

  16. Lymphocyte transformation studies in drug hypersensitivity.

    Science.gov (United States)

    Warrington, R J; Tse, K S

    1979-05-05

    In a group of patients with clinically diagnosed drug hypersensitivity the in vitro lymphocyte response to the suspected drug was assessed by the lymphocyte transformation test. The test gave positive results in all 15 patients with penicillin-induced immediate or accelerated allergic reactions and positive immediate skin-test reactivity to the major or the minor antigenic determinant of penicillin, or both, but in only 3 of the 12 patients with delayed-onset maculopapular rashes induced by penicillin, despite positive immediate reactivity to the skin-test reagents.Lymphocyte stimulation greater than five times the control level was demonstrated for five patients with penicillin-induced erythroderma, Stevens-Johnson syndrome or a serum-sickness-like illness, or with methicillin-induced interstitial nephritis, all of whom had negative reactions to the appropriate skin-test reagents. A low level of stimulation was seen in eight other skin-test-negative patients with possible allergic reactions induced by penicillins. However, in all subjects tested the stimulation was significantly greater than the mean for control subjects.For 9 of 11 patients with isoniazid-induced hepatitis or maculopapular rashes, but for only 8 of 31 patients with eruptions induced by a variety of drugs other than penicillins and isoniazid, significant stimulation occurred in the lymphocyte transformation test.It is concluded that the lymphocyte transformation test is useful in the detection of hypersensitivity to the penicillins (although in IgE-mediated reactions skin testing is clearly preferable) and isoniazid but is of limited value in the demonstration of hypersensitivity to other drugs.

  17. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy.

    Science.gov (United States)

    Themeli, Maria; Kloss, Christopher C; Ciriello, Giovanni; Fedorov, Victor D; Perna, Fabiana; Gonen, Mithat; Sadelain, Michel

    2013-10-01

    Progress in adoptive T-cell therapy for cancer and infectious diseases is hampered by the lack of readily available, antigen-specific, human T lymphocytes. Pluripotent stem cells could provide an unlimited source of T lymphocytes, but the therapeutic potential of human pluripotent stem cell-derived lymphoid cells generated to date remains uncertain. Here we combine induced pluripotent stem cell (iPSC) and chimeric antigen receptor (CAR) technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture. These iPSC-derived, CAR-expressing T cells display a phenotype resembling that of innate γδ T cells. Similar to CAR-transduced, peripheral blood γδ T cells, the iPSC-derived T cells potently inhibit tumor growth in a xenograft model. This approach of generating therapeutic human T cells 'in the dish' may be useful for cancer immunotherapy and other medical applications.

  18. SLAM family receptors in normal immunity and immune pathologies.

    Science.gov (United States)

    Wu, Ning; Veillette, André

    2016-02-01

    The signaling lymphocytic activation molecule (SLAM) family is a group of six receptors restricted to hematopoietic cells. Most of these receptors are self-ligands, and thus are triggered in the context of interactions between hematopoietic cells. By way of their cytoplasmic domain, SLAM-related receptors associate with the SLAM-associated protein (SAP) family of adaptors, which control the signals and functions of SLAM family receptors. Recent findings have provided new insights into the key roles of SLAM family receptors in normal immunity, their involvement in human diseases and their usefulness as drug targets to treat human malignancies. These data are reviewed herein.

  19. Macrophages and lymphocytes differentially modulate the ability of RANTES to inhibit HIV-1 infection.

    Science.gov (United States)

    Gross, Eleanore; Amella, Carol A; Pompucci, Lorena; Franchin, Giovanni; Sherry, Barbara; Schmidtmayerova, Helena

    2003-11-01

    The beta-chemokines MIP-1alpha, MIP-1beta, and RANTES inhibit HIV-1 infection of CD4+ T cells by inhibiting interactions between the virus and CCR5 receptors. However, while beta-chemokine-mediated inhibition of HIV-1 infection of primary lymphocytes is well documented, conflicting results have been obtained using primary macrophages as the virus target. Here, we show that the beta-chemokine RANTES inhibits virus entry into both cellular targets of the virus, lymphocytes and macrophages. However, while virus entry is inhibited at the moment of infection in both cell types, the amount of virus progeny is lowered only in lymphocytes. In macrophages, early-entry restriction is lost during long-term cultivation, and the amount of virus produced by RANTES-treated macrophages is similar to the untreated cultures, suggesting an enhanced virus replication. We further show that at least two distinct cellular responses to RANTES treatment in primary lymphocytes and macrophages contribute to this phenomenon. In lymphocytes, exposure to RANTES significantly increases the pool of inhibitory beta-chemokines through intracellular signals that result in increased production of MIP-1alpha and MIP-1beta, thereby amplifying the antiviral effects of RANTES. In macrophages this amplification step does not occur. In fact, RANTES added to the macrophages is efficiently cleared from the culture, without inducing synthesis of beta-chemokines. Our results demonstrate dichotomous effects of RANTES on HIV-1 entry at the moment of infection, and on production and spread of virus progeny in primary macrophages. Since macrophages serve as a reservoir of HIV-1, this may contribute to the failure of endogenous chemokines to successfully eradicate the virus.

  20. Expression of molecules involved in B lymphocyte survival and differentiation by synovial fibroblasts.

    Science.gov (United States)

    Edwards, J C; Leigh, R D; Cambridge, G

    1997-06-01

    The synovitis of rheumatoid arthritis (RA) is one of few pathological lesions in which B lymphocyte accumulation progresses to the extent of germinal centre formation. The present study was designed to assess the ability of synovial fibroblasts to express molecules implicated in B lymphocyte survival and differentiation, both in vivo, and in response to cytokines in vitro. Normal and diseased synovia were examined by indirect immunofluorescence. In all tissues synovial intimal fibroblasts showed co-expression of vascular cell adhesion molecule-1 (VCAM-1) and complement decay-accelerating factor (DAF) comparable to that of follicular dendritic cells (FDC), but not complement receptor 2 (CR2). In rheumatoid synovia, subintimal cells showed variable expression of VCAM-1 and DAF, with bright co-expression of VCAM-1, DAF and CR2 in lymphoid follicle centres. B lymphocytes, some of which were proliferating cell nuclear antigen-positive, were present in contact with subintimal cells expressing VCAM-1 with or without DAF or CR2. B lymphocytes were rarely present in the intimal layer, and, where present, showed fragmentation. In vitro, synovial fibroblasts exposed to tumour necrosis factor-alpha (TNF-alpha) in combination with interferon-gamma (IFN-gamma) showed enhanced expression of VCAM-1, in comparison with fibroblasts from skin and lung and, unlike skin and lung fibroblasts, also expressed DAF and CR2. These findings support the hypothesis that synovial targeting in RA involves an enhanced ability of synovial fibroblasts to support B lymphocyte survival. This appears to be dependent, not on the constitutive expression of VCAM-1 and DAF on intimal cells, but on the increased ability of subintimal cells to respond to proinflammatory cytokines, perhaps critically in the expression of VCAM-1.

  1. Rho and Rap guanosine triphosphatase signaling in B cells and chronic lymphocytic leukemia.

    Science.gov (United States)

    Mele, Silvia; Devereux, Stephen; Ridley, Anne J

    2014-09-01

    Chronic lymphocytic leukemia (CLL) cells proliferate predominantly in niches in the lymph nodes, where signaling from the B cell receptor (BCR) and the surrounding microenvironment are critical for disease progression. In addition, leukemic cells traffic constantly from the bloodstream into the lymph nodes, migrate within lymphatic tissues and egress back to the bloodstream. These processes are driven by chemokines and their receptors, and depend on changes in cell migration and integrin-mediated adhesion. Here we describe how Rho and Rap guanosine triphosphatases (GTPases) contribute to both BCR signaling and chemokine receptor signaling, particularly by regulating cytoskeletal dynamics and integrin activity. We propose that new inhibitors of BCR-activated kinases are likely to affect CLL cell trafficking via Rho and Rap GTPases, and that upstream regulators or downstream effectors could be good targets for therapeutic intervention in CLL.

  2. Expression of lymphocyte coding genes in peripheral blood and lymphocyte infiltration in cardiac tissues influenced by cyclosporin A in heterotopic heart transplantation model in rats.

    Science.gov (United States)

    Xu, Xiu-fang; Xin, Yi; Zhang, Ying; Huang, Yi-min; Li, Wen-bin; Li, Na; Lin, Zheng; Zhou, Yu-jie; Zhang, Zhao-guang

    2013-12-01

    suppressed gig18 transcription in peripheral lymphocytes. After 24h, sodium channel beta-1 was positively expressed in the cyclosporine A group. The relationship between molecular surface receptor expression and coding genes in cardiac tissue and peripheral blood after transplant indicates that early detection of acute rejection and anti-rejection drugs' curative effect can be assessed. © 2013 Elsevier B.V. All rights reserved.

  3. Role of signaling lymphocytic activation molecule in T helper cell responses

    Directory of Open Access Journals (Sweden)

    Jan E. de Vries

    1998-01-01

    Full Text Available Signaling lymphocytic activation molecule (SLAM; CDw150 is a 70 kDa glycoprotein. Signaling lymphocytic activation molecule is constitutively expressed on memory T cells, CD56+ T cells, a subset of T cell receptor γδ+ cells, immature thymocytes and, at low levels, on a proportion of peripheral blood B cells. Signaling lymphocytic activation molecule is rapidly upregulated on all T and B cells after activation. Engagement of SLAM by F(ab’2 fragments of an anti-SLAM monoclonal antibody (mAb A12 enhances antigen-specific T cell proliferation. In addition, mAb A12 was directly mitogenic for T cell clones and activated T cells. T cell proliferation induced by mAb A12 is independent of interleukin (IL-2, IL-4, IL-12 and IL-15, but is cyclosporin A sensitive. Ligation of SLAM during antigen-specific T cell proliferation resulted in upregulation of interferon (IFN-γ production, even by allergen-specific T helper cell (Th 2 clones, whereas the levels of IL-4 and IL-5 production were only marginally affected. The mAb A12 was unable to induce IL-4 and IL-5 production by Th1 clones. Co-stimulation of skin-derived Der P1-specific Th2 cells from patients with atopic dermatitis via SLAM resulted in the generation of a population of IFN-γ-producing cells, thereby reverting their phenotype to a Th0 pattern. Signaling lymphocytic activation molecule is a high-affinity self ligand mediating homophilic cell interaction. In addition, soluble SLAM enhances both T and B cell proliferation. Collectively, these data indicate that SLAM molecules act both as receptors and ligands that are not only involved in T cell expansion but also drive the expanding T cells during immune responses into the Th0/Th1 pathway. This suggests that signaling through SLAM plays a role in directing Th0/Th1 development.

  4. Preferential S phase entry and apoptosis of CD4(+) T lymphocytes of HIV-1-infected patients after in vitro cultivation.

    Science.gov (United States)

    Patki, A H; Zielske, S P; Sieg, S F; Lederman, M M

    2000-12-01

    We have studied the relationship between spontaneous apoptosis and cell cycle perturbations in circulating peripheral blood lymphocytes of HIV-1-infected patients and healthy controls. PBMC obtained from HIV-1-infected patients and healthy controls were incubated in culture medium for 48 h. Cells were separated into CD4(+) and CD8(+) populations using immunomagnetic beads. Apoptosis and cell cycle phases were measured by propidium iodide staining and bromodeoxyuridine (BrdU) incorporation followed by flow cytometric analyses. In experiments using cells obtained from HIV-1-infected patients, spontaneous apoptosis was more frequent in CD4(+) T lymphocytes than in CD8(+) T lymphocytes (17.6% vs 9.5%, P lymphocytes was comparable (4.5% vs 5.1%). Lymphocytes obtained from patients were more frequently in S phase than healthy controls' cells (2.2 +/- 0.9% vs 0.5 +/- 0.2%, P 0.4). Kinetic analyses using BrdU and PI staining revealed that S phase cells were more likely to become apoptotic than resting (G(0)-G(1)) cells (28.4% +/- 10.3% vs 11.3% +/- 9.9% in patients, P Lymphocytes obtained from HIV-1-infected persons are activated in vivo to enter S phase and to undergo spontaneous apoptosis after brief in vitro cultivation. The present studies indicate that most apoptotic cells in this system are CD4(+) and kinetic analyses reveal that S phase cells are more likely to undergo spontaneous apoptosis than G(0)-G(1) cells. Accelerated cell death in HIV-1 disease may contribute to the failure of lymphocyte responsiveness to appropriate T cell receptor stimulation.

  5. Piperine blocks interleukin-2-driven cell cycle progression in CTLL-2 T lymphocytes by inhibiting multiple signal transduction pathways.

    Science.gov (United States)

    Doucette, Carolyn D; Greenshields, Anna L; Liwski, Robert S; Hoskin, David W

    2015-04-02

    Piperine, a pungent alkaloid found in the fruits of black pepper plants, has diverse physiological effects, including the ability to inhibit immune cell-mediated inflammation. Since the cytokine interleukin-2 (IL-2) is essential for the clonal expansion and differentiation of T lymphocytes, we investigated the effect of piperine on IL-2 signaling in IL-2-dependent mouse CTLL-2 T lymphocytes. Tritiated-thymidine incorporation assays and flow cytometric analysis of Oregon Green 488-stained cells showed that piperine inhibited IL-2-driven T lymphocyte proliferation; however, piperine did not cause T lymphocytes to die or decrease their expression of the high affinity IL-2 receptor, as determined by flow cytometry. Western blot analysis showed that piperine blocked the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5 without affecting the upstream phosphorylation of Janus kinase (JAK) 1 and JAK3. In addition, piperine inhibited the IL-2-induced phosphorylation of extracellular signal-regulated kinase 1/2 and Akt, which are signaling molecules that regulate cell cycle progression. Piperine also suppressed the expression of cyclin-dependent kinase (Cdk) 1, Cdk4, Cdk6, cyclin B, cyclin D2, and Cdc25c protein phosphatase by IL-2-stimulated T lymphocytes, indicating G0/G1 and G2/M cell cycle arrest. Piperine-mediated inhibition of IL-2 signaling and cell cycle progression in CTLL-2 T lymphocytes suggests that piperine should be further investigated in animal models as a possible natural source treatment for T lymphocyte-mediated transplant rejection and autoimmune disease.

  6. Dietary palmitic acid influences LDL-mediated lymphocyte proliferation differently to other mono- and polyunsaturated fatty acids in rats.

    Science.gov (United States)

    Tinahones, F J; Gómez-Zumaquero, J M; Monzón, A; Rojo-Martínez, G; Pareja, A; Morcillo, S; Cardona, F; Olveira, G; Soriguer, F

    2004-10-01

    Recent studies suggest that the biological effects of saturated fatty acids depend on the length of their chain. We compared the effect of diets containing different fatty acids on plasma lipids and lymphocyte proliferation in the presence of lovastatin and with increasing amounts of LDL. Lymphocytes from rats fed with a diet rich in palmitic acid had a greater lymphocyte proliferation capacity than those from rats fed with diets rich in oleic acid, linoleic acid, or fish oil. This effect was maintained when small amounts of polyunsaturatwed fatty acids (PUFA; sunflower oil) were added to the palmitic acid diet. LDL receptor activity, measured by the capacity of lovastatin to revert the inhibition of lymphocyte proliferation with increasing amounts of LDL in the medium, was greater in the rats fed with palmitic acid, and was similar to the other groups when small amounts of PUFA were added. All the groups had similar levels of plasma cholesterol, but the LDL levels were significantly lower in the group fed with palmitic acid plus PUFA. The highest HDL-cholesterol (HDLc) levels were found in the palmitic acid group and the lowest LDL-cholesterol (LDLc)/HDLc ratio in the palmitic acid plus PUFA group. These results suggest that diets rich in palmitic acid do not raise total cholesterol, but reduce LDLc or keep it normal, and raise HDLc levels. This effect may be partly due to an increase in LDL receptor activity. The inclusion of small amounts of PUFA in the diet rich in palmitic acid substantially modified the LDL receptor response in the lymphocytes, suggesting that the proportion of different families of dietary fatty acids may be more important than the individual amount of each in absolute terms to explain their effects on plasma lipids and lipoproteins.

  7. Is lymphocytic (hashimoto) thyroiditis associated with suicide?

    Science.gov (United States)

    Cina, Stephen J; Perper, Joshua A

    2009-09-01

    The histologic diagnosis of lymphocytic (Hashimoto) thyroiditis requires lymphocytic inflammation of the thyroid gland in combination with Hourthle cell metaplasia of follicular epithelial cells. Clinically, this autoimmune process has been associated with hypothyroidism and psychiatric conditions including depression. This retrospective study was designed to quantify the incidence and severity of lymphocytic thyroiditis in a series of nonconsecutive suicides compared with a cohort of motor vehicle accident victim controls. Eighty-one suicide victims (61 male, 20 female; age range 13-79 years, average 43) were compared with 88 age and gender matched controls (64 males, 24 females; age range 19-85 years, average 36). The degree of lymphocytic inflammation of the thyroid gland was graded on a scale of 0 to 3 (0 = no inflammation, 1 = mild inflammation, 2-3 moderate-to-marked inflammation with Hourthle cell metaplasia). Slides from each case were reviewed while blinded to the cause and manner of death in each case. Of these 169 total cases, 8 (4.7%) received a score of 3, whereas additional 7 (4.1%) received a grade of 2. Eighty-six percent of all of the cases showed no significant inflammation and recorded a score of 0. Of the 81 suicides, 3 had a score of 3, and 3 had a score of 2 (combined incidence of 7.4%). Within the control group, 5 of 88 cases scored 3 and another 4 scored 2 (combined incidence = 10.2%). Three males and 5 females scored 3 with an age range of 23 to 63 years, average 42. Incidental data tabulated showed that 19% of suicide victims were on psychoactive medications compared with 6% in the motor vehicle accident control group. No one on this study was on thyroid hormone replacement therapy. Depression is strongly linked to suicide and lymphocytic thyroiditis may be a cause of depression. Based on this study, however, the presence of lymphocytic thyroiditis cannot be used as a histologic adjunct to discriminate between suicide and accident in

  8. Rapid diagnosis of vitamin D-dependent rickets type II by use of phytohemagglutinin-stimulated lymphocytes.

    Science.gov (United States)

    Takeda, E; Kuroda, Y; Saijo, T; Toshima, K; Naito, E; Kobashi, H; Iwakuni, Y; Miyao, M

    1986-03-28

    The interactions of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] with phytohemagglutinin (PHA)-stimulated lymphocytes from normal subjects and three patients with vitamin D-dependent rickets (DDR) type II were investigated. Impaired nuclear uptake and normal cytosol binding of [3H]1,25-(OH)2D3 were observed with PHA-stimulated lymphocytes of these patients as with their cultured skin fibroblasts. Furthermore, the incorporation of [14C]thymidine into PHA-stimulated lymphocytes of the patients was not reduced by 1,25-(OH)2D3, which is known to inhibit proliferation of various cells. These findings suggest that 1,25-(OH)2D3 receptors are reduced or absent in patients with DDR type II. Thus, the capacities of cytosol binding and nuclear uptake of 1,25-(OH)2D3 in PHA-stimulated lymphocytes seem to reflect those of endo-organs such as the intestine and bone. These findings show that a test of the effect of 1,25-(OH)2D3 on thymidine incorporation into PHA-stimulated lymphocytes is useful for rapid diagnosis of DDR type II.

