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1
Puc, Irwin, Tzu-Chuan Ho, Ko-Lun Yen, Amrita Vats, Jih-Jin Tsai, Po-Lin Chen, Yu-Wen Chien, Yu-Chih Lo, and Guey Chuen Perng. "Cytokine Signature of Dengue Patients at Different Severity of the Disease." International Journal of Molecular Sciences 22, no. 6 (March 12, 2021): 2879. http://dx.doi.org/10.3390/ijms22062879.
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Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.
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Pelikan, Zdenek. "Expression of Surface Markers on the Blood Cells during the Delayed Asthmatic Response to Allergen Challenge." Allergy & Rhinology 5, no. 2 (January 2014): ar.2014.5.0087. http://dx.doi.org/10.2500/ar.2014.5.0087.
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Patients with bronchial asthma develop various types of asthmatic response to bronchial challenge with allergen, such as immediate/early asthmatic response (IAR), late asthmatic response (LAR) or delayed asthmatic response (DYAR), because of different immunologic mechanisms. The DYAR, occurring between 24 and 56 hours after the bronchial allergen challenge (p < 0.01), differs from IAR and LAR in clinical as well as immunologic features. This study investigates the expression of CD molecules (markers) on the surface of particular cell populations in the peripheral blood and their changes during the DYAR. In 17 patients developing the DYAR (p < 0.01), the bronchial challenge with allergen was repeated 2–6 weeks later. The repeated DYAR (p < 0.001) was combined with recording of CD molecule expression on various types of blood cells by means of flow cytometry up to 72 hours after the challenge. The results were expressed in percent of the mean relative fluorescence intensity. The DYAR was accompanied by (a) increased expression of CD11b, CD11b/18, CD16, CD32, CD35, CD62E, CD62L, CD64, and CD66b on neutrophils; CD203C on basophils; CD25and CD62L on eosinophils; CD14, CD16, CD64, and CD86 on monocytes; CD3, CD4, CD8, CD11a, CD18, and CD69 on lymphocytes; CD16, CD56, CD57, and CD94 on natural killer (NK) cells; and CD31, CD41, CD61, CD62P, and CD63 on thrombocytes and (b) decreased expression of CD18 and CD62L on eosinophils, CD15 on neutrophils, and CD40 on lymphocytes. These results suggest involvement of cell-mediated hypersensitivity mechanism, on participation of Th1- lymphocytes, neutrophils, monocytes, NK cells, and thrombocytes in the DYAR.
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Cerqueira, Bruno Antônio Veloso, Wendell Vilas Boas, Magda Oliveira Seixas, Elder Trindade Damasceno, Cyntia Cajado Souza, Mitermayer Galvão Reis, and Marilda Souza Goncalves. "Expression Levels of CD11b, CD18, CD32, CD62L (L-Selectin) and CD62P (P-Selectin) and Its Role in Sickle Cell Anemia Inflammatory State." Blood 112, no. 11 (November 16, 2008): 2504. http://dx.doi.org/10.1182/blood.v112.11.2504.2504.