  9. Single-channel and whole-cell recordings of mitogen-regulated inward currents in human cloned helper T lymphocytes.

    Science.gov (United States)

    Kuno, M; Goronzy, J; Weyand, C M; Gardner, P

    Cytoplasmic free Ca2+ [( Ca2+]i) appears to be an important signal for DNA synthesis in early stages of lymphocyte activation. In spite of many experimental studies which employ fluorescent Ca2+ indicator dye to demonstrate an early increase of [Ca2+]i in T-lymphocytes after stimulation with lectins, specific antigens, and monoclonal antibodies to T-lymphocyte receptors, the mechanism responsible for the rise of [Ca2+]i is unknown. We have used the extracellular patch clamp technique to investigate this mechanism. Unitary inward currents, mediated by Ca2+ or Ba2+, were recorded in the membrane of T-lymphocytes. The inward current channel was characterized by a conductance of 7 pS and extrapolated reversal potential (Erev) 110 mV positive to resting potential (Vr). While gating kinetic parameters were not affected by membrane potential changes, the probability of channel opening markedly increased upon activation of the T-lymphocyte by the mitogenic lectin, phytohaemagglutinin (PHA). PHA also evoked a cadmium-sensitive, inward Ba2+ current on whole-cell clamp. We suggest that this mitogen-regulated channel introduces Ca2+ into the cytoplasm upon activation and represents a new class of voltage-independent Ca2+ channels.

  10. Abnormally High Expression of BAFF on T Lymphocytes from Lung Cancer-associated Pleural Effusions and Its Potent Anti-tumor Effect

    Institute of Scientific and Technical Information of China (English)

    Haiyan XU; Xiaozhou HE; Yibei ZHU; Tiangzan YAN; Hongbin MA; Xueguang ZHANG

    2007-01-01

    In the present study, the expressions of B cell activating factor belonging to the tumor necrosis factor family (BAFF) and its receptors (BAFF-R and TACI) on T lymphocytes from malignant pleural effusion (MPE) were examined by fluorescence-activated cell sorting (FACS) analysis, and compared with those on the T lymphocytes from non-malignant pleural effusion (NMPE) and healthy controls. It was found that CD3 positive T lymphocytes (including CD4, CD8, and part of CD25 and CD69 positive cells) of MPE in lung cancer highly and consistently expressed the BAFF molecule, while high expressions of BAFF could only be found in phytohemagglutinin (PHA) or interleukin 2 (IL-2) induced T lymphocytes from NMPE or healthy controls. These results were consistent with the results from BAFF mRNA detection by real-time PCR. In addition, T lymphocytes from MPE expressed significantly more BAFF-R than those from NMPE or healthy controls, while the expression of TACI was increased on CD4+ T cells but decreased on CD8+ T cells when compared with controls. The Annexin/PI assay suggested that recombinant human BAFF (rhBAFF) could promote the survival rate of T lymphocytes from MPE, while the decoy receptor TACI-Fc fusion protein could promote the apoptosis rate of T lymphocytes. Cytokines in the supernatant detected by ELISA assay showed that rhBAFF could significantly upregulate the secretion of IFN-γ in vitro,and the IFN-γ level in the TACI-Fc-treated group resembled that of the control groups. All of these results indicated that the abnormally high expression of BAFF on T lymphocytes from MPE may play a role of antitumor effect.

  11. Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Morzadec, Claudie; Macoch, Mélinda; Robineau, Marc; Sparfel, Lydie [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France); Fardel, Olivier [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France); Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes (France); Vernhet, Laurent, E-mail: laurent.vernhet@univ-rennes1.fr [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France)

    2012-08-01

    Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans. -- Highlights: ► Arsenic inhibits secretion of IL-17A from human naïve and memory Th17 lymphocytes. ► Arsenic represses early expression of IL-17A gene in human activated T lymphocytes. ► Arsenic interferes with activation of

  12. Mean dose to lymphocytes during radiotherapy treatments

    Energy Technology Data Exchange (ETDEWEB)

    Brandan, M.E.; Perez-Pastenes, M.A. [Instituto de Fisica (Mexico); Ostrosky-Wegman, P.; Gonsebatt, M.E. [Instituto de Investigaciones Biomedicas (Mexico); Diaz-Perches, R. [Hospital General de Mexico (Mexico)

    1994-10-01

    Using a probabilistic model with parameters from four radiotherapy protocols used in Mexican hospitals for the treatment of cervical cancer, the authors have calculated the distribution of dose to cells in peripheral blood of patients. Values of the mean dose to the lymphocytes during and after a {sup 60}Co treatment are compared to estimates from an in vivo chromosome aberration study performed on five patients. Calculations indicate that the mean dose to the circulating blood is about 2% of the tumor dose, while the mean dose to recirculating lymphocytes may reach up to 7% of the tumor dose. Differences up to a factor of two in the dose to the blood are predicted for different protocols delivering equal tumor doses. The data suggest mean doses higher than the predictions of the model. 10 refs., 3 figs., 2 tabs.

  13. Bioluminescent assay for human lymphocyte blast transformation.

    Science.gov (United States)

    Bulanova, E G; Budagyan, V M; Romanova, N A; Brovko LYu; Ugarova, N N

    1995-05-01

    One of the basic tests of in vitro evaluation of immune cell functional activity is a proliferative response of lymphocytes on the action of external stimuli such as mitogenic lectines, antigens, etc. We compared two methods used to assess the lymphocyte functional status. (1) [3H]thymidine incorporation and (2) bioluminescence for determination of intracellular ATP in blast cells. Comparison has been done for healthy donors and patients with proven low immunological status. The proposed bioluminescent method for evaluation of the proliferative response was shown to be sensitive enough for diagnostic purposes. This method allows one to process a large number of samples at the same time and correlates highly with the radionuclide test use hazardous radioactive materials.

  14. Lymphocyte transformation in presumed ocular histoplasmosis

    Energy Technology Data Exchange (ETDEWEB)

    Ganley, J.P.; Nemo, G.J.; Comstock, G.W.; Brody, J.A.

    1981-08-01

    Lymphocytes from individuals with inactive macular disciform lesions of presumed ocular histoplasmosis challenged with three histoplasmin antigens incorporated tritiated thymidine at a significantly higher rate than histoplasmin-stimulated lymphocytes of matched control and peripheral scar groups. This finding is consistent with the etiologic association of the disciform ocular syndrome and previous systemic infection with Histoplasma capsulatum. The disciform group had a higher mean response than the other two groups to pokeweed mitogen but not to phytohemagglutinin and had higher mean counts per minute to the specific antigens Toxoplasma gondii, Blastomyces dermatitidis, Cryptococcus neoformans, Mycobacterium tuberculosis, M battery, and M gaus, but not to Candida albicans. These data would suggest that individuals with the disciform lesion of presumed ocular histoplasmosis have a hyperreactive cellular immune response; this response may play an important role in the development of the disciform.

  15. Obinutuzumab for previously untreated chronic lymphocytic leukemia.

    Science.gov (United States)

    Abraham, Jame; Stegner, Mark

    2014-04-01

    Obinutuzumab was approved by the Food and Drug Administration in late 2013 for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). The approval was based on results of an open-label phase 3 trial that showed improved progression-free survival (PFS) with the combination of obinutuzumab plus chlorambucil compared with chlorambucil alone. Obinutuzumab is a monoclonal antibody that targets CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. After binding to CD20, obinutuzumab mediates B-cell lysis by engaging immune effector cells, directly activating intracellular death signaling pathways, and activating the complement cascade. Immune effector cell activities include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

  16. The Danish National Chronic Lymphocytic Leukemia Registry

    DEFF Research Database (Denmark)

    da Cunha-Bang, Caspar; Geisler, Christian Hartmann; Enggaard, Lisbeth;

    2016-01-01

    , and for decision on treatment initiation as well as characteristics included in the CLL International Prognostic Index are collected. DESCRIPTIVE DATA: To ensure full coverage of Danish CLL patients in the registry, both continuous queries in case of missing data, and cross-referencing with the Danish National......, 3,082 patients have been registered. CONCLUSION: The Danish National CLL Registry is based within the Danish National Hematology Database. The registry covers a cohort of all patients diagnosed with CLL in Denmark since 2008. It forms the basis for quality assessment of CLL treatment in Denmark......AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate...

  17. Metabolism pathways in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rozovski, Uri; Hazan-Halevy, Inbal; Barzilai, Merav; Keating, Michael J; Estrov, Zeev

    2016-01-01

    Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells' metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells' metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells' metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.

  18. Guillain-Barré综合征患者B淋巴细胞辅助受体CD l9表达的研究%Expression of CO-receptor CD 1 9 on peripheral B lymphocytes in patients with Guillain-Barre syndrome

    Institute of Scientific and Technical Information of China (English)

    袁学谦; 朱太卿; 张莉峰; 王慧贞; 王焕荣; 王爱丽; 张东锋

    2011-01-01

    目的 本研究通过检测Guillain-Barre综合征(GBS)患者外周血单个核细胞CD l9蛋白的表达,探讨CD l9与GBS及其严重程度之间的关系.方法 利用流式细胞术检测GBS组(36例)和正常对照组(20例)的CD l9蛋白表达,按病程将GBS组分为急性期亚组与恢复期亚组,并分析与疾病严重程度之间的关系.结果 与正常对照组221±78个比较,GBS组742±128个B细胞数量显著升高,差异有统计学意义(P0.05).与恢复期GBS组87.27±6.04%比较,急性期GBS组81.20+5.25%CD l9+CD20+无明显差异(P>0.05).与轻症GBS组632+68个比较,重症GBS组797+130个B细胞数量无明显差异(P>0.05).与轻症GBS组82.53+5.03%比较,重症GBS组85.84+6.77%CD l9+CD20+无明显差异(P>0.05).结论 CD l9在GBS中表达显著升高,但与病程和病情严重程度无关.%Objective To explore the corlation between the expression of CD19 and the severity of GBS. The expression of CD19 of B lymphocyte in peripheral blood mononuclear cells( PBMNCs )of the disease was tested.Methods GBS group( 36 cases )and healthy controls( HC )group( 20 cases )were investigated. The expression of CD 19 on peirpheral B lymphocytes were examined by flow cytometry. According to course of disease, GBS group was divided into acute subgroup and recovery subgroup. Furthermore, the corelation between the expression of CD 19 and the severity of the disease was analyzed. Results Compared with HC group[ 221 + 78 ], B lymphocyte numbers[ 742 + 128 ]were significantly higher( P < 0. 01 ). Compared with HC group[ 62.21 + 7. 85% ], the CD 19 + CD20+ increased significantly ( P <0.0 1 )in GBS group[ 83.92 +6.23% ]. Compared with recovery subgroup[ 686 + 108 ],B lymphocyte numbers were of no significant differences( P > 0.05 )in the acute subgroup[ 810 + 124 ]. Compared with recovery subgroup[ 87.27 + 6.04% ], the CD19 + CD20 + was of no significant differences( P > 0.05 ) in the acute subgroup[ 81.20 + 5.251% ]. Compared with mild

  19. NK cell function is markedly impaired in patients with chronic lymphocytic leukaemia but is preserved in patients with small lymphocytic lymphoma.

    Science.gov (United States)

    Parry, Helen M; Stevens, Tom; Oldreive, Ceri; Zadran, Bassier; McSkeane, Tina; Rudzki, Zbigniew; Paneesha, Shankara; Chadwick, Caroline; Stankovic, Tatjana; Pratt, Guy; Zuo, Jianmin; Moss, Paul

    2016-10-18

    Chronic lymphocytic leukemia (B-CLL) and small lymphocytic lymphoma (SLL) are part of the same disease classification but are defined by differential distribution of tumor cells. B-CLL is characterized by significant immune suppression and dysregulation but this is not typical of patients with SLL. Natural killer cells (NK) are important mediators of immune function but have been poorly studied in patients with B-CLL/SLL. Here we report for the first time the NK cell phenotype and function in patients with B-CLL and SLL alongside their transcriptional profile. We show for the first time impaired B-CLL NK cell function in a xenograft model with reduced activating receptor expression including NKG2D, DNAM-1 and NCRs in-vitro. Importantly, we show these functional differences are associated with transcriptional downregulation of cytotoxic pathway genes, including activating receptors, adhesion molecules, cytotoxic molecules and intracellular signalling molecules, which remain intact in patients with SLL. In conclusion, NK cell function is markedly influenced by the anatomical site of the tumor in patients with B-CLL/SLL and lymphocytosis leads to marked impairment of NK cell activity. These observations have implications for treatment protocols which seek to preserve immune function by limiting the exposure of NK cells to tumor cells within the peripheral circulation.

  20. B cell acute lymphocytic leukemia in pregnancy.

    Science.gov (United States)

    Bottsford-Miller, Justin; Haeri, Sina; Baker, Arthur M; Boles, Jeremiah; Brown, Mark

    2011-08-01

    Acute lymphocytic leukemia (ALL) is a rare occurrence in pregnancy and can be rapidly fatal if left untreated. The need for immediate treatment of ALL, coupled with the maternal-fetal risks from the chemotherapy regimen render a therapeutic dilemma in pregnant women with ALL. We report a case of ALL diagnosed in the 24th week of pregnancy to outline our management strategy, to demonstrate the feasibility of treatment with multi-agent chemotherapy, and to provide a review of the literature.

  1. GABA, a natural immunomodulator of T lymphocytes

    DEFF Research Database (Denmark)

    Bjurstöm, Helen; Wang, Junyang; Ericsson, Ida

    2008-01-01

    gamma-aminobutyric acid (GABA) is the main neuroinhibitory transmitter in the brain. Here we show that GABA in the extracellular space may affect the fate of pathogenic T lymphocytes entering the brain. We examined in encephalitogenic T cells if they expressed functional GABA channels that could......M and higher GABA concentrations decreased T cell proliferation. The results are consistent with GABA being immunomodulatory....

  2. Lymphocytic hypophysitis masquerading as pituitary adenoma

    Directory of Open Access Journals (Sweden)

    Rajneesh Mittal

    2012-01-01

    Full Text Available Introduction: Pituitary hypophysitis (PH is characterized by pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be autoimmune or secondary to systemic diseases or infections. Based on the histopathological findings PH is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous, necrotizing and Immunoglobulin- G4 (IgG4 plasmacytic types. Objective: To report a case of lymphocytic hypophysitis (LH. Case Report: A 15-year-old girl presented with history of headache, amenorrhea, and history of polyuria for past 4 months. Initial evaluation had suppressed follicular stimulating hormone (<0.01 mIU/ml, high prolactin levels (110.85 ng/ml and diabetes insipidus (DI. Magnetic resonance imaging of sella was suggestive of pituitary macroadenoma with partial compression over optic chiasma. Patient underwent surgical decompression. Yellowish firm tissue was evacuated and xanthochromic fluid was aspirated. Histopathology was suggestive of LH. She resumed her cycles postoperatively after 4 months, prolactin levels normalized, however, she continues to have DI and is on desmopressin spray. This case has been presented here for its rare presentation in an adolescent girl because it is mostly seen in young females and postpartum period and its unique presentation as an expanding pituitary mass with optic chiasma compression. Conclusion: Definitive diagnosis of LH is based on histopathological evaluation. Therapeutic approach should be based on the grade of suspicion and clinical manifestations of LH.

  3. [Circadian rhythm of human lymphocyte subpopulations].

    Science.gov (United States)

    Pasqualetti, P; Colantonio, D; Casale, R; Colangeli, S; Natali, G

    1988-01-01

    Circadian rhythm of lymphocyte subsets was investigated in four healthy subjects, males, aged 35-58 years old. After a period of ambiental synchronization, venous blood samples were taken during a span of a day at 0.00 a.m., 4.00 a.m., 8.00 a.m., noon, 4.00 p.m. and 8.00 p.m. Lymphocyte subsets (OKT3, OKT4, OKT8, OKB7, OKJa1) were determined by monoclonal antibodies method, and serum level of cortisol by radioimmunoassay method. The OKT4/OKT8 ratio was also calculated. Data were analyzed by chronograms (mean +/- 1SD) and by cosinor method. Results show a significant circadian rhythm for each lymphocyte subset and for serum cortisol levels. The lowest levels of all circulating subsets were seen between noon and 4.00 p.m. and the highest levels around midnight, inversely related with the circadian rhythm of serum cortisol. The OKT4/OKT8 ratio, on the contrary, was relatively constant during the day, without a significant circadian rhythm. These observations have laboratoristic, clinical, and therapeutic implications and should be considered in the course of immunological studies.

  4. Normal lymphocyte immunophenotype in an elderly population

    Directory of Open Access Journals (Sweden)

    Sâmia Macedo Queiroz Mota Castellão Tavares

    2014-06-01

    Full Text Available OBJECTIVE: The aim of this work was to evaluate the lymphocyte immunophenotype in an elderly population.METHODS: This study enrolled 35 over 60-year-old volunteers and a control group composed of 35 young adults. The study included elderly without diseases that might affect the functioning of the immune system. These individuals were consulted by doctors and after a physical examination, laboratory tests were performed using a Beckman Coulter (r flow cytometer. The GraphPad Prism computer program was employed for statistical analysis with the level of significance being set for p-values <0.05.RESULTS: There is a statistically significant reduction in the number of lymphocytes (CD8 +, CD2 + and CD3 + cells in the elderly compared to young adults. These low rates are explained by changes attributed to aging and may be partly responsible for the reduction in the cellular immune response, lower proliferative activity and the low cytotoxicity of lymphocytes.CONCLUSION: These parameters showed greater impairment of adaptive immunity in the elderly population and can therefore explain the greater fragility of the aged body to developing diseases.

  5. Sudden unexpected death associated with lymphocytic thyroiditis.

    Science.gov (United States)

    Vestergaard, Vibeke; Drostrup, Dorthe Høj; Thomsen, Jørgen L

    2007-04-01

    A forensic autopsy study comprising 125 cases was carried out retrospectively in order to evaluate pathological changes in the thyroid gland in different groups of death. The five groups selected consecutively were: (i) opiate addicts who died from an overdose, (ii) alcoholics who died as a result of their alcohol abuse, (iii) cases of fatal poisoning other than opiate addicts, (iv) unknown cause of death and (v) controls without prior disease. Tissue samples from the thyroid gland were cut and stained with haematoxylin and eosin and van Gieson. Histology examinations were subsequently performed blind with semiquantitative assessment of the following six parameters: (a) height of the follicular epithelium, (b) the amount of lymphocytes, (c) the presence of plasma cells, (d) hyperplastic follicular changes, (e) oxyphilic changes, and (f) fibrosis. The most striking result was the finding of extensive lymphocytic infiltration of the thyroid parenchyma in five of the 124 cases, of which four belonged in the group of 'unknown cause of death'. This discovery leads to reflections regarding lymphocytic thyroiditis as a cause of death, either by itself or in combination with other disorders. Silent (painless) thyroiditis, especially, is easily overlooked at autopsy as there are no macroscopic changes and often no prior symptoms or history of thyroid disease pointing towards this condition. Analyses of thyroid hormones are unreliable in predicting endocrine status in life. Routine microscopy of the thyroid gland is therefore advocated in cases of sudden unexpected death in order to diagnose thyroid disease, in particular silent (painless) thyroiditis.

  6. Two structurally identical mannose-specific jacalin-related lectins display different effects on human T lymphocyte activation and cell death.

    Science.gov (United States)

    Benoist, Hervé; Culerrier, Raphaël; Poiroux, Guillaume; Ségui, Bruno; Jauneau, Alain; Van Damme, Els J M; Peumans, Willy J; Barre, Annick; Rougé, Pierre

    2009-07-01

    Plant lectins displaying similar single sugar-binding specificity and identical molecular structure might present various biological effects. To explore this possibility, the effects on human lymphocytes of two mannose-specific and structurally closely related lectins, Morniga M from Morus nigra and artocarpin from Artocarpus integrifolia were investigated. In silico analysis revealed that Morniga M presents a more largely open carbohydrate-binding cavity than artocarpin, probably allowing interactions with a broader spectrum of carbohydrate moieties. In vitro, Morniga M interacted strongly with the lymphocyte surface and was uptaken quickly by cells. Morniga M and artocarpin triggered the proliferation and activation of human T and NK lymphocytes. A minority of B lymphocytes was activated in artocarpin-treated culture, whereas Morniga M favored the emergence of CD4+ CD8+ T lymphocytes. Moreover, cell death occurred in activated PBMC, activated T lymphocytes, and Jurkat T leukemia cells incubated with Morniga M only. The biological effects of both lectins were dependent on carbohydrate recognition. The Morniga M-induced cell death resulted, at least in part, from caspase-dependent apoptosis and FADD-dependent receptor-mediated cell death. Finally, Morniga M, but not artocarpin, triggered AICD of T lymphocytes. In conclusion, both lectins trigger lymphocyte activation, but only Morniga M induces cell death. In spite of similar in vitro mannose-binding specificities and virtually identical structure, only Morniga M probably interacts with carbohydrate moieties bound to molecules able to induce cell death. The present data suggest that subtle alterations in N-glycans can distinguish activation and cell death molecules at the lymphocyte surface.