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Abstract Vascular occlusions (VOC) underlie most of the acute and chronic sickle cell anemia (SCA) clinical complications and have been correlated to soluble adhesion molecules up regulation and leukocyte activation. A sequential process involving adhesion through selectins and integrins governs leukocyte recruitment to activated endothelium and to sickle red blood cells (RBC), resulting in heterotypic aggregation and VOC. The chronic hemolysis is the major cause of oxidative stress and it can induce transcriptions factors involved in the recruitment of adherent leukocytes in venules. In this work, we assessed the inflammatory potential of leukocytes in venous blood samples by examining cell surface antigens expression by flow cytometry, activation state and its association with hemolytic state in SCA patients group. The study was approved by the FIOCRUZ ethical committee and informed consents were signed by patients or official responsible. Leukocytes were obtained from 22 SCA patients and 22 healthy controls after RBC lyses and labeled with monoclonal anti-CD11b, anti-CD18, anti-CD32, anti-CD62L (L-Selectin) and anti-CD62P (P-Selectin). Leukocyte activation was stimulated by LPS. Statistical analyses were performed using SPSS version 9.0. The basal expression levels on leukocytes cell surface antigens from patients were not different from the control group. However, the CD62L expression levels were associated to C-reactive protein (CRP) higher levels and decrease of fetal hemoglobin in SCA patients (p=0.012). The SCA patients had higher CRP levels when compared to reference levels. Moreover, the data showed a co-expression of CD11b with CD18 (p<0.0001) and CD62P (p=0.011).The platelet count was positively correlated to CD11b expression (p=0.016) and the alanine transaminase high levels with the CD62P expression (p=0.012). Our results demonstrate a leukocyte chronic activation state by expression of CD62L related to CRP higher levels. Interestingly, the platelets could be activated by the indirect activation of CD62P by CD11b, participating of the inflammation state presents at vaso-occlusive events. It seems that the stress oxidative generated by the hemolytic state can contribute to endothelial dysfunction and vaso-occlusive events by CD62L activation in SCA. Fetal hemoglobin is a prognostic factor for several sickle cell complications and we showed that it can ameliorate the CD62L expression on leukocytes, decreasing the chronic inflammatory state of this disease. CD62L serves to as a homing receptor for naïve T lymphocytes and dendritic cells to lymph nodes, mediating the biding of T cells to high endothelial venules, in this view, this can be important marker to inflammatory state and vascular complications in SCA.
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Howard, C. J. "Ruminant cluster CD62L." Veterinary Immunology and Immunopathology 52, no. 4 (August 1996): 255–56. http://dx.doi.org/10.1016/0165-2427(96)05571-7.
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Burgess, Melinda, Peter Mollee, Richa Singhania, Catherine Cheung, Lynne Chambers, Reynolds Brent, Louise Smith, Nicholas Saunders, Nigel McMillan, and Devinder S. Gill. "CD62L Expression Is Associated With Chronic Lymphocytic Leukemia (CLL) Cell Survival In Vitro and Represents a Novel Therapeutic Target In CLL." Blood 122, no. 21 (November 15, 2013): 4136. http://dx.doi.org/10.1182/blood.v122.21.4136.4136.
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Abstract Background Recent advances in the treatment of chronic lymphocytic leukemia (CLL) have improved overall patient survival, however, the disease remains incurable. There is accumulating evidence that CLL cell resistance to apoptosis is attributable to microenvironmental factors mediated by cell-cell interactions and dysregulation of cytokine signals. Despite this resistance to apoptosis in vivo, CLL cells undergo rapid spontaneous apoptosis when removed from the body. Recently, we and others have demonstrated that this in vitro apoptosis could be reduced by culture of CLL cells at high density and/or in the presence of accessory and stromal cells. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of CLL. Methods and Results To dissect the complex microenvironmental interactions present in vitro,we profiled the immunophoenotypic changes that occur in long-term CLL PBMC cultures using flow cytometry. Significant changes were observed for 25 antigens, with increases observed in the expression of CD26, CD40, CD58, CD62L and CD103 and decreased expression observed in CD11c, CD32, CD49f, CD62P, CD80, CD106, CD140a, CD141, CD184, CD206 and CD273. The most highly upregulated marker was CD62L (L-selectin, a homing receptor thought to play a role in CLL cell trafficking) and this expression was confirmed in a further subset of patient samples. Using confocal microscopy CD62L expression was present in proliferation and survival niches involved in CLL in the bone marrow and lymph nodes. The pro-survival role of CD62L was examined using a functional blocking antibody which resulted in the significant loss of CLL cell survival. PBMCs from normal healthy controls were unaffected by CD62L antibody treatment, which reinforces that the response is restricted to CLL cells. Furthermore, CD62L antibody treatment caused a specific reduction of CD5+/CD19+ cells with a 49% reduction when compared to untreated PBMCs. This cytotoxic mediated response of CD62L blockade was not abrogated by the presence of stromal cell line HS-5, or endothelial cell line HUVECs suggesting that anti-CD62L therapy may be effective in vivo where pro-survival microenvironmental interactions are intact. We also demonstated a significant increase in cytotoxic responses when anti-CD62L treatment was combined with both fludarabine and mafosfamide compared to either each agent alone, or any two agents combined. Conclusion Immunophenotypic analysis of CLL cultures demonstrated that the expression of several cell surface markers change throughout in vitro culture. These markers are suggestive of cell-cell interactions that clearly provide survival signals. Blocking the activation and homing marker, CD62L, regulates CLL cell survival in vitro and induces cell death equivalent to current CLL chemotherapeutics. Overall, CD62L is a novel prosurvival effector that may represent an attractive therapeutic target in CLL. Disclosures: No relevant conflicts of interest to declare.