  7. Induction of injury to endothelium of pulmonary artery due to entero-superantigen by up-regulation of lymphocyte chemokine receptor 5%T淋巴细胞趋化因子受体5表达上调介导了肠毒素超抗原对肺动脉内皮的损伤

    Institute of Scientific and Technical Information of China (English)

    吴礼襄; 萧正伦; 孔天翰

    2011-01-01

    pulmonary artery endothelial cell (HPAEC) and explore its possible mechanism. Methods HPAEC was cocultured with SEB-activated T cells supernatant, and the secretion of chemotactic factors from HPAEC was examined. The Transwell inserts was used in chemoattraction assays. After HPAECs were cocultured with T cells and 10 ng/ml SEB for 3 days, HPAEC damage was monitored by microscopy and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Results Three kinds of tested chemokines showed a time-dependent increase in all supernatant of HPAEC incubated with different concentrations of T cells. After 72 hours, the monocyte chemoattractant protein-1 (MCP-1,ng/ml) in 1 × 10-2, 1 × 10-1 , 1× 100 T cell supernatant groups was 1. 240± 0. 103, 4. 200± 0. 305, 6. 500±0. 500, respectively, macrophage inflammatory protein-1a (MIP-1α, ng/ml) was 0. 210 ± 0. 015, 0. 287 ±0. 012, 0. 531 ± 0. 037, respectively, and Rantes (ng/ml) was 1. 420 ± 0. 074, 7. 634 ± 0. 630, 15. 700 ±1. 300, respectively. Rantes presented a two-phase secretion mode : in early 6 hours it increased swiftly, but relatively slow at 12, 24, 48, 72 hours. T cell adherent to polycarbonate membrane increased after SEB stimulation in superantigen group compared with control group without SEB stimulation (86. 38± 14. 50 vs.16. 50± 2. 50, P< 0. 01 ). When 10 ng/ml SEB activated T cell was cocultured with HPAEC, more of originally suspended cultured T cells adhered to HPAEC monolayer [(15. 50±1.08)% vs. (1.60±0. 22)%,P<0.01], whereas the cell adhesion ratio decreased markedly in 1 μg/ml Met-Rantes group [(4. 39±0. 66)%, P < 0. 01 ). FACs test of HPAEC-adherent T cell showed lymphocyte chemokine receptor 5 (CCR5)/CD4 and CCR5/CD8 increased over 2. 5 folds and 2.8 folds compared with 100 ng/ml SEB activated T cell. Cell death rate of HPAEC was increased when cocultured with SEB-activated T cell in superantigen group compared with HPAEC normal incubation group [(32. 50±4

  8. Transfer of cholesterol from macrophages to lymphocytes in culture.

    Science.gov (United States)

    de Bittencourt Júnior, P I; Curi, R

    1998-02-01

    A major feature of macrophage metabolism is its capacity to produce and export cholesterol. Several reports have shown that the manipulation of lymphocyte cholesterol content elicits important changes in lymphocyte proliferation. These findings lead to an inquiry as to whether macrophage-derived cholesterol released into the lymphocyte surroundings may be transferred to the latter thus affecting lymphocyte function. In this study, cholesterol transfer from macrophages to lymphocytes was examined in vitro using rat cells in culture. The findings indicate that there may be a significant transfer of cholesterol from [4-14C]cholesterol labeled resident peritoneal macrophages to mesenteric lymph node resting lymphocytes (up to 173.9 +/- 2.7 pmol/10(7) lymphocytes/10(7) macrophages when co-cultivated for 48 h), in a lipoprotein-dependent manner. This represents the mass transfer of ca. 17 nmoles of cholesterol molecules per 10(7) lymphocytes from 10(7) macrophages (calculated on the basis of specific radioactivity incorporated into macrophages after the pre-labelling period), which suggests that macrophages are capable of replacing the whole lymphocyte cholesterol pool every 21 h. Moreover, an 111%-increase in the total cholesterol content of lymphocytes was found after co-cultivation with macrophages for 48 h. When compared to peritoneal cells, monocytes/macrophages obtained from circulating blood leukocytes presented a much higher cholesterol transfer capacity to lymphocytes (3.06 +/- 0.10 nmol/10(7) lymphocytes/10(7) macrophages co-cultivated for 24 h). Interestingly, inflammatory macrophages dramatically reduced their cholesterol transfer ability (by up to 91%, as compared to resident macrophages). Cholesterol transfer may involve a humoral influence, since it is not only observed when cells are co-cultivated in a single-well chamber system (cells in direct contact), but also in a two-compartment system (where cells can communicate but not by direct contact). Co

  9. Alteration of peripheral blood lymphocyte subsets in acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Miroslawa Pietruczuk; Milena I Dabrowska; Urszula Wereszczynska-Siemiatkowska; Andrzej Dabrowski

    2006-01-01

    AIM: To evaluate peripheral blood lymphocyte subsets in patients with acute pancreatitis (AP).METHODS: Twenty patients with mild AP (M-AP) and 15 with severe AP (S-AP) were included in our study. Peripheral blood lymphocytes were examined at d 1-3, 5,10 and 30 by means of flow cytometry.RESULTS: A significant depletion of circulating lymphocytes was found in AP. In the early AP, the magnitude of depletion was similar for T- and B- lymphocytes. In the late course of S-AP, B-lymphocytes were much more depleted than T-lymphocytes. At d 10, strong shift in the CD7+/CD19+ ratio implicating predominance of Tover B-lymphocytes in S-AP was found. Among T-lymphocytes, the significant depletion of the CD4+ population was observed in M-AP and S-AP, while CD8+ cells were in the normal range. Lymphocytes were found to strongly express activation markers: CD69, CD25, CD28,CD38 and CD122. Serum interleukin-2 (IL-2), IL-4, IL-5,IL-10, interferon-γ (IFN-γ) and tumor necrosis factor-α(TNF-α) levels were significantly increased in both forms of AP. The magnitude of elevation of cytokines known to be produced by Th2 was much higher than cytokines produced by Th1 cells.CONCLUSION: AP in humans is characterized by significant reduction of peripheral blood T- and B-lymphocytes.

  10. The role of apoptosis in the development and function of T lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Nu ZHANG; Heather HARTIG; Ivan DZHAGALOV; David DRAPER; You Wen HE

    2005-01-01

    Apoptosis plays an essential role in T cell biology. Thymocytes expressing nonfunctional or autoreactive TCRs are eliminated by apoptosis during development. Apoptosis also leads to the deletion of expanded effector T cells during immune responses. The dysregulation of apoptosis in the immune system results in autoimmunity, tumorogenesis and immunodeficiency. Two major pathways lead to apoptosis: the intrinsic cell death pathway controlled by Bcl-2 family members and the extrinsic cell death pathway controlled by death receptor signaling. These two pathways work together to regulate T lymphocyte development and function.

  11. C1-esterase inhibitor blocks T lymphocyte proliferation and cytotoxic T lymphocyte generation in vitro

    DEFF Research Database (Denmark)

    Nissen, Mogens Holst; Bregenholt, S; Nording, J A

    1998-01-01

    We have previously shown that activated C1s complement and activated T cells cleave beta2-microglobulin (beta2m) in vitro leading to the formation of desLys58 beta2m. This process can specifically be inhibited by C1-esterase inhibitor (C1-inh). Furthermore we showed that exogenously added desLys58...... beta2m in nanomolar amounts to a one-way allogenic mixed lymphocyte culture (MLC) increased the endogenous production of IL-2 and the generation of allo-specific cytotoxic T lymphocytes. C1-inh was purified from fresh human plasma and added to human or murine MLC and mitogen-stimulated lymphocyte...... of allospecific cytotoxic activity, and changed the endogenous production of IL-2, IL-4, IL-10, IL-12 and IFN-gamma. These data clearly demonstrate a regulatory function of C1-inh on T cell-mediated immune functions....

  12. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Barrientos, Jacqueline C

    2016-09-01

    Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma.

  13. GABAA receptor plasticity in Jurkat T cells.

    Science.gov (United States)

    Dionisio, Leonardo; Arias, Verónica; Bouzat, Cecilia; Esandi, María del Carmen

    2013-12-01

    GABAA receptors (GABAAR) mediate inhibitory neurotransmission in the human brain. Neurons modify subunit expression, cellular distribution and function of GABAAR in response to different stimuli, a process named plasticity. Human lymphocytes have a functional neuronal-like GABAergic system with GABAAR acting as inhibitors of proliferation. We here explore if receptor plasticity occurs in lymphocytes. To this end, we analyzed human T lymphocyte Jurkat cells exposed to different physiological stimuli shown to mediate plasticity in neurons: GABA, progesterone and insulin. The exposure to 100 μM GABA differently affected the expression of GABAAR subunits measured at both the mRNA and protein level, showing an increase of α1, β3, and γ2 subunits but no changes in δ subunit. Exposure of Jurkat cells to different stimuli produced different changes in subunit expression: 0.1 μM progesterone decreased δ and 0.5 μM insulin increased β3 subunits. To identify the mechanisms underlying plasticity, we evaluated the Akt pathway, which is involved in the phosphorylation of β subunits and receptor translocation to the membrane. A significant increase of phosphorylated Akt and on the expression of β3 subunit in membrane occurred in cells exposed 15 h to GABA. To determine if plastic changes are translated into functional changes, we performed whole cell recordings. After 15 h GABA-exposure, a significantly higher percentage of cells responded to GABA application when compared to 0 and 40 h exposure, thus indicating that the detected plastic changes may have a role in GABA-modulated lymphocyte function. Our results reveal that lymphocyte GABAAR are modified by different stimuli similarly and by similar mechanisms to those in neurons. This property is of significance for the development of future therapies involving pharmacological modulation of the immune response. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  14. TACI Expression and Signaling in Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Mamara, Antigoni; Germenis, Anastasios E.; Kompoti, Maria; Palassopoulou, Maria; Mandala, Eudokia; Banti, Anastasia; Giannakoulas, Nikolaos

    2015-01-01

    TACI is a membrane receptor of BAFF and APRIL, contributing to the differentiation and survival of normal B cells. Although malignant B cells are also subjected on TACI signaling, there is a remarkable intradisease and interindividual variability of TACI expression in B-cell malignancies. The aim of our study was to explore the possible role of TACI signaling in the biology of chronic lymphocytic leukemia (CLL), including its phenotypic and clinical characteristics and prognosis. Ninety-four patients and 19 healthy controls were studied. CLL patients exhibited variable TACI expression, with the majority of cases displaying low to undetectable TACI, along with low to undetectable BAFF and increased APRIL serum levels compared to healthy controls. CLL cells with high TACI expression displayed a better survival capacity in vitro, when cultured with BAFF and/or APRIL. Moreover, TACI expression was positively correlated with the presence of monoclonal gammopathy and inversely with CD11c expression. Therefore, our study provides further evidence for the contribution of BAFF/APRIL signaling to CLL biology, suggesting also that TACI detection might be useful in the selection of patients for novel targeting therapeutic approaches. PMID:25950010

  15. TACI Expression and Signaling in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Antigoni Mamara

    2015-01-01

    Full Text Available TACI is a membrane receptor of BAFF and APRIL, contributing to the differentiation and survival of normal B cells. Although malignant B cells are also subjected on TACI signaling, there is a remarkable intradisease and interindividual variability of TACI expression in B-cell malignancies. The aim of our study was to explore the possible role of TACI signaling in the biology of chronic lymphocytic leukemia (CLL, including its phenotypic and clinical characteristics and prognosis. Ninety-four patients and 19 healthy controls were studied. CLL patients exhibited variable TACI expression, with the majority of cases displaying low to undetectable TACI, along with low to undetectable BAFF and increased APRIL serum levels compared to healthy controls. CLL cells with high TACI expression displayed a better survival capacity in vitro, when cultured with BAFF and/or APRIL. Moreover, TACI expression was positively correlated with the presence of monoclonal gammopathy and inversely with CD11c expression. Therefore, our study provides further evidence for the contribution of BAFF/APRIL signaling to CLL biology, suggesting also that TACI detection might be useful in the selection of patients for novel targeting therapeutic approaches.

  16. Venetoclax for the treatment of chronic lymphocytic leukemia.

    Science.gov (United States)

    Gentile, Massimo; Petrungaro, Annamaria; Uccello, Giuseppina; Vigna, Ernesto; Recchia, Anna Grazia; Caruso, Nadia; Bossio, Sabrina; De Stefano, Laura; Palummo, Angela; Storino, Francesca; Martino, Massimo; Morabito, Fortunato

    2017-10-03

    Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.

  17. Hormone (ACTH, T3) content of immunophenotyped lymphocyte subpopulations.

    Science.gov (United States)

    Pállinger, Éva; Kiss, Gergely Attila; Csaba, György

    2016-12-01

    Cells of the immune system synthesize, store, and secrete polypeptide and amino acid type hormones, which also influence their functions, having receptors for different hormones. In the present experiment immunophenotyped immune cells isolated from bone marrow, thymus, and peritoneal fluid of mice were used for demonstrating the adrenocorticotropic hormone (ACTH) and triiodothyronine (T3) hormone production of differentiating immune cells. Both hormones were found in each cell type, and in each maturation state, which means that all cells are participating in the hormonal function of the immune system. The lineage-independent presence of ACTH and T3 in differentiating hematopoietic cells denotes that their expression ubiquitous during lymphocyte development. Higher ACTH and T3 content of B cells shows that these cells are the most hormonally active and suggests that the hormones may have an autocrine regulatory role in B cell development. Developing T cells showed heterogeneous hormone production which was associated with their maturation state. Differences in the hormone contents of immune cells isolated from different organs indicate that their hormone production is defined by their differentiation or maturation state, however, possibly also by the local microenvironment.

  18. Antiviral Effect of Interferon Lambda Against Lymphocytic Choriomeningitis Virus.

    Science.gov (United States)

    Lukacikova, Lubomira; Oveckova, Ingrid; Betakova, Tatiana; Laposova, Katarina; Polcicova, Katarina; Pastorekova, Silvia; Pastorek, Jaromir; Tomaskova, Jana

    2015-07-01

    Lambda interferons inhibit replication of many viruses, but their role in the inhibition of lymphocytic choriomeningitis virus (LCMV) infection remains unclear. In this study, we examined the antiviral effects of interferon (IFN)-λ2 and IFN-λ3 against LCMV in A549 cells. We found that IFN-λ2 is a more potent inhibitor of LCMV strain MX compared with IFN-λ3, whereas both cytokines have similar antiviral effects against an immunosuppressive variant of LCMV, clone-13. We also demonstrated that the antiviral activity of IFN-λ2 is more effective if it is delivered early rather than after establishment of a long-term infection, suggesting that virus replication is only partially responsive to the cytokine. In agreement with this observation, we showed that LCMV infection significantly reduces IFNLR1 mRNA expression in infected cells. In addition, LCMV infection, to some extent, compromises the signal transduction pathway of IFN-λ2. This implies that IFN receptors as well as their downstream signaling components could be selectively targeted either directly by LCMV proteins or indirectly by cellular factor(s) that are induced or activated by LCMV infection.

  19. Chronic lymphocytic leukemia: a clinical review including Korean cohorts

    Science.gov (United States)

    Jeon, Young-Woo; Cho, Seok-Goo

    2016-01-01

    Only 5th decade ago, chronic lymphocytic leukemia (CLL) was only recognized as disease group of presenting features like peripheral lymphocytosis, organomegaly including of splenomegaly. As understanding of disease biology and molecular diagnostic tools are getting improved gradually, characterization of variation in CLL’s clinical courses was facilitated, resulting in better risk stratification and targeted treatments. Consequently multiple new targeted agents have been used in treatment of CLL, it makes improved clinical outcome. Rituximab containing chemoimmunotherapy (combination of rituximab, fludarabine, and cyclophosphamide) have shown better overall response rate and progression-free survival on fit patients’ group in front-line setting, result in standard first-line therapeutic option for CLL. Furthermore, after introducing that the B-cell receptor is crucial for the evolution and progression of CLL, emerging treatments targeting highly activated surface antigens and oncogenic signaling pathways have been associated with several successes in recent decades. These include new anti-CD 20 monoclonal antibody (obinutuzumab), the bruton tyrosine kinase inhibitor (ibrutinib), the phosphatidylinositol 3-kinase inhibitor (idelalisib), and B-cell CLL/lymphoma 2 inhibitor (ABT-199 and ABT-263). So, we discuss not only general pathophysiology of CLL, but also rapidly advancing treatment strategies that are being studied or approved for treatment of CLL. PMID:27044858

  20. Large granular lymphocyte leukemia: natural history and response to treatment.

    LENUS (Irish Health Repository)

    Fortune, Anne F

    2012-02-01

    Large granular lymphocyte leukemia (T-LGL) is an indolent T lymphoproliferative disorder that was difficult to diagnose with certainty until clonality testing of the T cell receptor gene became routinely available. We studied the natural history and response to treatment in 25 consecutive patients with T-LGL diagnosed between 2004 and 2008 in which the diagnosis was confirmed by molecular analysis, to define an effective treatment algorithm. The median age at diagnosis was 61 years (range 27-78), with a male to female ratio of 1:1.8 and presenting features of fatigue (n = 13), recurrent infections (n = 9), and\\/or abnormal blood counts (n = 5). Thirteen patients with symptomatic disease were treated as follows: pentostatin (nine patients), cyclosporine (six patients), methotrexate (three patients), and alemtuzumab in two patients in whom pentostatin was ineffective. Pentostatin was the single most effective therapy, with a response rate of 75% and minimal toxicity. The overall survival (OS) and progression-free survival (PFS) 37 months from diagnosis were 80% and 52%, respectively. Treatment of T-LGL should be reserved for patients with symptomatic disease, but in this series, pentostatin treatment was less toxic and more effective than cyclosporine or methotrexate.

  1. Suppressive effects of antigens on the activity of specific activated lymphocytes: A test to define the specificity of activated lymphocytes

    Institute of Scientific and Technical Information of China (English)

    HU Jun; PAN Sheng-jun; CAI Zhen-jie; GUAN De-lin; LIU Xiao-cheng

    2006-01-01

    Objective:With the regular mixed lymphocytes culture (MLC) to detect the allograft rejection, the reactivity of the activated lymphocytes (primed lymphocytes) of a recipient shows sometimes increase and sometimes decrease against the antigens from the donor, which is inconsistent with the clinical results. In order to establish a convenient method for testing the specificity of the activated lymphocytes in vitro, so as to know the rejection occurred or not by testing the existence of the specific activated lymphocytes against donor's HLA antigens in the recipient's peripheral blood. Methods: Anti-IL-2 neutralizing monoclonal antibody (anti-IL-2 N-mAb) and immunosuppressors were introduced in this test system in the presence of specific stimulators and activated lymphocytes. Results: When the activated lymphocytes were chosen from the one-way MLC 4 d to undergo re-stimulation by specific stimulators, the activity of activated lymphocytes in the treatment group was suppressed significantly compared with that in the control group. The result of this test method is consistent with the biopsy in the clinical diagnosis of rejection.Conclusion :It suggests that the activated lymphocytes can be inactivated by specific antigens in certain conditions. This can be a useful tool to define the specificity of the activated lymphocytes.

  2. Lipid raft-dependent plasma membrane repair interferes with the activation of B lymphocytes.

    Science.gov (United States)

    Miller, Heather; Castro-Gomes, Thiago; Corrotte, Matthias; Tam, Christina; Maugel, Timothy K; Andrews, Norma W; Song, Wenxia

    2015-12-21

    Cells rapidly repair plasma membrane (PM) damage by a process requiring Ca(2+)-dependent lysosome exocytosis. Acid sphingomyelinase (ASM) released from lysosomes induces endocytosis of injured membrane through caveolae, membrane invaginations from lipid rafts. How B lymphocytes, lacking any known form of caveolin, repair membrane injury is unknown. Here we show that B lymphocytes repair PM wounds in a Ca(2+)-dependent manner. Wounding induces lysosome exocytosis and endocytosis of dextran and the raft-binding cholera toxin subunit B (CTB). Resealing is reduced by ASM inhibitors and ASM deficiency and enhanced or restored by extracellular exposure to sphingomyelinase. B cell activation via B cell receptors (BCRs), a process requiring lipid rafts, interferes with PM repair. Conversely, wounding inhibits BCR signaling and internalization by disrupting BCR-lipid raft coclustering and by inducing the endocytosis of raft-bound CTB separately from BCR into tubular invaginations. Thus, PM repair and B cell activation interfere with one another because of competition for lipid rafts, revealing how frequent membrane injury and repair can impair B lymphocyte-mediated immune responses.

  3. T and B lymphocytes in the marmoset: a natural haemopoietic chimera

    Energy Technology Data Exchange (ETDEWEB)

    Niblack, G.D.; Gengozian, N.

    1976-01-01

    The thymus-derived (T) lymphocyte and bone marrow-derived (B) lymphocyte populations of the marmoset were characterized using specific cell surface markers. Approximately 85% of the thymocytes formed rosettes with neuraminidase-treated sheep erythrocytes (E/sub n/). The percentage (approximately 69%) of peripheral blood lymphocytes (PBL) forming rosettes with E/sub n/ was the same as that which stained with fluorescently labelled goat anti-marmoset thymocyte serum (ATS). These two assays identified the same cell population since treatment of cells with ATS and complement resulted in a concomitant decrease in E/sub n/ rosette formation. Marmoset PBL also formed rosettes with human erythrocytes sensitized with antibody and complement (HEAC); since the percentage (approximately 20%) HEAC rosette was the same as that of cells stained with fluorescently labelled goat anti-marmoset IgG, these cells were considered to be B cells. A small percentage of cells (aproximately 1.5%) possessed both types of receptors. The mean percentages of T and B cells present in PBL of single-born, presumably non-chimeric animals, were the same as that of isosexual and heterosexual chimeras.

  4. Atypical aleukemic presentation of large granular lymphocytic leukemia: a case report

    Directory of Open Access Journals (Sweden)

    Bagacean C

    2016-12-01

    Full Text Available Cristina Bagacean,1,2 Adrian Tempescul,3 Mariana Patiu,1,4 Bogdan Fetica,4 Horia Bumbea,5,* Mihnea Zdrenghea1,4,* 1Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Laboratory of Immunology and Immunotherapy, University Hospital Brest, 3Department of Hematology, Institute of Cancerology and Hematology, Brest University Medical School, Brest, France; 4Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, 5Department of Hematology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania *These authors contributed equally to this work Abstract: Large granular lymphocytic leukemia (LGLL is a rare lymphoproliferative disorder of transformed natural killer or T-cells attributed to chronic exposure to the proinflammatory cytokine IL-15. Diagnosis of the majority of T-cell LGLL is established by documenting clonal large granular lymphocytes (LGLs in peripheral blood, by morphology and immunophenotype. The proteasome inhibitor bortezomib is known to target molecular pathways downstream of the IL-15 receptor signaling and has been proposed as a therapy in these patients. We report an uncommon presentation of LGLL with chronic neutropenia lacking typical blood LGLs, which failed to respond to bortezomib but obtained a very good partial remission with a classical methotrexate regimen. Keywords: large granular lymphocytes, lymphoproliferative, Felty, neutropenia, bortezomib

  5. Biopsy variability of lymphocytic infiltration in breast cancer subtypes and the ImmunoSkew score

    Science.gov (United States)

    Khan, Adnan Mujahid; Yuan, Yinyin

    2016-11-01

    The number of tumour biopsies required for a good representation of tumours has been controversial. An important factor to consider is intra-tumour heterogeneity, which can vary among cancer types and subtypes. Immune cells in particular often display complex infiltrative patterns, however, there is a lack of quantitative understanding of the spatial heterogeneity of immune cells and how this fundamental biological nature of human tumours influences biopsy variability and treatment resistance. We systematically investigate biopsy variability for the lymphocytic infiltrate in 998 breast tumours using a novel virtual biopsy method. Across all breast cancers, we observe a nonlinear increase in concordance between the biopsy and whole-tumour score of lymphocytic infiltrate with increasing number of biopsies, yet little improvement is gained with more than four biopsies. Interestingly, biopsy variability of lymphocytic infiltrate differs considerably among breast cancer subtypes, with the human epidermal growth factor receptor 2-positive (HER2+) subtype having the highest variability. We subsequently identify a quantitative measure of spatial variability that predicts disease-specific survival in HER2+ subtype independent of standard clinical variables (node status, tumour size and grade). Our study demonstrates how systematic methods provide new insights that can influence future study design based on a quantitative knowledge of tumour heterogeneity.

  6. Aryl hydrocarbon mono-oxygenase activity in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Griffin, G.D.; Schuresko, D.D.

    1981-06-01

    Aryl hydrocarbon mono-oxygenase (AHM), an enzyme of key importance in metabolism of xenobiotic chemicals such as polynuclear aromatic hydrocarbons (PNA), is present in human lymphocytes. Studies investing the relation of activity of AHM in human lymphocytes to parameters such as disease state, PNA exposure, in vitro mitogen stimulation, etc. have been summarized in this report. Some studies have demonstrated increased AHM activity in lymphocytes from cigarette smokers (compared to nonsmokers), and in lung cancer patients when compared to appropriate control groups. These observations are confused by extreme variability in human lymphocyte AHM activities, such variability arising from factors such as genetic variation in AHM activity, variation in in vitro culture conditions which affect AHM activity, and the problematical relationship of common AHM assays to actual PNA metabolism taking place in lymphocytes. If some of the foregoing problems can be adequately addressed, lymphocyte AHM activity could hold the promise of being a useful biomarker system for human PNA exposure.

  7. The association between chronic lymphocytic thyroiditis and thyroid tumors.

    Science.gov (United States)

    Tamimi, Dalal M

    2002-04-01

    An association between lymphocytic thyroiditis and thyroid papillary carcinoma is still controversial. To assess the relationship, a histopathologic analysis of surgically resected thyroid tumors together with the frequency and severity of chronic lymphocytic infiltration of the thyroid among patients with follicular adenoma, follicular carcinoma, and papillary carcinoma was performed. The prevalence of lymphocytic infiltrate, which is indicative of autoimmune thyroiditis, was significantly higher in patients with papillary carcinoma (58%) than in patients with follicular carcinoma (20%) or follicular adenoma (14%). The lymphocytic infiltration within the tumor compared with the severity of thyroiditis in the nontumorous tissue. Therefore, the association between chronic lymphocytic thyroiditis and papillary carcinoma was confirmed. The possibility that an immunologic mechanism involved in the pathogenesis of papillary carcinoma stimulates lymphocytic infiltration in the thyroid tissue through an autoimmune mechanism is suggested.

  8. Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes.

    Science.gov (United States)

    Labenski, Verena; Suerth, Julia D; Barczak, Elke; Heckl, Dirk; Levy, Camille; Bernadin, Ornellie; Charpentier, Emmanuelle; Williams, David A; Fehse, Boris; Verhoeyen, Els; Schambach, Axel

    2016-08-01

    Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non-self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated proviruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering.

  9. Inability of a Fusion Protein of IL-2 and Diphtheria Toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to Eliminate Regulatory T Lymphocytes in Patients With Melanoma

    Science.gov (United States)

    Attia, Peter; Maker, Ajay V.; Haworth, Leah R.; Rogers-Freezer, Linda; Rosenberg, Steven A.

    2006-01-01

    Summary Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration–approved doses of Denileukin Diftitox (seven patients at 9 μg/kg, six patients at 18 μg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 μg/kg (−2.01 ± 0.618 copies of Foxp3/103 copies of β-actin; P = 0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4+CD25+ cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma. PMID:16224276

  10. Chronic lymphocytic leukemia: case-based session.

    Science.gov (United States)

    Rai, K R; Döhner, H; Keating, M J; Montserrat, E

    2001-01-01

    Drs. Hartmut Döhner, Michael J. Keating, Kanti R. Rai and Emili Montserrat form the panel to review chronic lymphocytic leukemia (CLL) while focusing on the clinical features of a particular patient. The pace of progress in CLL has accelerated in the past decade. The pathophysiological nature of this disease, as had been known in the past, was based largely on the intuitive and empiric notions of two leaders in hematology, William Dameshek and David Galton. Now the works of a new generation of leaders are providing us with the scientific explanations of why CLL is a heterogeneous disease, perhaps consisting of at least two separate entities. In one form of CLL, the leukemic lymphocytes have a surface immunoglobulin (Ig) variable region gene that has undergone somatic mutations, with tell-tale markers suggesting that these cells had previously traversed the germinal centers. Such patients have a distinctly superior prognosis than their counterparts whose leukemic lymphocytes IgV genes have no mutations (these are indeed immunologically naive cells), who have a worse prognosis. The introduction of fluorescence in situ hybridization (FISH) technique has provided us with new insights into the diverse chromosomal abnormalities that can occur in CLL, and which have significant impact on the clinical behavior and prognosis of patients with this disease. Major advances in therapeutics of CLL also have occurred during the past decade. Two monoclonal antibodies, Campath-1H (anti-CD52) and rituximab (anti-CD20), and one nucleoside analogue, fludarabine, have emerged as three agents of most promise in the front-line treatment of this disease. Studies currently in progress reflect our attempts to find the most effective manner of combining these agents to improve the overall survival statistics for CLL patients. As in many other hematological malignancies, high dose chemotherapy followed by autologous or HLA-compatible allogeneic stem cells rescue strategies are under study as

  11. Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

    Science.gov (United States)

    2017-10-05

    B-Cell Chronic Lymphocytic Leukemia; Monoclonal B-Cell Lymphocytosis; Lymhoma, Small Lymphocytic; Chronic Lymphocytic Leukemia; Lymphoplasmacytic Lymphoma; Waldenstrom Macroglobulinemia; Splenic Marginal Zone Lymphoma

  12. Phenotypic and Functional Analysis of Porcine T Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    李华; 陈应华

    2001-01-01

    Porcine and other higher mammals express clusters of differentiation (CD) antigens on the surface of T lymphocytes, such as CD2, CD3, CD4, CD8, etc. However, in porcine, a high percentage of the CD4+ CD8-T lymphocyte subpopulation exist in the peripheral blood and the ratio of the CD4+ and CD8+ T lymphocyte subpopulations is reversed. These differences bring new challenges to better understanding of the phenotype and function of porcine T lymphocytes in antigen recognition and immune response.

  13. Chronic pain: cytokines, lymphocytes and chemokines.

    Science.gov (United States)

    de Miguel, Marcia; Kraychete, Durval Campos; Meyer Nascimento, Roberto Jose

    2014-01-01

    Chronic pain is a debilitating condition and, in most cases, difficult to treat. A prominent example of this is neuropathic pain. Understanding pathophysiological mechanisms of pain and, therefore, making this knowledge into an effective treatment is still a challenge to experts. Pain can now be considered as a neuro-immune disorder, since recent data indicate critical involvement of innate and adaptive immune responses following injury, and this interaction plays an important role in the onset and perpetuation of chronic pain. The aim of this article is to review the relationship between immune system and chronic pain, especially about neuropathic pain, and focusing on cytokines, chemokines and lymphocytes.

  14. Spinal epidural compression in chronic lymphocytic leukemia.

    Science.gov (United States)

    Michalevicz, R; Burstein, A; Razon, N; Reider, I; Ilie, B

    1989-11-01

    Spinal epidural compression is a rare neurologic complication in patients with lymphoma. It occurs mostly in those with intermediate-grade to high-grade malignancy disease. This type of neurologic involvement has not been described in chronic lymphocytic leukemia (CLL). A patient with a long, stable CLL course developed spinal epidural compression and consequently died. The frequency of spinal epidural compression in lymphoma, according to the histologic subtypes and the considerations in making the right choice of therapy are discussed in light of the presented case.

  15. HLA-DP related suppression of mixed lymphocyte reaction with alloactivated lymphocytes

    DEFF Research Database (Denmark)

    Ødum, Niels; Hofmann, B; Jakobsen, B K

    1986-01-01

    We studied the influence of HLA class I and class II antigens on the suppression of the MLR induced by primed lymphocytes (PLs) alloactivated in vitro. The suppression of 14 different PLs of 83 MLRs was analyzed. The PLs were primed against (i) HLA-DP (SB) (ii) HLA-DR/DQ or (iii) both HLA-DP and DR...

  16. Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma.

    Science.gov (United States)

    Alexander, Alan A Z; Maniar, Amudhan; Cummings, Jean-Saville; Hebbeler, Andrew M; Schulze, Dan H; Gastman, Brian R; Pauza, C David; Strome, Scott E; Chapoval, Andrei I

    2008-07-01

    The expression of CD56, a natural killer cell-associated molecule, on alphabeta T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of gammadelta T cells. However, antitumor effector functions of CD56(+) gammadelta T cells are poorly characterized. To investigate the potential effector role of CD56(+) gammadelta T cells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2-expanded gammadelta T cells from peripheral blood mononuclear cells of healthy donors. Thirty to 70% of expanded gammadelta T cells express CD56 on their surface. Interestingly, although both CD56(+) and CD56(-) gammadelta T cells express comparable levels of receptors involved in the regulation of gammadelta T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56(+) gammadelta T lymphocytes are capable of killing squamous cell carcinoma and other solid tumor cell lines. This effect is likely mediated by the enhanced release of cytolytic granules because CD56(+) gammadelta T lymphocytes expressed higher levels of CD107a compared with CD56(-) controls following exposure to tumor cell lines. Lysis of tumor cell lines is blocked by concanamycin A and a combination of anti-gammadelta T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56(+) gammadelta T cells involves the perforin-granzyme pathway and is mainly gammadelta T-cell receptor/NKG2D dependent. Importantly, CD56-expressing gammadelta T lymphocytes are resistant to Fas ligand and chemically induced apoptosis. Our data indicate that CD56(+) gammadelta T cells are potent antitumor effectors capable of killing squamous cell carcinoma and may play an important therapeutic role in patients with head and neck cancer and other malignancies.

  17. Benzene metabolites induce apoptosis in lymphocytes.

    Science.gov (United States)

    Martínez-Velázquez, M; Maldonado, V; Ortega, A; Meléndez-Zajgla, J; Albores, A

    2006-08-01

    Benzene is an important environmental pollutant with important health implications. Exposure to this aromatic hydrocarbon is associated with hematotoxicity, and bone marrow carcinogenic effects. It has been shown that benzene induces oxidative stress, cell cycle alterations, and programmed cell death in cultured cells. Hepatic metabolism of benzene is thought to be a prerequisite for its bone marrow toxicity. Nevertheless, there are no reports on the cellular effects of reactive intermediates derived from hepatic metabolism of benzene. Thus, the goal of this project was to determine the cellular alterations of benzene metabolites produced by the cultured hepatic cell line HepG2. Supernatants collected from these cells were applied to a culture of freshly isolated lymphocytes. A higher decrease in cell viability was found in cells exposed to these supernatants than to unmetabolized benzene. This viability decrease was due to apoptosis, as determined by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) assay and internucleosomal fragmentation of DNA. When supernatants were analyzed by HPLC, we found that not all the hydrocarbon was biotransformed, since a 28 microM concentration (37%) remained. The only metabolite found in the culture medium was muconic acid. The present results show that muconic acid derived from benzene metabolism is able to cooperate with the pollutant for the induction of apoptosis in rat lymphocytes.

  18. Spondylarthritis in the absence of B lymphocytes.

    Science.gov (United States)

    Baeten, Dominique; Kruithof, Elli; Breban, Maxime; Tak, Paul P

    2008-03-01

    The highly effective treatment of rheumatoid arthritis by B cell depletion and the presence of B cells in the peripheral and axial lesions of patients with spondylarthritis (SpA) raise the question as to whether B lymphocytes could also be an appropriate therapeutic target in the latter disease. We describe 2 male HLA-B27-positive patients who had active SpA despite absence of B cells. One patient developed SpA with sacroiliitis and asymmetric oligoarthritis after having been diagnosed as having severe Bruton agammaglobulinemia. Since extensive investigations excluded an infectious origin of the SpA, this case illustrates that functional B cells and/or gamma globulins are not strictly required for SpA pathogenesis. The second patient had severe axial and peripheral SpA that was treated successfully with etanercept. After discontinuation of etanercept treatment because of non-Hodgkin's B cell lymphoma, both axial and peripheral SpA symptoms relapsed rapidly, and this exacerbation of articular disease activity was not modulated by successful B cell depletion therapy for the lymphoma. Although case reports have obvious limitations, our clinical observations provide evidence that active SpA can occur in the absence of functional mature B cells and thus emphasize the need for systematic studies of the exact role and function of B lymphocytes in this disease.

  19. Secondary autoimmune cytopenias in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rogers, Kerry A; Woyach, Jennifer A

    2016-04-01

    Secondary autoimmune cytopenias in chronic lymphocytic leukemia are distinct clinical entities that require specific management. These autoimmune disorders have a complex pathogenesis that involves both the leukemic cells and the immune environment in which they exist. The mechanism is not the same in all cases, and to varying degrees involves the chronic lymphocytic leukemia (CLL) cells in antibody production, antigen presentation, and stimulation of T cells and bystander polyclonal B cells. Diagnosis of autoimmune cytopenias can be challenging as it is difficult to differentiate between autoimmunity and bone marrow failure due to disease progression. There is a need to distinguish these causes, as prognosis and treatment are not the same. Evidence regarding treatment of secondary autoimmune cytopenias is limited, but many effective options exist and treatment can be selected with severity of disease and patient factors in mind. With new agents to treat CLL coming into widespread clinical use, it will be important to understand how these will change the natural history and treatment of autoimmune cytopenias.

  20. Clonal heterogeneity of synovial fluid T lymphocytes from patients with rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Duby, A.D.; Sinclair, A.K.; Osborne-Lawrence, S.L. (Univ. of Texas Southwestern Medical Center, Dallas (USA)); Zeldes, W.; Kan, Li; Fox, D.A. (Univ. of Michigan, Ann Arbor (USA))

    1989-08-01

    Although substantial evidence suggests that synovial T lymphocytes are critical in the pathogenesis of rheumatoid arthritis (RA), little is known regarding their antigenic specificities, antigen receptor gene rearrangements, and mechanisms of activation. To assess the extend of expansion of specific clones among RA synovial fluid T cells, Southern blot analyses of T-cell receptor (TCR) gene rearrangements were performed on 40 RA synovial fluid T-cell clones, as well as on fresh and polyclonally activated T cells from RA synovial fluid, RA peripheral blood, and normal peripheral blood. Two of the clones had identical TCR rearrangement patterns, but the remainder were unique. The nonclonal RA T-cell samples showed the same pattern of TCR {beta}-chain rearrangement that was observed among normal peripheral blood T cells, indicating no dominant clonal T-cell population in these samples. It was noted that with sufficient exposure of autoradiograms of the Southern blots, discrete TCR gene rearrangements, representing in some cases common D{sub {beta}}J{sub {beta}} (D, diversity; J, joining) rearrangements, were evident in T cells from peripheral blood of normal individuals and patients with RA, as well as T cells from RA synovial fluid. Taken together, the findings indicate that only a minor degree of oligoclonality can be demonstrated among T lymphocytes from RA synovial fluid.