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Xu, Heping, Ayyakkannu Manivannan, Isabel Crane, Rosemary Dawson, and Janet Liversidge. "Critical but divergent roles for CD62L and CD44 in directing blood monocyte trafficking in vivo during inflammation." Blood 112, no. 4 (August 15, 2008): 1166–74. http://dx.doi.org/10.1182/blood-2007-06-098327.
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Abstract Using noninvasive in vivo imaging and experimental autoimmune uveoretinitis as a model, we show for the first time that the mechanisms controlling blood monocyte recirculation through peripheral and lymphoid tissues alter during inflammation. The recirculation of monocytes in mice with ocular inflammation but not controls was found to depend on the selectin CD62-ligand (CD62L) and on CD44. Not only was rolling efficiency ablated or markedly reduced in antibody-treated mice, but most of the labeled monocytes also disappeared from the circulation within seconds, anti-CD44–treated monocytes homing to the lymph nodes and anti–CD62L-treated monocytes homing to the spleen. Our data indicate that, although PSGL-1 has a partial role in the transmigration of monocytes into the inflamed retina, CD62L has a key role in regulating recruitment of monocytes to lymphoid tissue from the blood during inflammation and that CD44 is required to maintain CD62L+ inflammatory monocytes within the circulation during inflammation. This effect was systemic, because sequestered monocytes accumulated in mesenteric as well as draining cervical lymph nodes, and inflammation dependent, because depletion of circulating blood monocytes was much reduced or absent in normal mice and accumulations of adoptively transferred monocytes in the lymphoid tissues did not occur.
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Nesterova, I. V., V. V. Malinovskaya, S. V. Khaydukov, D. L. Nguyen Thi, G. A. Chudilova, and L. V. Lomtatidze. "DIFFERENTIATED EFFECTS OF GLUCOSAMINYLMURAMILDIPEPTIDE ON THE NONTRANSFORMED AND EXPERIMENTALLY TRANSFORMED PHENOTYPE OF CD62L+CD63+CD66d+ NEUTROPHILIC GRANULOCYTES IN CONVENTIONALLY HEALTHY PEOPLE." Medical Immunology (Russia) 20, no. 6 (December 15, 2018): 847–54. http://dx.doi.org/10.15789/1563-0625-2018-6-847-854.
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Modern studies have shown a high plasticity and phenotypic diversity of neutrophilic granulocytes (NG) provided by different receptors, which are diagnostic markers for the functional capacity of the cell in the course of their activities. We investigated NG from peripheral blood, obtained from healthy people of both sexes aged from 26 to 66 years. Evaluation of the neutrophil membrane receptor expression was carried out by flow cytometry. The relative amount of neutrophilic granulocytes expressing membrane CD62L, CD63, CD66d receptors and the intensity of their expression were determined according to their fluorescence intensities. The surface NG membrane receptors, i.e., CD62L, CD63, CD66d were studied upon the in vitro experimental influence of the following bacterial peptides: N-formyl-methionyl-leucyl-phenylalanine (FMLP, model 1); glucosaminylmuramyldipeptide (GMDP, model 2), and simultaneous incubation of NG blood with fMLP and GMDP (model 3). The in vitro treatment with fMLP in the in vitro model was used to transform the NG phenotype of conventionally healthy subjects, expressing CD62, CD63, CD66d molecules. The treatment caused a significantly decrease in both CD62L and the CD62L expression in relative amounts of neutrophilic granulocytes with a parallel increase of CD63 expression density. The effect of GMDP on the NG phenotype of conditionally healthy subjects did not change the amount of CD62L+NG and CD63+NG, and did not affect CD62L and CD63 expression density on the surface of NG. However, the amount of CD66d+NG was significantly increased with the unchanged expression of CD66d molecules. GMDP introduced together with the bacterial fMLP peptide was shown to neutralize some features of the NG phenotype transformation caused by fMLP, i.e., the amount of CD62L+ NG was restored by 22 % and the CD62L expression density increased significantly. At the same time, GMDP did not correct the negative effect of fMLP upon the number of CD63+NG and CD66d+NG, and on the CD63 and CD66d expression. Simultaneous addition of fMLP and GMDP did significantly increase the amount of CD66d+NG and expression density of CD63 molecules on the CD63+NG membrane as compared to intact NG of conditionally healthy subjects. The obtained data are important in order to justify some new immunotherapeutic strategies aimed at correction of the negatively transformed NG phenotype, which accompanies some infectious and inflammatory diseases of bacterial etiology with atypical clinical course.