  1. Role of signaling pathways and miRNAs in chronic lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    LI Pei-pei; WANG Xin

    2013-01-01

    Objective To summarize the recent findings of dysregulation of signaling pathways and miRNAs in chronic lymphocytic leukemia (CLL).Data sources We searched PubMed database with the keywords "chronic lymphocytic leukemia","signal pathway",or "miRNA" for relevant articles in recent years.Study selection Research articles and reviews about signaling pathways and miRNAs in CLL were chosen for review.Results Dysregulation of signaling pathways,such as B cell receptor,toll-like receptor,PI3K,nuclear factor KB,notch signaling pathway,Wnt/Fzd signaling pathway,and Hedgehog and Janus kinases/signal transducers and activators of transcription signaling pathway,as the terminal events of the aberrant gene expression and the pro-survival effects of microenvironment,plays a crucial role in the process of CLL.miRNAs,a novel found noncoding RNA,which regulate gene expression at transcription or post-transcription level and correlate with pathogenesis of CLL provide us new avenues to better evaluating prognosis and therapy of it.Conclusion Further investigation of the dysregulation of signaling pathways and miRNAs and their relationship may provide us a new prospective to understand the pathogenesis of CLL and may provide us new strategies to resolve the clinical nodi in treatment of CLL.

  2. The immunodeficiency of bone marrow-transplanted patients. II. CD8-related suppression by patient lymphocytes of the response of donor lymphocytes to mitogens, antigens, and allogeneic cells

    DEFF Research Database (Denmark)

    Ødum, Niels; Hofmann, B; Jacobsen, N

    1987-01-01

    Lymphocytes from 21 patients sampled 1-6 months after bone marrow transplantation (BMT) were tested for functional suppressor activity against marrow-donor lymphocytes in the lymphocyte transformation test. Suppression of donor responses to allogeneic (i.e. mixed lymphocyte reaction, MLR...

  3. Carbon nanotube-mediated delivery of nucleic acids does not result in non-specific activation of B lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Cai Dong [Department of Biology, Boston College, Chestnut Hill, MA 02467 (United States); Doughty, Cheryl A [Department of Biology, Boston College, Chestnut Hill, MA 02467 (United States); Potocky, Terra B [Department of Biology, Boston College, Chestnut Hill, MA 02467 (United States); Dufort, Fay J [Department of Biology, Boston College, Chestnut Hill, MA 02467 (United States); Huang Zhongping [NanoLab, Incorporated, Newton, MA 02458 (United States); Blair, Derek [Department of Biology, Boston College, Chestnut Hill, MA 02467 (United States); Kempa, Krzysztof [Department of Physics, Boston College, Chestnut Hill, MA 02467 (United States); Ren, Z F [Department of Physics, Boston College, Chestnut Hill, MA 02467 (United States); Chiles, Thomas C [Department of Biology, Boston College, Chestnut Hill, MA 02467 (United States)

    2007-09-12

    The efficient delivery of genes and proteins into primary mammalian cells and tissues has represented a formidable challenge. Recent advances in the research of carbon nanotubes (CNTs) offer much promise for their use as delivery platforms into mammalian cells. Ideally, CNT-mediated applications should not result in cellular toxicity nor perturb cellular homeostasis (e.g., result in non-specific activation of primary cells). It is therefore critical to evaluate the impact of CNT exposure on the cellular metabolism, proliferation and survival of primary mammalian cells. We investigated the compatibility of a recently developed CNT-mediated delivery method, termed nanospearing, with primary ex vivo cultures of B lymphocytes. Several parameters were evaluated to assess the impact of CNTs on naive B lymphocytes, including cell survival, activation, proliferation and intracellular signal transduction. Our results indicate that nanospearing does not result in the activation of naive primary B lymphocytes nor alter survival in ex vivo cultures. Herein, B cells exposed to CNTs were capable of responding to extrinsic pro-survival signals such as interleukin-4 and signaling by the B-cell antigen receptor in a manner similar to that of B cells cultured in the absence of CNTs. Our study demonstrates the biocompatibility of the CNT-mediated nanospearing procedure with respect to primary B lymphocytes.

  4. EXPRESSION OF SURFACE MARKERS ON CD4+T-LYMPHOCYTES IN NORMAL PREGNANCY AND PRE-ECLAMPSIA

    Directory of Open Access Journals (Sweden)

    V. A. Mikhailova

    2012-01-01

    Full Text Available Abstract. In course of physiological pregnancy, peripheral blood CD4+T-lymphocytes normally migrate to the uterine decidual tissue. Hence, this study aimed to compare expression profiles of adhesion molecules and chemokine receptors on the surface of CD4+T-lymphocytes from peripheral blood in healthy pregnancy and in pre-eclampsia. The amounts of CD4+T-lymphocytes expressing CD184, CD119, CD192, CD197, β7 integrin, CD29, CD49d, CD11b were elevated in healthy pregnant women, as compared with non-pregnant women. The amounts of CD4+T-lymphocytes expressing CD49d, CD44, CD47, as well as intensity of CD47, CD29, CD49d, CD44, Integrin β7, CD54 expression proved to be decreased in cases of preeclampsia when compared with healthy pregnancy. This work was supported by grants ГК N 02.740.11.0711 from Russian Ministry of Education and Science, and Presidential grants НШ-3594.2010.7, МД-150.2011.7.

  5. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  6. Identification of putative human T cell receptor delta complementary DNA clones

    Energy Technology Data Exchange (ETDEWEB)

    Hata, S.; Brenner, M.B.; Krangel, M.S.

    1987-10-30

    A novel T cell receptor (TCR) subunit termed TCR delta, associated with TCY ..gamma.. and CD3 polypeptides, were recently found on a subpopulation of human T lymphocytes. T cell-specific complementary DNA clones present in a human TCR..gamma..delta T cell complementary DNA library were obtained and characterized in order to identify candidate clones encoding TCR delta. One cross-hybridizing group of clones detected transcripts that are expressed in lymphocytes bearing TCR ..gamma..delta but not in other T lymphocytes and are encoded by genes that are rearranged in TCR ..gamma..delta lymphocytes but deleted in other T lymphocytes. Their sequences indicate homology to the variable, joining, and constant elements of other TCR and immunoglobulin genes. These characteristics are strong evidence that the complementary DNA clones encode TCR delta.

  7. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2017-10-09

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  8. 9 CFR 113.42 - Detection of lymphocytic choriomeningitis contamination.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Detection of lymphocytic choriomeningitis contamination. 113.42 Section 113.42 Animals and Animal Products ANIMAL AND PLANT HEALTH... contamination. The test for detection of lymphocytic choriomeningitis (LCM) virus provided in this section...

  9. Lymphocytes and liver fibrosis in HIV & HCV coinfection

    NARCIS (Netherlands)

    Feuth, M.|info:eu-repo/dai/nl/371501547

    2014-01-01

    Coinfection with HIV has an important impact on immunity against hepatitis C virus (HCV). In the present dissertation, phenotypes of lymphocytes derived from the peripheral blood of HCV-infected patients were studied into detail, with special attention to changes in phenotype of lymphocytes associat

  10. Lymphocyte apoptosis in the pathogenesis of type 1 diabetes mellitus

    African Journals Online (AJOL)

    EL-HAKIM

    is an emerging evidence that T cell-induced apoptosis is a dominant effector mechanism ... Patients were subjected to clinical evaluation with special ... The percentage of CD95 on T-lymphocytes could not be ..... Correlation between CD3 lymphocytes and CD95 antigen .... control.36 On the other hand, Tchórzewski et al.1.

  11. Effect of praziquantel on human lymphocyte proliferation in vitro

    DEFF Research Database (Denmark)

    Odum, Niels; Theander, T G; Bygbjerg, I C

    1984-01-01

    The antischistosomal drugs tartar emetic and niridazole exert immunosuppression both in vitro and in vivo. In the present study the influence of praziquantel (Biltricide), a potent schistosomicidal drug, on human lymphocyte proliferation in vitro was investigated. Praziquantel 80 micrograms...... no suppressive effect on human lymphocyte proliferation in vitro....

  12. Carotenoid levels in human lymphocytes, measured by Raman microspectroscopy

    NARCIS (Netherlands)

    Ramanauskaite, R B; SegersNolten, IGMJ; DeGrauw, K J; Sijtsema, N M; VanderMaas, L; Greve, J; Otto, C; Figdor, C G

    1997-01-01

    Carotenoid levels in lymphocytes obtained from peripheral blood of healthy people have been investigated by Raman microspectroscopy. We observed that carotenoids are concentrated in so-called ''Gall bodies''. The level of carotenoids in living human lymphocytes was found to be age-dependent and to d

  13. T-lymphocyte subsets in recurrent aphthous ulceration

    DEFF Research Database (Denmark)

    Pedersen, A; Klausen, B; Hougen, H P;

    1989-01-01

    Peripheral T-lymphocyte subsets: T-helper (OKT4) and T-suppressor (OKT8) cells were studied quantitatively in 20 patients with recurrent aphthous ulceration (RAU) in ulcerative, as well as inactive, stages of the disease. The figures were compared with T-lymphocyte subsets from matched control do...

  14. Lymphocytes and liver fibrosis in HIV & HCV coinfection

    NARCIS (Netherlands)

    Feuth, M.

    2014-01-01

    Coinfection with HIV has an important impact on immunity against hepatitis C virus (HCV). In the present dissertation, phenotypes of lymphocytes derived from the peripheral blood of HCV-infected patients were studied into detail, with special attention to changes in phenotype of lymphocytes associat

  15. Lymphocytes as a neural probe : potential for studying psychiatric disorders

    NARCIS (Netherlands)

    Gladkevich, A; Kauffman, HF; Korf, J

    There is an increasing body evidence pointing to a close integration between the central nervous system (CNS) and immunological functions with lymphocytes playing therein a central role. The authors provide arguments to consider blood lymphocytes as a convenient probe of-an albeit-limited number of

  16. Endothelial PI 3-kinase activity regulates lymphocyte diapedesis.

    Science.gov (United States)

    Nakhaei-Nejad, Maryam; Hussain, Amer M; Zhang, Qiu-Xia; Murray, Allan G

    2007-12-01

    Lymphocyte recruitment to sites of inflammation involves a bidirectional series of cues between the endothelial cell (EC) and the leukocyte that culminate in lymphocyte migration into the tissue. Remodeling of the EC F-actin cytoskeleton has been observed after leukocyte adhesion, but the signals to the EC remain poorly defined. We studied the dependence of peripheral blood lymphocyte transendothelial migration (TEM) through an EC monolayer in vitro on EC phosphatidylinositol 3-kinase (PI 3-kinase) activity. Lymphocytes were perfused over cytokine-activated EC using a parallel-plate laminar flow chamber. Inhibition of EC PI 3-kinase activity using LY-294002 or wortmannin decreased lymphocyte TEM (48 +/- 6 or 34 +/- 7%, respectively, vs. control; mean +/- SE; P structure" after intercellular adhesion molecule-1 ligation, whereas this was inhibited by jasplakinolide treatment. A similar fraction of lymphocytes migrated on control or LY-294002-treated EC and localized to interendothelial junctions. However, lymphocytes failed to extend processes below the level of vascular endothelial (VE)-cadherin on LY-294002-treated EC. Together these observations indicate that EC PI 3-kinase activity and F-actin remodeling are required during lymphocyte diapedesis and identify a PI 3-kinase-dependent step following initial separation of the VE-cadherin barrier.

  17. Lymphocytes in patients with psoriasis promote proliferation of keratinocytes

    Institute of Scientific and Technical Information of China (English)

    DENG An-mei; ZHONG Ren-qian; CHEN Sun-xiao; ZHOU Ye; KONG Xian-tao

    2002-01-01

    Objective: To analyze the effect of lymphocytes on proliferation of keratinocytes in patients with psoriasis. Methods: Lymphocytes in lesion and peripheral blood were isolated and amplified, then cultured together with normal keratinocytes. By MTT method, the living cells were quantified in the mixed culture.Results: Compared with normal controls, lymphocytes from lesion and peripheral blood of psoriasis both promote the proliferation of keratinocytes (P<0. 01 and P<0. 05 respectively). The concentrations of IL-2 and IFN-γ in the mixture of lesion lymphocytes and keratinocytes were significantly higher than that of controls.Tripterygium glycosides inhibited this promotion. Conclusion: Lymphocytes in patients with psoriasis (mainly Thl cell) play an important role in proliferation of keratinocytes. This psoriasis cell model is useful for studies on signal transduction in psoriasis.

  18. Lymphocyte respiration in children with Trisomy 21

    Directory of Open Access Journals (Sweden)

    Aburawi Elhadi H

    2012-12-01

    Full Text Available Abstract Background This study measured lymphocyte mitochondrial O2 consumption (cellular respiration in children with trisomy 21. Methods Peripheral blood mononuclear cells were isolated from whole blood of trisomy 21 and control children and these cells were immediately used to measure cellular respiration rate. [O2] was determined as a function of time from the phosphorescence decay rates (1/τ of Pd (II-meso-tetra-(4-sulfonatophenyl-tetrabenzoporphyrin. In sealed vials containing lymphocytes and glucose as a respiratory substrate, [O2] declined linearly with time, confirming the zero-order kinetics of O2 conversion to H2O by cytochrome oxidase. The rate of respiration (k, in μM O2 min-1, thus, was the negative of the slope of [O2] vs. time. Cyanide inhibited O2 consumption, confirming that oxidation occurred in the mitochondrial respiratory chain. Results For control children (age = 8.8 ± 5.6 years, n = 26, the mean (± SD value of kc (in μM O2 per min per 107 cells was 1.36 ± 0.79 (coefficient of variation, Cv = 58%; median = 1.17; range = 0.60 to 3.12; -2SD = 0.61. For children with trisomy 21 (age = 7.2 ± 4.6 years, n = 26, the values of kc were 0.82 ± 0.62 (Cv = 76%; median = 0.60; range = 0.20 to 2.80, pp6.1 mU/L. Fourteen of 26 (54% children with trisomy 21 had kc values of 0.20 to 0.60 (i.e., kc positively correlated with body-mass index (BMI, R >0.302, serum creatinine (R >0.507, blood urea nitrogen (BUN, R >0.535 and albumin (R >0.446. Conclusions Children with trisomy 21 in this study have reduced lymphocyte bioenergetics. The clinical importance of this finding requires further studies.

  19. The Danish National Chronic Lymphocytic Leukemia Registry

    Directory of Open Access Journals (Sweden)

    da Cunha-Bang C

    2016-10-01

    Full Text Available Caspar da Cunha-Bang,1 Christian Hartmann Geisler,2 Lisbeth Enggaard,3 Christian Bjørn Poulsen,4 Peter de Nully Brown,2 Henrik Frederiksen,5 Olav Jonas Bergmann,6 Elisa Jacobsen Pulczynski,7 Robert Schou Pedersen,8 Linda Højberg Nielsen,9 Ilse Christiansen,10 Carsten Utoft Niemann2 1Department of Internal Medicine, Roskilde Hospital, Roskilde, Denmark; 2Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3Department of Hematology, Herlev Hospital, Herlev, Denmark; 4Department of Hematology, Roskilde Hospital, Roskilde, Denmark; 5Department of Hematology, Odense University Hospital, Odense, Denmark; 6Department of Hematology, Vejle Hospital, Vejle, Denmark; 7Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 8Department of Hematology, Holstebro Hospital, Holstebro, Denmark; 9Department of Hematology, Esbjerg Hospital, Esbjerg, Denmark; 10Department of Hematology, Aalborg University Hospital, Aalborg, Denmark Aim: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes. Study population: All patients diagnosed with CLL in Denmark from 2008 onward are included in the registry. Patients are followed in one of nine hematology centers. All centers participate in the registry and are all obliged to collect data. Main variables: Predefined data are collected at the time of diagnosis, and follow-up at the time of significant events: treatment, progression, transplantation, and death. Parameters included in the International Workshop on Chronic Lymphocytic Leukaemia criteria for diagnosis, and for decision on treatment initiation as well as characteristics included in the CLL

  20. An immunoglobulin C kappa-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system.

    NARCIS (Netherlands)

    Ait-Azzouzene, D.; Verkoczy, L.; Peters, J.H.; Gavin, A.; Skog, P.; Vela, J.L.; Nemazee, D.

    2005-01-01

    Understanding immune tolerance mechanisms is a major goal of immunology research, but mechanistic studies have generally required the use of mouse models carrying untargeted or targeted antigen receptor transgenes, which distort lymphocyte development and therefore preclude analysis of a truly

  1. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

    NARCIS (Netherlands)

    J. Lei (Jieping); A. Rudolph (Anja); K.B. Moysich (Kirsten); M. Rafiq (Meena); T.W. Behrens (Timothy); E.L. Goode (Ellen); P.D.P. Pharoah (Paul); P. Seibold (Petra); P.A. Fasching (Peter); I.L. Andrulis (Irene); V. Kristensen (Vessela); F.J. Couch (Fergus); U. Hamann (Ute); M.J. Hooning (Maartje); H. Nevanlinna (Heli); U. Eilber (Ursula); M.K. Bolla (Manjeet); J. Dennis (Joe); Q. Wang (Qing); A. Lindblom (Annika); A. Mannermaa (Arto); D. Lambrechts (Diether); M. García-Closas (Montserrat); P. Hall (Per); G. Chenevix-Trench (Georgia); M. Shah (Mitul); R.N. Luben (Robert); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); G.G. Alnæs (Grethe Grenaker); A.-L. Borresen-Dale (Anne-Lise); S. Nord (Silje); J.E. Olson (Janet); B. Hallberg (Boubou); C. Vachon (Celine); D. Torres (Diana); H.U. Ulmer (Hans); T. Rud̈iger (Thomas); A. Jager (Agnes); C.H.M. van Deurzen (Carolien); M.M.A. Tilanus-Linthorst (Madeleine); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); S. Margolin (Sara); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); V. Kataja (Vesa); S. Hatse (Sigrid); H. Wildiers (Hans); A. Smeets (Ann); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); J. Li (Jingmei); M.K. Humphreys (Manjeet); K.-A. Phillips (Kelly-Anne); S.C. Linn (Sabine); S. Cornelissen (Sten); S.A.J. van den Broek (Sandra Alexandra); D. Kang (Daehee); J.-Y. Choi (J.); S.K. Park (Sue); K.Y. Yoo; C.-N. Hsiung (Chia-Ni); P.-E. Wu (Pei-Ei); M.-F. Hou (Ming-Feng); C-Y. Shen (Chen-Yang); S.-H. Teo; N.A.M. Taib (Nur Aishah Mohd); C.-H. Yip (Cheng-Har); G.F. Ho (Gwo Fuang); K. Matsuo (Keitaro); H. Ito (Hidemi); H. Iwata (Hisato); K. Tajima (Kazuo); A.M. Dunning (Alison); J. Benítez (Javier); K. Czene (Kamila); L. Sucheston (Lara); T. Maishman (Tom); W. Tapper (William); D. Eccles (Diana); D.F. Easton (Douglas); M.K. Schmidt (Marjanka); J. Chang-Claude (Jenny)

    2015-01-01

    textabstractIntroduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we st

  2. Mitochondrial apoptosis of lymphocyte is induced in type 2 diabetes

    Institute of Scientific and Technical Information of China (English)

    Xu Hui; Chen Yanbo; Li Yanxiang; Xia Fangzhen; Han Bing; Zhang Huixin; Zhai Hualing

    2014-01-01

    Background Lymphocyte function and homeostasis is associated with immune defence to infection.Apoptosis of lymphocytes might be a considerably important component which has an impact on immunity to infections in people with hyperglycemia.The aim of this study was to explore the mitochondrial apoptosis pathway of lymphocyte in diabetic patients.Methods Sixty patients with type 2 diabetes mellitus and fifty healthy volunteers were included in this study.Annexin V and propidiumiodide (Pl) were joined in the isolated lymphocytes and the rate of lymphocyte apoptosis was calculated with flow cytometry.Observation of the lymphocytes was done using transmission electron microscopy; mitochondria had been extracted and then mitochondrial membrane potential (MMP) was detected to assess mitochondrial function; the mRNA level of Bcl-2,cytochrome c (Cyt-C),caspase-9 and caspase-3 were analyzed by real-time reverse transcriptionpolymerase chain reaction (RT-PCR).Results Apoptosis rate of lymphocyte was significantly higher in diabetic group than that in normal control group (P <0.05).Transmission electron microscopy showed lymphocyte shrinkage and breakage,chromatin condensation and less mitochondria; a fall in MMP levels was also evident; Bcl-2 concentration was reduced and the expressions of caspase-9,caspase-3 and Cyt-C were elevated (P <0.05) in diabetic patients.Conclusions The rate of lymphocyte apoptosis was significantly higher in type 2 diabetic patients than that in normal population.Mitochondrial apoptosis pathway may play a very important role in decreasing function of lymphocyte in diabetes.

  3. Expression of protooncogenes during lymphocyte activation by growth factors.

    Science.gov (United States)

    Bulanova, E G; Budagyan, V M; Yarilin, A A; Mazurenko, N N

    1997-09-01

    Effects of growth factors of non-immune origin including somatotropin (ST) and platelet-derived growth factor (PDGF) on the expression of the proteins encoded by c-fos, c-myc, c-fun, and c-ets family protooncogenes were studied for the first time. The dynamics of the oncoprotein expression in activated CD(3+)-lymphocytes was investigated by immunoblotting. The accumulation of the Fos and Myc proteins was enhanced in T-lymphocytes treated with ST, PDGF, or phytohemagglutinin; the accumulation was maximum at 30-60 min and decreased in 2 h; the data indicate that the oncoproteins participate in the early lymphocyte activation by various growth factors. The Jun protein appears only in 3 h after the onset of lymphocyte activation; this suggests independent participation of Fos in the early stages of lymphocyte activation prior to the appearance of Jun, preceding the joint action of Fos and Jun within the AP-1 transcription complex. The products of the c-ets family are differentially activated by the studied growth factors. Resting lymphocytes actively accumulate the Ets-1 protein; ST and PDGF activation decreases Ets-1 expression in 2 h. The Ets-2 protein is not detected in resting cells and PDGF-activated lymphocytes, whereas lymphocyte activation by ST is associated with accumulation of Ets-2. The data suggest that the product of the c-ets-1 gene is more important in the regulation of resting cells and the product of the c-ets-2 gene is important during activation of lymphocytes by ST. The results indicate that activation of lymphocytes with growth factors of non-immune origin is mediated by several signal transduction pathways.

  4. Transfusion-induced, Fc gamma-receptor-blocking antibodies: spectrum of cellular reactivity.

    Science.gov (United States)

    Forwell, M A; Peel, M G; Froebel, K S; Belch, J J; MacSween, R N; Sandilands, G P

    1986-06-01

    In this study we have shown that transfusion-induced Fc gamma R-blocking antibodies have the capacity to react with various cell types which are known to possess this receptor i.e., lymphocytes (T and B cells), polymorphs and platelets. In contrast we were unable to demonstrate any reactivity with K (or NK) lymphocytes or with monocytes. The spectrum of cellular reactivity exhibited by these antibodies suggests that their effect on the immune system may be complex.

  5. Metal ion levels and lymphocyte counts

    DEFF Research Database (Denmark)

    Penny, Jeannette Ø; Varmarken, Jens-Erik; Ovesen, Ole

    2013-01-01

    . RESULTS: The T-lymphocyte counts for both implant types declined over the 2-year period. This decline was statistically significant for CD3(+)CD8(+) in the THA group, with a regression coefficient of -0.04 × 10(9)cells/year (95% CI: -0.08 to -0.01). Regression analysis indicated a depressive effect...... of cobalt ions in particular on T-cells with 2-year whole-blood cobalt regression coefficients for CD3+ of -0.10 (95% CI: -0.16 to -0.04) × 10(9) cells/parts per billion (ppb), for CD3+CD4+ of -0.06 (-0.09 to -0.03) × 10(9) cells/ppb, and for CD3(+)CD8(+) of -0.02 (-0.03 to -0.00) × 10(9) cells/ppb...

  6. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds...... with potential tumor specificity. Our starting point is a diverse fungal collection of thousands of Penicillium and Aspergillus species. These fungi have proven to be a very rich source of various bioactive compounds and yet our dereplication investigations have demonstrated that there are still numerous unknown...... compounds to be identified within these species. Until now we have found that 11 out of 289 fungal extracts are active against CLL cells. Using our established chemotaxonomic discovery approach we have dereplicated and fractionated these extracts to track the activity into single fractions/compounds.2...

  7. Molecular Mechanisms of Lymphocyte-Mediated Cytotoxicity

    Institute of Scientific and Technical Information of China (English)

    Zusen Fan; Qixiang Zhang

    2005-01-01

    Granule-mediated cytotoxicity is the major mechanism for lymphocytes to kill viruses, intracellular bacteria and tumors. The cytotoxic granules move to the immunological synapse by exocytosis after recognition of a killer cell.The contents of the granules are delivered into target cells with the help of perforin by endocytosis. A group of serine protease granzymes cleave their critical substrates to initiate DNA damage and cell death. The most abundant granzymes are granzyme A and B. They induce cell death through alternate and nonoverlapping pathways. The substrates and functions of the majority of the orphan granzymes have not yet been identified. It is possible that the diversity of granzymes provides fail-safe mechanisms for killing viruses and tumor cells.

  8. Role of angiogenesis in chronic lymphocytic leukemia.

    Science.gov (United States)

    Letilovic, Tomislav; Vrhovac, Radovan; Verstovsek, Srdan; Jaksic, Branimir; Ferrajoli, Alessandra

    2006-09-01

    Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

  9. Chronic lymphocytic leukemia in African Americans.

    Science.gov (United States)

    Coombs, Catherine C; Falchi, Lorenzo; Weinberg, J Brice; Ferrajoli, Alessandra; Lanasa, Mark C

    2012-11-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the United States with almost 4390 attributable deaths per year. Epidemiologic data compiled by the Surveillance, Epidemiology and End Results (SEER) program identifies important differences in incidence and survival for African Americans with CLL. Although the incidence of CLL is lower among African Americans than among Caucasians (4.6 and 6.2 per 100 000 men, respectively), age-adjusted survival is inferior. African American patients with CLL are almost twice as likely to die from a CLL-related complication in the first 5 years after diagnosis as are Caucasian patients with CLL. The biologic basis for these observations is almost entirely unexplored, and a comprehensive clinical analysis of African American patients with CLL is lacking. This is the subject of the present review.

  10. Thyroid carcinoma: immunology, irradiation, and lymphocytic infiltration

    Energy Technology Data Exchange (ETDEWEB)

    Shull, J.H.; Sharon, N.; Victor, T.A.; Scanlon, E.F.

    1979-06-01

    Patients undergoing thyroidectomies at Evanston (I11) Hospital, during a six-month period had immunological studies performed preoperatively. No differential could be found between those with carcinoma or benign pathologic findings. T- and B-cell distribution and lymphocytic response to mitogens varied widely. Quantitative immunoglobulins showed slightly increased levels of IgG in patients wih carcinoma and thyroiditis in comparison with those patients with adenomas. Antithyroglobulin antibodies were negative in all patients. Pathology slides from 107 patients with thyroid carcinoma between 1972 and 1978 at Evanston Hospital were reviewed for the presence of thyroiditis, either focal or diffuse. It was found that 50% of all carcinomas had either diffuse or focal thyroiditis. Diffuse thyroiditis was more common in patients with no history of irradiation and papillary carcinoma, and in younger age groups.

  11. Mediastinal irradiation for chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Sawitskii, A.; Rai, K.R.; Aral, I.; Silver, R.T.; Glicksman, A.S.; Carey, R.W.; Scialla, S.; Cornell, C.J. Jr.; Seligman, B.; Shapiro, L.

    1976-12-01

    Thirty-one patients with chronic lymphocytic leukemia were treated with mediastinal radiation. In none of the patients was complete remission achieved; either partial remission or clinical improvement was achieved in 52 percent, but the duration of response was short. The response rate was 77 percent for the patients receiving a total radiation dose greater than 3,000 rads and 45 percent for those receiving less than 3,000 rads. Severe life-threatening toxicity was noted in 11 patients and seven of these patients died; two patients died with progressive disease. Severe toxicity was manifested by one or more of the following: bone marrow aplasia, pancytopenia, gram-negative sepsis, generalized herpes zoster and severe esophagitis. Neither the total dose of radiation nor the dose per week correlated with the severity of reaction or death.

  12. Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available The clinical course of chronic lymphocytic leukemia (CLL may be complicated at any time by autoimmune phenomena.The most common ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA and immune thrombocytopenia (ITP. Pure red cell aplasia (PRCA and autoimmune agranulocytosis (AG are, indeed, more rarely seen. However, they are probably underestimated due to the possible misleading presence of cytopenias secondary to leukemic bone marrow involvement or to chemotherapy cytotoxicity. The source of autoantibodies is still uncertain, despite the most convincing data are in favor of the involvement of resting normal B-cells. In general, excluding the specific treatment of underlying CLL, the managementof these complications is not different from that of idiopathic autoimmune cytopenias or of those associated to other causes. Among different therapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective.

  13. Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2'-deoxycytidine.

    Science.gov (United States)

    Dubovsky, Jason A; Powers, John J; Gao, Yang; Mariusso, Luis F; Sotomayor, Eduardo M; Pinilla-Ibarz, Javier A

    2011-09-01

    T cell immune dysfunction has an important role in the profound immune suppression that characterizes chronic lymphocytic leukemia (CLL). Improper polarization of T cells has been proposed as one of the mechanism involved. Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Recent in vitro evidence indicates that this plasticity may be phenotypically altered by using methylation inhibitors which are approved for clinical use in certain types of cancer. These results beg the question: can the ineffective polarization of T lymphocytes in the context of CLL be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has studied the effects of 5-aza-2'-deoxycytidine (5A2) in helper and cytotoxic T lymphocytes from healthy donors and CLL patients in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our data indicates that 5A2 treatment can depolarize Th2 cells to effectively secrete interferon gamma, signal via T-bet, and achieve demethylation of critical Th1 specific promoters. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. In conclusion our data seeks to define a modality in which improper or ineffective T cell polarization can be altered by 5AZA and could be incorporated in future therapeutic interventions.

  14. [Lymphocytic duodenosis: etiological study and clinical presentations].

    Science.gov (United States)

    Santolaria, Santos; Dominguez, Manuel; Alcedo, Javier; Abascal, Manuel; García-Prats, M Dolores; Marigil, Miguel; Vera, Jesus; Ferrer, Margarita; Montoro, Miguel

    2013-11-01

    Lymphocytic duodenosis (LD) is a characteristic lesion in the initial phases of celiac disease (CD) but can be associated with many other entities. The aim of this study was to evaluate the prevalence of distinct causes of LD and possible differences in clinical presentation according to etiology. A retrospective study was performed that included 194 patients diagnosed with LD (more than 25 intraepithelial lymphocytes per 100 epithelial cells). A preestablished strategy to evaluate the cause of the disease was followed that included celiac serology (antitransglutaminase antibodies), HLA-DQ2/DQ8 genotypes, diagnosis of Helicobacter pylori and small intestinal bacterial overgrowth (SIBO). Diagnosis of CD was established on the basis of clinical and histological response to a gluten-free diet in patients with positive serology or compatible findings on HLA-DQ2 (at least one of the alleles) or -DQ8 (both alleles) study. The most frequent cause of LD was CD (39%), followed by SBBO (22%), H.pylori (14%), CD and SIBO (12%), and other causes (13%). Most of the patients (83%) had a compatible HLA-DQ2 or -DQ8 genotype. In these patients, the most frequent diagnosis was CD (46%), while in the absence of HLA-DQ2/DQ8, the most frequent diagnoses were SIBO (44%) and H. pylori (22%). CD was the most frequent diagnosis in patients referred for dyspepsia, diarrhea and anemia, while H. pylori was the most frequent diagnosis in patients with abdominal pain. The most common causes of LD in our environment are CD, followed by SIBO and H. pylori infection. Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

  15. Lymphocytes subsets in children with febrile convulsions.

    Science.gov (United States)

    Tuncer, Oğuz; Karaman, Sait; Caksen, Hüseyin; Oner, Ahmet Faik; Odabas, Dursun; Yilmaz, Cahide; Atas, Bülent

    2007-07-01

    In this study, lymphocytes subsets including blood CD3, CD4, CD8, CD16, CD19, and CD56 values were analyzed in children with febrile convulsion (FC) to determine whether there was the association of lymphocytes subsets in the pathogenesis of FC. The study includes 48 children with FC, and 55 healthy age matched control subjects, followed in Yüzüncü Yil University, Faculty of Medicine, Department of Pediatrics between October 2003 and June 2004. Blood CD3, CD4, CD8, CD16, CD19, and CD56 values were examined in the study and control groups. The analyses were performed in the Hematology Laboratory, Yüzüncü Yil University Faculty of Medicine, with flow cytometer device (Coulter Epics XL2, Flow Cytometer). A total of 48 children [17 girls (35.5%) and 31 boys (64.5%)], aged 6 months to 60 months (mean 22.20 +/- 13.75 months) with FC and 55 healthy children [28 girls (51%) and 27 boys (49%)], aged 6 months to 60 months (mean 28.87 +/- 17.04 months) were included in the study. When compared with the control group, the study found significantly decreased blood CD3 and CD4 values in the study group (p .05). When comparing the children with and without positive family history for FC, the study did not find any difference for all CD values between the groups (p >.05). Similarly, there was not significant difference in CD values between the children with simple and complex FC (p >.05). The findings suggested that decreased blood CD3 and CD4 values might be responsible for the infections connected with FC or that they might be related to the pathogenesis of FC in some children.

  16. Multiple dysfunctions in developmental and activational stages of T lymphocytes, B lymphocytes and monocytes in ARC and AIDS patients.

    Science.gov (United States)

    Sei, Y; Tsang, P H; Petrella, R J; Bekesi, J G

    1987-11-01

    Peripheral blood leukocytes from ARC and AIDS patients were examined before and after phytohemagglutinin (PHA) stimulation by dual color flow cytometry and monoclonal antibodies which identify developmental and activational stages of T lymphocytes, B cells and monocytes. There was a persistent elevation in the total number of circulating Ia+ lymphocytes with progressive selection for B1+ Ia+ lymphocytes and T suppressor cells and a concurrent reduction in the antigen-presenting monocytes. Following PHA stimulation there was a marked decrease in all subsets of Ia+ lymphocytes and monocytes. These results indicate (a) multicellular dysfunctions in the immunosurveillance mechanisms in AIDS, and (b) that many functional subsets of circulating lymphocytes and monocytes were already activated and therefore poorly responsive to additional antigenic or mitogenic stimuli.

  17. The evolution of adaptive immunity in vertebrates.

    Science.gov (United States)

    Hirano, Masayuki; Das, Sabyasachi; Guo, Peng; Cooper, Max D

    2011-01-01

    Approximately 500 million years ago, two types of recombinatorial adaptive immune systems (AISs) arose in vertebrates. The jawed vertebrates diversify their repertoire of immunoglobulin domain-based T and B cell antigen receptors mainly through the rearrangement of V(D)J gene segments and somatic hypermutation, but none of the fundamental AIS recognition elements in jawed vertebrates have been found in jawless vertebrates. Instead, the AIS of jawless vertebrates is based on variable lymphocyte receptors (VLRs) that are generated through recombinatorial usage of a large panel of highly diverse leucine-rich-repeat (LRR) sequences. Whereas the appearance of transposon-like, recombination-activating genes contributed uniquely to the origin of the AIS in jawed vertebrates, the use of activation-induced cytidine deaminase for receptor diversification is common to both the jawed and jawless vertebrates. Despite these differences in anticipatory receptor construction, the basic AIS design featuring two interactive T and B lymphocyte arms apparently evolved in an ancestor of jawed and jawless vertebrates within the context of preexisting innate immunity and has been maintained since as a consequence of powerful and enduring selection, most probably for pathogen defense purposes.

  18. Apoptotic depletion of infiltrating mucosal lymphocytes associated with Fas ligand expression by Helicobacter pylori-infected gastric mucosal epithelium: human glandular stomach as a site of immune privilege.

    Science.gov (United States)

    Koyama, S

    2000-04-01

    H. pylori infection almost invariably results in chronic gastritis, but only a proportion of patients develops severe destruction of epithelial glandular structure or peptic ulcer. To confirm the recent data obtained in testis and eye, showing that Fas ligand is involved in the phenomenon of "immune privilege," expression of Fas receptor and its ligand of the stomach was investigated in a panel of gastric biopsies obtained from patients H. pylori-positive (N = 42) and with H. pylori-negative (N = 18) by two-color flow cytometry. The results show that membrane-bound Fas ligand protein is constitutively expressed on freshly isolated human gastric mucosal epithelium coupled with infiltrating lymphocytes. There was significant overexpression of Fas receptor and its ligand, and a higher frequency of apoptotic cell death detected by TUNEL in epithelium and infiltrating lymphocytes in H. pylori-infected patients. These findings suggest that involvement of Fas receptor and its ligand system contributes to some extent to mucosal damage in H. pylori-associated gastritis. However, the more specific findings are apoptotic depletion of invading mucosal lymphocytes associated with Fas ligand expression by gastric epithelium. These provide the first direct quantitative evidence to support Fas receptor counterattack and/or paracrine fratricide as a mechanism of immune privilege in vivo in the H. pylori-infected glandular stomach.

  19. Oligoclonal CD8 lymphocytes from persons with asymptomatic human immunodeficiency virus (HIV) type 1 infection inhibit HIV-1 replication.

    Science.gov (United States)

    Toso, J F; Chen, C H; Mohr, J R; Piglia, L; Oei, C; Ferrari, G; Greenberg, M L; Weinhold, K J

    1995-10-01

    CD8 lymphocytes from asymptomatic human immunodeficiency virus (HIV) type 1-infected patients can suppress virus production from infected CD4 cells. Suppressive activity is separate and distinct from cytotoxic T lymphocyte (CTL) reactivities and is likely mediated by a soluble factor(s). The majority of HIV-1 suppression studies have been done in the context of bulk CD8 cell cultures. In this study, viral suppression was characterized by clonal populations of CD8 cells derived from HIV-1-infected patients. Most of the suppressive clones were devoid of detectable CTL reactivity against env-, gag-, pol-, and nef-expressing targets. Among the suppressive clones derived from an individual patient, a marked heterogeneity was evident with respect to phenotypic markers, cytokine production, and T cell receptor V beta expression. These results suggest that noncytolytic virus suppression is oligoclonal in nature. Clones provide tools for future studies aimed at understanding the mechanism of suppression and identifying the suppressive factor.

  20. CR2-mediated activation of the complement alternative pathway results in formation of membrane attack complexes on human B lymphocytes

    DEFF Research Database (Denmark)

    Nielsen, C H; Marquart, H V; Prodinger, W M;

    2001-01-01

    Normal human B lymphocytes activate the alternative pathway of complement via complement receptor type 2 (CR2, CD21), that binds hydrolysed C3 (iC3) and thereby promotes the formation of a membrane-bound C3 convertase. We have investigated whether this might lead to the generation of a C5...... convertase and consequent formation of membrane attack complexes (MAC). Deposition of C3 fragments and MAC was assessed on human peripheral B lymphocytes in the presence of 30% autologous serum containing 4.4 mM MgCl2/20 mM EGTA, which abrogates the classical pathway of complement without affecting...... the alternative pathway. Blockade of the CR2 ligand-binding site with the monoclonal antibody FE8 resulted in 56 +/- 13% and 71 +/- 9% inhibition of the C3-fragment and MAC deposition, respectively, whereas the monoclonal antibody HB135, directed against an irrelevant CR2 epitope, had no effect. Blockade...