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Drescher, Hannah K., Angela Schippers, Stefanie Rosenhain, Felix Gremse, Laura Bongiovanni, Alain de Bruin, Sreepradha Eswaran, et al. "L-Selectin/CD62L Is a Key Driver of Non-Alcoholic Steatohepatitis in Mice and Men." Cells 9, no. 5 (April 29, 2020): 1106. http://dx.doi.org/10.3390/cells9051106.
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CD62L (L-Selectin) dependent lymphocyte infiltration is known to induce inflammatory bowel disease (IBD), while its function in the liver, especially in non-alcoholic steatohepatitis (NASH), remains unclear. We here investigated the functional role of CD62L in NASH in humans as well as in two mouse models of steatohepatitis. Hepatic expression of a soluble form of CD62L (sCD62L) was measured in patients with steatosis and NASH. Furthermore, CD62L−/− mice were fed with a methionine and choline deficient (MCD) diet for 4 weeks or with a high fat diet (HFD) for 24 weeks. Patients with NASH displayed increased serum levels of sCD62L. Hepatic CD62L expression was higher in patients with steatosis and increased dramatically in NASH patients. Interestingly, compared to wild type (WT) mice, MCD and HFD-treated CD62L−/− mice were protected from diet-induced steatohepatitis. This was reflected by less fat accumulation in hepatocytes and a dampened manifestation of the metabolic syndrome with an improved insulin resistance and decreased cholesterol and triglyceride levels. Consistent with ameliorated disease, CD62L−/− animals exhibited an enhanced hepatic infiltration of Treg cells and a strong activation of an anti-oxidative stress response. Those changes finally resulted in less fibrosis in CD62L−/− mice. Additionally, this effect could be reproduced in a therapeutic setting by administrating an anti-CD62L blocking antibody. CD62L expression in humans and mice correlates with disease activity of steatohepatitis. CD62L knockout and anti-CD62L-treated mice are protected from diet-induced steatohepatitis suggesting that CD62L is a promising target for therapeutic interventions in NASH.
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Vassena, Lia, Erica Giuliani, Herwig Koppensteiner, Sebastian Bolduan, Michael Schindler, and Margherita Doria. "HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+T Lymphocytes." Journal of Virology 89, no. 10 (March 11, 2015): 5687–700. http://dx.doi.org/10.1128/jvi.00611-15.