  1. Experimental study of possible involvement of some apoptosis mechanisms in pathogenesis of the HIV infection: 2. The CD4+ T lymphocytes depletion in the HIV infection occurs through activation-induced apoptosis.

    Science.gov (United States)

    Topârceanu, F; Bârnaure, F; Iucu, C T; Spulbăr, E; Pătru, C

    1999-01-01

    The present work is a part of a complex experimental study aimed at the demonstration of the two previously published hypotheses regarding the involvement of apoptosis in general in the viral infection and especially in HIV infection (1). Our researches have shown that the significant lowering of the number of peripheral CD4+ T lymphocytes in HIV-infected children is associated with a marked increase of the soluble interleukin 2-receptor (sIL2-R)# concentration, in comparison with HIV-negative, healthy or acute infections exhibiting controls. As sIL-2R is a circulating marker of cell activation, we investigated the role of monocytes (antigen-presenting cells) in the viability of peripheral lymphocytes isolated from HIV-infected children in comparison with the controls. Lymphocytes cultivation in the absence and in the presence of autologous monocytes led to the following conclusions: 1) freshly isolated lymphocytes from HIV-positive individuals undergo an accelerated spontaneous apoptosis in comparison with that of lymphocytes isolated from HIV-negative individuals: 2) the normal antiapoptotic effect of monocytes on lymphocytes diminishes gradually in the HIV infection, changing into a proapoptotic effect, corresponding to the sIL-2R augmentation to increasingly higher values. Our results show that peripheral CD4+ T-lymphocyte depletion in HIV infection occurs through apoptosis and the activation-induced cell death is one of the possible apoptosis mechanisms.

  2. Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

    Science.gov (United States)

    Mandala, Wilson L; Msefula, Chisomo L; Gondwe, Esther N; Gilchrist, James J; Graham, Stephen M; Pensulo, Paul; Mwimaniwa, Grace; Banda, Meraby; Taylor, Terrie E; Molyneux, Elizabeth E; Drayson, Mark T; Ward, Steven A; Molyneux, Malcolm E; MacLennan, Calman A

    2015-11-18

    Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/μl) and uncomplicated malaria (3,700/μl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/μl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria. Copyright © 2016 Mandala et al.

  3. T- and B-lymphocyte chimerism in the marmoset

    Energy Technology Data Exchange (ETDEWEB)

    Niblack, G.D.; Kateley, J.R.; Gengozian, N.

    1977-01-01

    Marmosets are natural blood chimeras, this condition resulting from the high frequency of fraternal twinning and the consistent development of placental vascular anastomoses between the two embryos. Identification of chimerism by sex-chromosome analysis of cultured blood lymphocytes provided a means of determining the proportion of chimerism among T and B lymphocytes. Peripheral blood lymphocytes were enriched for T or B cells by filtration through a nylon column (yields >95% T-cells) or inactivation of T lymphocytes by treatment with a goat anti-marmoset thymocyte antiserum in the presence of complement (yields >95% B cells). Mitogenic stimulation of these separated, enriched cell populations yielded metaphase plates which could be scored for percentage male and female cells. Tests on five different blood chimeras showed the T- and B-lymphocyte chimerism to be the same. Stimulation of blood lymphocytes with cells from another species of marmoset in a mixed lymphocyte culture test revealed the chimeric T-cell response (i.e., host and co-twin cells) to be similar to that obtained with a mitogenic lectin. The demonstration of equivalent T- and B-cell chimerism in these animals suggests derivation of these cells from a common stem cell pool and the response of both T-cell populations to an antigenic stimulus in proportions similar to their percentage chimerism suggests complete immunologic tolerance exists in this species for co-twin histocompatibility antigens.

  4. High homocysteine levels prevent via H2 S the CoCl2 -induced alteration of lymphocyte viability.

    Science.gov (United States)

    Bruzzese, Laurie; Fenouillet, Emmanuel; Fromonot, Julien; Durand-Gorde, Josée-Martine; Condo, Jocelyne; Kipson, Nathalie; Mottola, Giovanna; Deharo, Pierre; Guieu, Régis; Ruf, Jean

    2016-08-01

    High homocysteine (HCy) levels are associated with lymphocyte-mediated inflammatory responses that are sometimes in turn related to hypoxia. Because adenosine is a potent lymphocyte suppressor produced in hypoxic conditions and shares metabolic pathways with HCy, we addressed the influence of high HCy levels on the hypoxia-induced, adenosine-mediated, alteration of lymphocyte viability. We treated mitogen-stimulated human lymphocytes isolated from healthy individuals and the human lymphoma T-cell line CEM with cobalt chloride (CoCl2 )to reproduce hypoxia. We found that CoCl2 -altered cell viability was dose-dependently reversed using HCy. In turn, the HCy effect was inhibited using DL-propargylglycine, a specific inhibitor of the hydrogen sulphide (H2 S)-synthesizing enzyme cystathionine-γ-lyase involved in HCy catabolism. We then addressed the intracellular metabolic pathway of adenosine and HCy, and the role of the adenosine A2A receptor (A2 A R). We observed that: (i) hypoxic conditions lowered the intracellular concentration of HCy by increasing adenosine production, which resulted in high A2 A R expression and 3', 5'-cyclic adenosine monophosphate production; (ii) increasing intracellular HCy concentration reversed the hypoxia-induced adenosinergic signalling despite high adenosine concentration by promoting both S-adenosylhomocysteine and H2 S production; (iii) DL-propargylglycine that inhibits H2 S production abolished the HCy effect. Together, these data suggest that high HCy levels prevent, via H2 S production and the resulting down-regulation of A2 A R expression, the hypoxia-induced adenosinergic alteration of lymphocyte viability. We point out the relevance of these mechanisms in the pathophysiology of cardiovascular diseases.

  5. Fulminant lymphocytic choriomeningitis virus-induced inflammation of the CNS involves a cytokine-chemokine-cytokine-chemokine cascade

    DEFF Research Database (Denmark)

    Christensen, Jeanette E; Simonsen, Stine; Fenger, Christina

    2009-01-01

    Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30...... the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular...... source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8+ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells...

  6. Involvement of lymphocyte function-associated antigen-1 (LFA-1) in HIV infection: inhibition by monoclonal antibody

    DEFF Research Database (Denmark)

    Hansen, J E; Nielsen, C; Mathiesen, Lars Reinhardt;

    1991-01-01

    Monoclonal antibodies (MAbs) against the alpha- and beta-chain of lymphocyte-associated antigen-1 (LFA-1) were examined for inhibition of HIV-1 infection in vitro. Infection of the T cell line MT4 and the monocytic cell line U937 by isolates HTLVIIIB and SSI-002, respectively was inhibited...... in a concentration dependent manner by MAb against the beta-chain but not against the alpha-chain. No cross-reactivity was found between MAb against LFA-1 and against the CD4 receptor (MAb Leu3a). MAbs against the beta-chain and the CD4 receptor were found to act synergistically in inhibiting HIV infection....... These data indicate that the beta-chain of LFA-1 in addition to the CD4 receptor may be involved in HIV infection in vitro....

  7. SLAM family receptors and SAP adaptors in immunity.

    Science.gov (United States)

    Cannons, Jennifer L; Tangye, Stuart G; Schwartzberg, Pamela L

    2011-01-01

    The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia. SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC. SLAM family members are now recognized as important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion. In this review, we cover recent findings on the roles of SLAM family receptors and the SAP family of adaptors, with a focus on their regulation of the pathways involved in the pathogenesis of XLP and other immune disorders.

  8. CCR5 susceptibility to ligand-mediated down-modulation differs between human T lymphocytes and myeloid cells.

    Science.gov (United States)

    Fox, James M; Kasprowicz, Richard; Hartley, Oliver; Signoret, Nathalie

    2015-07-01

    CCR5 is a chemokine receptor expressed on leukocytes and a coreceptor used by HIV-1 to enter CD4(+) T lymphocytes and macrophages. Stimulation of CCR5 by chemokines triggers internalization of chemokine-bound CCR5 molecules in a process called down-modulation, which contributes to the anti-HIV activity of chemokines. Recent studies have shown that CCR5 conformational heterogeneity influences chemokine-CCR5 interactions and HIV-1 entry in transfected cells or activated CD4(+) T lymphocytes. However, the effect of CCR5 conformations on other cell types and on the process of down-modulation remains unclear. We used mAbs, some already shown to detect distinct CCR5 conformations, to compare the behavior of CCR5 on in vitro generated human T cell blasts, monocytes and MDMs and CHO-CCR5 transfectants. All human cells express distinct antigenic forms of CCR5 not detected on CHO-CCR5 cells. The recognizable populations of CCR5 receptors exhibit different patterns of down-modulation on T lymphocytes compared with myeloid cells. On T cell blasts, CCR5 is recognized by all antibodies and undergoes rapid chemokine-mediated internalization, whereas on monocytes and MDMs, a pool of CCR5 molecules is recognized by a subset of antibodies and is not removed from the cell surface. We demonstrate that this cell surface-retained form of CCR5 responds to prolonged treatment with more-potent chemokine analogs and acts as an HIV-1 coreceptor. Our findings indicate that the regulation of CCR5 is highly specific to cell type and provide a potential explanation for the observation that native chemokines are less-effective HIV-entry inhibitors on macrophages compared with T lymphocytes.

  9. Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns.

    Science.gov (United States)

    Yang, Dianer; Sun, Yu-Yo; Bhaumik, Siddhartha Kumar; Li, Yikun; Baumann, Jessica M; Lin, Xiaoyi; Zhang, Yujin; Lin, Shang-Hsuan; Dunn, R Scott; Liu, Chia-Yang; Shie, Feng-Shiun; Lee, Yi-Hsuan; Wills-Karp, Marsha; Chougnet, Claire A; Kallapur, Suhas G; Lewkowich, Ian P; Lindquist, Diana M; Murali-Krishna, Kaja; Kuan, Chia-Yi

    2014-12-03

    Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.

  10. Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates capacity of hematopoietic stem cells to undergo lymphocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Ahrenhoerster, Lori S.; Tate, Everett R.; Lakatos, Peter A. [Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee (United States); Program in Environmental and Occupational Health, Milwaukee, WI 53211 (United States); Wang, Xuexia [Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee (United States); Program in Biostatistics, Milwaukee, WI 53211 (United States); Laiosa, Michael D., E-mail: laiosa@uwm.edu [Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee (United States); Program in Environmental and Occupational Health, Milwaukee, WI 53211 (United States)

    2014-06-01

    The process of hematopoiesis, characterized by long-term self-renewal and multi-potent lineage differentiation, has been shown to be regulated in part by the ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous contaminant and the most potent AHR agonist, also modulates regulation of adult hematopoietic stem and progenitor cell (HSC/HPC) homeostasis. However, the effect of developmental TCDD exposure on early life hematopoiesis has not been fully explored. Given the inhibitory effects of TCDD on hematopoiesis and lymphocyte development, we hypothesized that in utero exposure to TCDD would alter the functional capacity of fetal HSC/HPCs to complete lymphocyte differentiation. To test this hypothesis, we employed a co-culture system designed to facilitate the maturation of progenitor cells to either B or T lymphocytes. Furthermore, we utilized an innovative limiting dilution assay to precisely quantify differences in lymphocyte differentiation between HSC/HPCs obtained from fetuses of dams exposed to 3 μg/kg TCDD or control. We found that the AHR is transcribed in yolk sac hematopoietic cells and is transcriptionally active as early as gestational day (GD) 7.5. Furthermore, the number of HSC/HPCs present in the fetal liver on GD 14.5 was significantly increased in fetuses whose mothers were exposed to TCDD throughout pregnancy. Despite this increase in HSC/HPC cell number, B and T lymphocyte differentiation is decreased by approximately 2.5 fold. These findings demonstrate that inappropriate developmental AHR activation in HSC/HPCs adversely impacts lymphocyte differentiation and may have consequences for lymphocyte development in the bone marrow and thymus later in life.

  11. Changes in the Expression of Transcription Factors Involved in Modulating the Expression of EPO-R in Activated Human CD4-Positive Lymphocytes.

    Science.gov (United States)

    Lisowska, Katarzyna A; Frackowiak, Joanna E; Mikosik, Anna; Witkowski, Jacek M

    2013-01-01

    We have recently described the presence of the erythropoietin receptor (EPO-R) on CD4(+) lymphocytes and demonstrated that its expression increases during their activation, reaching a level reported to be typical for erythroid progenitors. This observation suggests that EPO-R expression is modulated during lymphocyte activation, which may be important for the cells' function. Here we investigated whether the expression of GATA1, GATA3 and Sp1 transcription factors is correlated with the expression of EPO-R in human CD4(+) lymphocytes stimulated with monoclonal anti-CD3 antibody. The expression of GATA1, GATA3 and Sp1 transcription factors in CD4(+) cells was estimated before and after stimulation with anti-CD3 antibody by Western Blot and flow cytometry. The expression of EPO-R was measured using real-time PCR and flow cytometry. There was no change in the expression of GATA1 and GATA3 in CD4(+) lymphocytes after stimulation with anti-CD3 antibody. However, stimulation resulted in the significantly increased expression of the Sp1 factor. CD4(+) lymphocytes stimulated with anti-CD3 antibody exhibited an increase in both the expression level of EPOR gene and the number of EPO-R molecules on the cells' surface, the latter being significantly correlated with the increased expression of Sp1. Sp1 is noted to be the single transcription factor among the ones studied whose level changes as a result of CD4(+) lymphocyte stimulation. It seems that Sp1 may significantly affect the number of EPO-R molecules present on the surface of activated CD4(+) lymphocytes.

  12. Evaluation of lymphocyte subgroups in children with subacute sclerosing panencephalitis.

    Science.gov (United States)

    Yilmaz, C; Yuca, S A; Yilmaz, N; Oner, A F; Caksen, H

    2009-01-01

    The aetiology of subacute sclerosing panencephalitis (SSPE) remains to be fully elucidated, although it follows infection with a hypermutant defective M-protein measles virus. This study analysed peripheral blood lymphocyte subgroups to determine their role in the pathophysiology of SSPE. It included 22 children with SSPE aged 2 - 15 years (patient group) and 22 age- and gender-matched healthy children (control group). In children or= 6 years old, there were no significant differences in the lymphocyte subgroups. In conclusion, these findings suggest that a low CD4(+) lymphocyte count might be responsible for SSPE in younger children.

  13. Evolution of adaptive immune recognition in jawless vertebrates.

    Science.gov (United States)

    Saha, Nil Ratan; Smith, Jeramiah; Amemiya, Chris T

    2010-02-01

    All extant vertebrates possess an adaptive immune system wherein diverse immune receptors are created and deployed in specialized blood cell lineages. Recent advances in DNA sequencing and developmental resources for basal vertebrates have facilitated numerous comparative analyses that have shed new light on the molecular and cellular bases of immune defense and the mechanisms of immune receptor diversification in the "jawless" vertebrates. With data from these key species in hand, it is becoming possible to infer some general aspects of the early evolution of vertebrate adaptive immunity. All jawed vertebrates assemble their antigen-receptor genes through combinatorial recombination of different "diversity" segments into immunoglobulin or T-cell receptor genes. However, the jawless vertebrates employ an analogous, but independently derived set of immune receptors in order to recognize and bind antigens: the variable lymphocyte receptors (VLRs). The means by which this locus generates receptor diversity and achieves antigen specificity is of considerable interest because these mechanisms represent a completely independent strategy for building a large immune repertoire. Therefore, studies of the VLR system are providing insight into the fundamental principles and evolutionary potential of adaptive immune recognition systems. Here we review and synthesize the wealth of data that have been generated towards understanding the evolution of the adaptive immune system in the jawless vertebrates.

  14. Treatment Options by Stage (Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    ... also called biotherapy or immunotherapy. Chimeric antigen receptor (CAR) T-cell therapy CAR T-cell therapy is ... of Health FOLLOW US Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp ...

  15. General Information about Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... also called biotherapy or immunotherapy. Chimeric antigen receptor (CAR) T-cell therapy CAR T-cell therapy is ... of Health FOLLOW US Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp ...

  16. Treatment Option Overview (Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    ... also called biotherapy or immunotherapy. Chimeric antigen receptor (CAR) T-cell therapy CAR T-cell therapy is ... of Health FOLLOW US Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp ...

  17. Lymphocyte GH-axis hormones in immunity.

    Science.gov (United States)

    Weigent, Douglas A

    2013-01-01

    The production and utilization of common ligands and their receptors by cells of the immune and neuroendocrine systems constitutes a biochemical information circuit between and within the immune and neuroendocrine systems. The sharing of ligands and receptors allows the immune system to serve as the sixth sense notifying the nervous system of the presence of foreign entities. Within this framework, it is also clear that immune cell functions can be altered by neuroendocrine hormones and that cells of the immune system have the ability to produce neuroendocrine hormones. This review summarizes a part of this knowledge with particular emphasis on growth hormone (GH). The past two decades have uncovered a lot of detail about the actions of GH, acting through its receptor, at the molecular and cellular level and its influence on the immune system. The production and action of immune cell-derived GH is less well developed although its important role in immunity is also slowly emerging. Here we discuss the production of GH, GH-releasing hormone (GHRH) and insulin-like growth factor-1 (IGF-1) and their cognate receptors on cells of the immune system and their influence via endocrine/autocrine/paracrine and intracrine pathways on immune function. The intracellular mechanisms of action of immune cell-derived GH are still largely unexplored, and it is anticipated that further work in this particular area will establish an important role for this source of GH in normal physiology and in pathologic situations.

  18. Ultrastructural localization of extracellular matrix proteins of the lymph node cortex: evidence supporting the reticular network as a pathway for lymphocyte migration

    Directory of Open Access Journals (Sweden)

    Sobocinski Gregg P

    2010-08-01

    Full Text Available Abstract Background The lymph node (LN is a crossroads of blood and lymphatic vessels allowing circulating lymphocytes to efficiently recognize foreign molecules displayed on antigen presenting cells. Increasing evidence indicates that after crossing high endothelial venules, lymphocytes migrate within the node along the reticular network (RN, a scaffold of fibers enwrapped by fibroblastic reticular cells (FRC. Light microscopy has shown that the RN contains specific extracellular matrix (ECM proteins, which are putative molecular "footholds" for migration, and are known ligands for lymphocyte integrin adhesion receptors. Results To investigate whether ECM proteins of the RN are present on the outer surface of the FRC and are thus accessible to migrating lymphocytes, ultrastructural immunohistochemical staining of cynomolgus monkey LN was performed using antibodies to human ECM proteins that were successfully employed at the light microscopic level. The fibrillar collagens I and III were observed primarily within the reticular network fibers themselves. In contrast, the matrix proteins laminin, fibronectin, collagen IV, and tenascin were observed within the reticular fibers and also on the outer membrane surface of the FRC. Conclusions These findings suggest a molecular basis for how the RN functions as a pathway for lymphocyte migration within the lymph node.

  19. Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4-mediated signaling via PI3 kinase-dependent Akt activation.

    Directory of Open Access Journals (Sweden)

    Karin Knieke

    Full Text Available Efficient adaptive immune responses require the localization of T lymphocytes in secondary lymphoid organs and inflamed tissues. To achieve correct localization of T lymphocytes, the migration of these cells is initiated and directed by adhesion molecules and chemokines. It has recently been shown that the inhibitory surface molecule CD152 (CTLA-4 initiates Th cell migration, but the molecular mechanism underlying this effect remains to be elucidated. Using CD4 T lymphocytes derived from OVA-specific TCR transgenic CD152-deficient and CD152-competent mice, we demonstrate that chemokine-triggered signal transduction is differentially regulated by CD152 via phosphoinositide 3-kinase (PI3K-dependent activation of protein kinase B (PKB/Akt. In the presence of CD152 signaling, the chemoattractant CCL4 selectively induces the full activation of Akt via phosphorylation at threonine 308 and serine 473 in pro-inflammatory Th lymphocytes expressing the cognate chemokine receptor CCR5. Akt signals lead to cytoskeleton rearrangements, which are indispensable for migration. Therefore, this novel Akt-modulating function of CD152 signals affecting T cell migration demonstrates that boosting CD152 or its down-stream signal transduction could aid therapies aimed at sensitizing T lymphocytes for optimal migration, thus contributing to a precise and effective immune response.

  20. The research progress of interleukin 7 receptor in the development of lymphocytes and pathogenesis of multiple sclerosis%白细胞介素7受体在淋巴细胞发育和多发性硬化中的研究进展

    Institute of Scientific and Technical Information of China (English)

    蔡世娇; 李玉皓

    2016-01-01

    白细胞介素7受体(IL7R)属于Ⅰ型细胞因子受体家族成员的跨膜受体,由特异性α链和γ链组成,在淋巴前体细胞、祖B细胞、T细胞、胸腺细胞、树突状细胞、髓样细胞及单核细胞中均可表达.生理情况下,IL7R是淋巴细胞发育中的关键调控分子.IL7R在多发性硬化(MS)的发生中发挥了重要的作用,其多态性与MS密切相关;IL7Rα中和抗体可显著改善实验性变态反应脑脊髓炎小鼠模型的表型.上述研究提示IL7R可能是MS新的治疗靶点.%Interleukin 7 receptor (IL7R) is a transmembrane receptor that belongs to the typeⅠcytokine receptor fami-ly. It consists of the cytokine-specific α-chain (IL7Rα, CD127) and the shared common cytokine γ-chain (γc, CD132). IL-7R is expressed in various cell types, including lymphoid precursor cells, pro-B cells, T cells, thymocytes, dendritic cells, myeloid cells and monocytes. Under physiological conditions, IL7R is a vital cytokine for development and survival of T and B cells. IL7R plays a key role in the pathogenesis of multiple sclerosis (MS). Single nucleotide polymorphisms (SNPs) in the gene encoding IL7Rαhave emerged through genetic studies of MS patients. In experimental autoimmune encephalomy-elitis (EAE) mouse model of MS, treatment with neutralizing anti-IL7Rαantibody results in significant improvement of EAE. Therefore, IL7R may serve as a novel target for MS therapies.

  1. Requirement for Innate Immunity and CD90+ NK1.1− Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

    Science.gov (United States)

    Moskalenko, Marina; Pan, Michael; Fu, Yichun; de Moll, Ellen H.; Hashimoto, Daigo; Mortha, Arthur; Leboeuf, Marylene; Jayaraman, Padmini; Bernardo, Sebastian; Sikora, Andrew G.; Wolchok, Jedd; Bhardwaj, Nina; Merad, Miriam; Saenger, Yvonne

    2015-01-01

    We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1−/− mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc−/−) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1− lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1− ILCs in chemo-immunotherapy. PMID:25600438

  2. Characterization of receptor-associated protein complex assembly in interleukin (IL)-2- and IL-15-activated T-cell lines

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Sánchez-Quiles, Virginia; Akimov, Vyacheslav

    2017-01-01

    to their functional dichotomy. In this study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is highly orchestrated by site-specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared...

  3. Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjogren's syndrome treated with Infliximab : a pilot study

    NARCIS (Netherlands)

    Anzola-Fuentes, L. K.; Chianelli, M.; Galli, F.; Glaudemans, A. W. J. M.; Martin, L. Martin; Todino, V.; Migliore, A.; Signore, A.

    2016-01-01

    Background: Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue (Tc-99m-EDDA/tricine-HYNI

  4. A simple method to detect complement receptors using baker's yeast: Y C rosettes.

    Science.gov (United States)

    Rivero, I; Abaca, H E; Vallés, R; Vannucci, J D; Diumenjo, M S; Moravenik, M B

    1979-01-01

    A technique is described to identify complement-receptor-bearing cells, using serum-treated baker's yeast as a ligand. The method consists of incubation of heat-killed baker's yeasts with fresh AB normal serum, freezing, thawing, and washing of the particles, followed by mixing with the cells. Serum is required to coat the yeasts for the rosette formation. Experiments designed to establish the serum factors responsible for the attachment of the particles to cells show that heat inactivation, chelating agents, or anti-C3 treatment prevent rosette formation. This is taken as evidence that yeasts (Y) are coated with complement (C) to compose the reagent for the YC rosette technique. The application of this technique to twenty-five normal individuals demonstrated that a mean of 11.6 per 100 lymphocytes (+/- 4.3) form rosettes; absolute number: 275 (+/- 160) rosette-forming lymphocytes per mm3. Either AB or autologous fresh serum can be used to coat the yeasts. A combined technique for YC plus E rosettes can be performed allowing the identification and enumeration of four populations of lymphocytes: (a) those having receptors for sheep erythrocytes, (b) complement-receptor-bearing lymphocytes, (c) those having both receptors (D lymphocytes), and (d) non-rosette-forming non-phagocytic cells.

  5. CD3 immunohistochemical staining in diagnosis of lymphocytic colitis

    DEFF Research Database (Denmark)

    Fiehn, Anne-Marie Kanstrup; Engel, Ulla; Holck, Susanne

    2016-01-01

    Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Traditionally, MC encompasses the 2 subgroups lymphocytic colitis (LC) and collagenous colitis, but recently, an additional subgroup, MC incomplete, has been introduced. Distinguishing between the subgroups relies exclusively...

  6. Prognostic significance of serum immunoglobulin pareprotein in chronic lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    杨舒

    2012-01-01

    Objective To investigate the incidence of serum immunoglobulin (Ig) paraprotein in chronic lymphocytic leukemia(CLL) ,and to explore its clinical associated laboratory features and prognostic implication. Methods Serum protein electrophoresis and immunofixation

  7. Lymphocyte apoptosis: role of uremia and permeability of dialysis membrane.

    Science.gov (United States)

    Soriano, Sagrario; Martín-Malo, Alejandro; Carracedo, Julia; Ramírez, Rafael; Rodríguez, Mariano; Aljama, Pedro

    2005-01-01

    Uremia is associated to host defense mechanism disorders. Lymphocyte apoptosis, which may cause alteration of the immune system, is increased in uremic patients. The aim of the present study was to determine if, in addition to uremia, dialysis membranes with different biocompatibility and permeability have an effect on lymphocyte apoptosis. Cell apoptosis and Fas expression were assessed using flow cytometry in four groups of patients: (1) uremic non-dialyzed (Non-D) patients; (2) hemodialysis (HD) patients on hemophan; (3) low-flux polysulfone, and (4) high-flux polysulfone membrane. Ten healthy volunteers were used as controls. At baseline, lymphocytes from patients on hemophan showed an increase in apoptosis (18.4 +/- 6.9%) as compared with Non-D (7.2 +/- 2.8%; p dialysis patients lymphocyte apoptosis is influenced not only by the biocompatibility but also by the permeability of the dialysis membrane.

  8. Chronic lymphocytic thyroiditis in a cynomolgus macaque (Macaca fascicularis).

    Science.gov (United States)

    Guzman, Roberto E; Radi, Zaher A

    2007-02-01

    Chronic lymphocytic thyroiditis characterized by multifocal follicular lymphoid cell infiltrates with germinal centers, thyroid acinar atrophy and pituitary cell hyperplasia/hypertrophy of the adenohypophysis was detected in a vehicle control, 4-year-old female Cynomolgus macaque in a routine toxicology study. Lymphoid cells of germinal centers were positive for the B-cell marker CD20 by immunohistochemistry (IHC), while remaining lymphocytes were positive for the T-cell marker CD3. Hypertrophied/hyperplastic pituitary cells were positive for thyroid stimulating hormone (TSH) by IHC, consistent with an adaptive response due to removal of hormonal negative feedback from the diseased thyroid gland. Features of this case are similar to chronic lymphocytic thyroiditis in humans, an autoimmune disorder also known as Hashimoto's disease. Chronic lymphocytic thyroiditis with compensatory pituitary changes may occur spontaneously in young, clinically normal cynomolgus macaques and its presence in drug treated animals should be interpreted with caution.

  9. The nature of the refractive granules in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Knowlton, N.P. Jr.; Hempelmann, L.H. [Los Alamos Scientific Lab., NM (United States)

    1949-04-19

    The number of refractive bodies in human lymphocytes increases in persons chronically exposed to low level doses of ionizing radiation. The observations of the optical properties, the histochemistry, and the method of formation of these bodies are described.

  10. Psychopatholgy, fundamental assumptions and CD-4 T lymphocyte ...

    African Journals Online (AJOL)

    in HIV-positive patients were associated with lower CD4 T-lymphocyte counts. Method: Self-rating .... depression) were excluded from participation. For comparison ... Examination (MMSE) and the HIV Dementia Scale (HDS). The. MMSE is the ...

  11. Consequences of TCDD treatment on intra-hepatic lymphocytes during liver regeneration.

    Science.gov (United States)

    Horras, Christopher J; Lamb, Cheri L; King, Allie L; Hanley, Jason R; Mitchell, Kristen A

    2012-01-01

    Increasing evidence demonstrates a physiological role for the aryl hydrocarbon receptor (AhR) in regulating hepatocyte cell cycle progression. Previous studies have used a murine model of liver regeneration to show that exposure to the potent exogenous AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppresses hepatocyte proliferation in vivo. Based on recent reports that natural killer (NK) cells negatively regulate liver regeneration, coupled with the well-established immunomodulatory effects of TCDD, it was hypothesized that alterations in lymphocyte activation contribute to the suppression of liver regeneration in TCDD-treated mice. To test this, mice were treated with TCDD (20 μg/kg) 1 day prior to 70% partial hepatectomy (PH), in which two-thirds of the liver was surgically resected. Lymphocytes were collected from the remnant liver and analyzed by flow cytometry. Whereas exposure to TCDD did not alter the number of NK cells or CD3(+) T-cells recovered from the regenerating liver, it reduced the percentage and number of intra-hepatic NKT cells 42 h after PH. With regard to lymphocyte activation, TCDD treatment transiently increased CD69 expression on NK and NKT cells 12 h after PH, but had no effect on intracellular levels of IFNγ in NK, NKT, or CD3(+) T-cells. To determine the relevance of NK cells to the suppression of liver regeneration by TCDD, mice were treated with anti-Asialo GM-1 (ASGM-1) antibody to deplete NK cells prior to TCDD treatment and PH, and hepatocyte proliferation was measured using bromodeoxyuridine incorporation. Exposure to TCDD was found to inhibit hepatocyte proliferation in the regenerating liver of NK cell-depleted mice and control mice to the same extent. Hence, it is unlikely that enhanced numbers or increased activation of NK cells contribute to the suppression of liver regeneration in TCDD-treated mice.

  12. Boron Induces Lymphocyte Proliferation and Modulates the Priming Effects of Lipopolysaccharide on Macrophages.

    Science.gov (United States)

    Routray, Indusmita; Ali, Shakir

    2016-01-01

    Chemical mediators of inflammation (CMI) are important in host defense against infection. The reduced capacity of host to induce the secretion of these mediators following infection is one of the factors in host susceptibility to infection. Boron, which has been suggested for its role in infection, is reported in this study to increase lymphocyte proliferation and the secretion of CMI by the lipopolysaccharide (LPS)-stimulated peritoneal macrophages in BALB/c mice. Boron was administered to mice orally as borax at different doses for 10 consecutive days, followed by the stimulation of animals with ovalbumin and isolation of splenocytes for proliferation assay. The lymphocyte subsets were determined by flow cytometry in spleen cell suspension. The mediators of inflammation, TNF-α, IL-6, IL-1β and nitric oxide (NO), were measured in culture supernatant of LPS-primed macrophages isolated from borax treated mice. TNF and ILs were measured by ELISA. NO was determined by Griess test. The expression of inducible nitric oxide synthase (iNOS) in macrophages was studied by confocal microscopy. Results showed a significant increase in T and B cell populations, as indicated by an increase in CD4 and CD19, but not CD8, cells. Boron further stimulated the secretion of TNF-α, IL-6, IL-1β, NO and the expression of iNOS by the LPS-primed macrophages. The effect was dose dependent and most significant at a dose level of 4.6 mg/kg b. wt. Taken together, the study concludes that boron at physiological concentration induces lymphocyte proliferation and increases the synthesis and secretion of pro-inflammatory mediators by the LPS-primed macrophages, more specifically the M1 macrophages, possibly acting through Toll-like receptor. The study implicates boron as a regulator of the immune and inflammatory reactions and macrophage polarization, thus playing an important role in augmenting host defense against infection, with possible role in cancer and other diseases.

  13. Boron Induces Lymphocyte Proliferation and Modulates the Priming Effects of Lipopolysaccharide on Macrophages.

    Directory of Open Access Journals (Sweden)

    Indusmita Routray

    Full Text Available Chemical mediators of inflammation (CMI are important in host defense against infection. The reduced capacity of host to induce the secretion of these mediators following infection is one of the factors in host susceptibility to infection. Boron, which has been suggested for its role in infection, is reported in this study to increase lymphocyte proliferation and the secretion of CMI by the lipopolysaccharide (LPS-stimulated peritoneal macrophages in BALB/c mice. Boron was administered to mice orally as borax at different doses for 10 consecutive days, followed by the stimulation of animals with ovalbumin and isolation of splenocytes for proliferation assay. The lymphocyte subsets were determined by flow cytometry in spleen cell suspension. The mediators of inflammation, TNF-α, IL-6, IL-1β and nitric oxide (NO, were measured in culture supernatant of LPS-primed macrophages isolated from borax treated mice. TNF and ILs were measured by ELISA. NO was determined by Griess test. The expression of inducible nitric oxide synthase (iNOS in macrophages was studied by confocal microscopy. Results showed a significant increase in T and B cell populations, as indicated by an increase in CD4 and CD19, but not CD8, cells. Boron further stimulated the secretion of TNF-α, IL-6, IL-1β, NO and the expression of iNOS by the LPS-primed macrophages. The effect was dose dependent and most significant at a dose level of 4.6 mg/kg b. wt. Taken together, the study concludes that boron at physiological concentration induces lymphocyte proliferation and increases the synthesis and secretion of pro-inflammatory mediators by the LPS-primed macrophages, more specifically the M1 macrophages, possibly acting through Toll-like receptor. The study implicates boron as a regulator of the immune and inflammatory reactions and macrophage polarization, thus playing an important role in augmenting host defense against infection, with possible role in cancer and other diseases.

  14. CCR4 versus CCR10 in human cutaneous TH lymphocyte trafficking.

    Science.gov (United States)

    Soler, Dulce; Humphreys, Tricia L; Spinola, Stanley M; Campbell, James J

    2003-03-01

    The chemokine receptors (CCRs) CCR4 and CCR10, and the cutaneous lymphocyte antigen (CLA), have each been proposed as critical mediators of skin-specific TH lymphocyte homing in mice and humans. CLA initiates skin homing by mediating E-selectin-dependent tethering and rolling within cutaneous venules, but the specific roles of CCR4 and CCR10 are unclear. We have generated an antihuman CCR10 monoclonal antibody (mAb; 1B5) to illuminate the individual contributions of these molecules. This mAb allows us to compare CCR10, CCR4, and CLA expression within human TH populations. The mAb 1B5 recognizes functional CCR10 expression, as chemotactic responsiveness to cutaneous T-cell-attracting chemokine (CTACK)/CCL27 (a CCR10 ligand) parallels the staining of TH subsets. We find CCR10 expressed by only a minority (approximately 30%) of blood-borne, skin-homing (CLA+/CCR4+) TH cells. However, essentially all members of the relatively small "effector" (CLA+/CCR4+/CD27-/CCR7-) skin-homing TH population express CCR10. Most skin-infiltrating lymphocytes in allergic delayed-type hypersensitivity (DTH) and bacterial chancroid skin lesions express both CCR4 and CLA, but only about 10% express CCR10. This suggests for the 2 models of TH skin homing studied here that CCR10+ TH cells have no advantage over other CLA+/CCR4+ TH cells in homing to cutaneous sites. We conclude that the skin-homing TH compartment is itself divided into distinct subpopulations, the smaller of which expresses both CCR4 and CCR10, and the larger of which expresses only CCR4. Thus, CCR10 is unlikely to be necessary for cutaneous homing of TH cells in the models studied here. CCR10 may instead play a role in the movement of specialized "effector" cutaneous TH cells to and/or within epidermal microenvironments.

  15. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

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    AnnaMaria Nosari

    2012-01-01

    Full Text Available

    Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles.

    Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  16. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-11-01

    Full Text Available Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  17. Leptomeningeal disease in chronic lymphocytic leukemia.

    Science.gov (United States)

    Lange, C P E; Brouwer, R E; Brooimans, R; Vecht, Ch J

    2007-12-01

    Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the western hemisphere, with an annual incidence of 3:100000. Commonly patients are asymptomatic but not rarely disease progression occurs in the setting of lymphadenopathy and extensive leukemic burden. Leptomeningeal involvement in patients with CLL is infrequent, with presenting symptoms of headache (23%), acute or chronic changes in mental status (28%), cranial nerve abnormalities (54%) including optic neuropathy (28%), weakness of lower extremities (23%) and cerebellar signs (18%). In this report, we discuss a CLL patient with leptomeningeal involvement, who presented with neurological symptoms as the first clinical sign, and a diagnosis of leptomeningeal was made based on CSF cytology and flow cytometry. Treatment consisted of radiation therapy and intrathecal chemotherapy with arabinoside-cytosine and systemic chemotherapy. On the basis of this patient-report together with 37 other previously reported cases, the clinical characteristics together with treatment options and outcome of leptomeningeal involvement in CLL are reviewed. Our case together with data from the literature indicate that a timely diagnosis and intensive treatment of leptomeningeal disease of CLL may lead to longstanding and complete resolution of neurological symptoms.

  18. Sampling site matters when counting lymphocyte subpopulations.

    Directory of Open Access Journals (Sweden)

    Benson Ogunjimi

    Full Text Available Clinical and scientific work routinely relies on antecubital venipunctures for hematological, immunological or other analyses on blood. This study tested the hypothesis that antecubital veins can be considered to be a good proxy for other sampling sites. Using a hematocytometer and a flow cytometer, we analyzed the cell counts from samples coming from the radial artery, the dorsal hand veins and the antecubital veins from 18 volunteers. Most surprisingly, we identified the greatest difference not to exist between arterial and venous circulation, but between the distal (radial artery & dorsal hand veins and proximal (antecubital veins sampling sites. Naïve T cells had a higher cell count distally compared to proximally and the reverse was true for effector memory T cells. Despite these differences there were high correlations between the different sampling sites, which partially supports our initial hypothesis. Our findings are crucial for the future design and interpretation of immunological research, and for clinical practice. Furthermore, our results suggest a role for interval lymph nodes in the trafficking of lymphocytes.

  19. Richter Syndrome in Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Vitale, Candida; Ferrajoli, Alessandra

    2016-02-01

    The term Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. RS is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. In the majority of cases, CLL transforms into RS as diffuse large B cell lymphoma (DLBCL), and a clonal relation between the two processes can be found. However, clonally unrelated RS can occur and transformations to other histologies beside DLBCL have been described. Recent data have shed some light on genetic characteristics that can influence and drive the transformation from CLL to RS. This molecular information has not been translated yet into significant treatment advances, and currently the therapy regimens for RS continue to rely on intensive chemotherapy combinations followed by stem cell transplant in suitable candidates. Based on the rapid pace of discoveries in the field of hematological malignancies and on the recent revolution in the therapeutic landscape for CLL and B cell lymphomas, new therapeutic options for RS might be available in the upcoming years.

  20. Tumor infiltrating lymphocytes in ovarian cancer.

    Science.gov (United States)

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.