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ABSTRACTLeukocyte recirculation between blood and lymphoid tissues is required for the generation and maintenance of immune responses against pathogens and is crucially controlled by the L-selectin (CD62L) leukocyte homing receptor. CD62L has adhesion and signaling functions and initiates the capture and rolling on the vascular endothelium of cells entering peripheral lymph nodes. This study reveals that CD62L is strongly downregulated on primary CD4+T lymphocytes upon infection with human immunodeficiency virus type 1 (HIV-1). Reduced cell surface CD62L expression was attributable to the Nef and Vpu viral proteins and not due to increased shedding via matrix metalloproteases. Both Nef and Vpu associated with and sequestered CD62L in perinuclear compartments, thereby impeding CD62L transport to the plasma membrane. In addition, Nef decreased total CD62L protein levels. Importantly, infection with wild-type, but not Nef- and Vpu-deficient, HIV-1 inhibited the capacity of primary CD4+T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1 infection impaired the signaling pathways and costimulatory signals triggered in primary CD4+T cells by CD62L ligation. We propose that HIV-1 dysregulates CD62L expression to interfere with the trafficking and activation of infected T cells. Altogether, this novel HIV-1 function could contribute to virus dissemination and evasion of host immune responses.IMPORTANCEL-selectin (CD62L) is an adhesion molecule that mediates the first steps of leukocyte homing to peripheral lymph nodes, thus crucially controlling the initiation and maintenance of immune responses to pathogens. Here, we report that CD62L is downmodulated on the surfaces of HIV-1-infected T cells through the activities of two viral proteins, Nef and Vpu, that prevent newly synthesized CD62L molecules from reaching the plasma membrane. We provide evidence that CD62L downregulation on HIV-1-infected primary T cells results in impaired adhesion and signaling functions upon CD62L triggering. Removal of cell surface CD62L may predictably keep HIV-1-infected cells away from lymph nodes, the privileged sites of both viral replication and immune response activation, with important consequences, such as systemic viral spread and evasion of host immune surveillance. Altogether, we propose that Nef- and Vpu-mediated subversion of CD62L function could represent a novel determinant of HIV-1 pathogenesis.
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Che Mohd Nassir, Che Mohd Nasril, Mazira Mohamad Ghazali, Amanina Ahmad Safri, Usman Jaffer, Wan Zaidah Abdullah, Nur Suhaila Idris, and Mustapha Muzaimi. "Elevated Circulating Microparticle Subpopulations in Incidental Cerebral White Matter Hyperintensities: A Multimodal Study." Brain Sciences 11, no. 2 (January 20, 2021): 133. http://dx.doi.org/10.3390/brainsci11020133.
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Asymptomatic (or “silent”) manifestations of cerebral small vessel disease (CSVD) are widely recognized through incidental findings of white matter hyperintensities (WMHs) as a result of magnetic resonance imaging (MRI). This study aims to examine the potential associations of surrogate markers for the evaluation of white matter integrity in CSVD among asymptomatic individuals through a battery of profiling involving QRISK2 cardiocerebrovascular risk prediction, neuroimaging, neurocognitive evaluation, and microparticles (MPs) titers. Sixty asymptomatic subjects (mean age: 39.83 ± 11.50 years) with low to moderate QRISK2 scores were recruited and underwent neurocognitive evaluation for memory and cognitive performance, peripheral venous blood collection for enumeration of selected MPs subpopulations, and 3T MRI brain scan with specific diffusion MRI (dMRI) sequences inclusive of diffusion tensor imaging (DTI). WMHs were detected in 20 subjects (33%). Older subjects (mean age: 46.00 ± 12.00 years) had higher WMHs prevalence, associated with higher QRISK2 score and reduced processing speed. They also had significantly higher mean percentage of platelet (CD62P)- and leukocyte (CD62L)-derived MPs. No association was found between reduced white matter integrity—especially at the left superior longitudinal fasciculus (LSLF)—with age and neurocognitive function; however, LSLF was associated with higher QRISK2 score, total MPs, and CD62L- and endothelial cell-derived MPs (CD146). Therefore, this study establishes these multimodal associations as potential surrogate markers for “silent” CSVD manifestations in the well-characterized cardiocerebrovascular demographic of relatively young, neurologically asymptomatic adults. Furthermore, to the best of our knowledge, this study is the first to exhibit elevated MP counts in asymptomatic CSVD (i.e., CD62P and CD62L), which warrants further delineation.
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Zhang, Jifeng, Brice E. Barefoot, Wenjian Mo, Divino Deoliveira, Jessica Son, Xiuyu Cui, Elizabeth Ramsburg, and Benny J. Chen. "CD62L− memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice." Blood 119, no. 26 (June 28, 2012): 6344–53. http://dx.doi.org/10.1182/blood-2011-03-342055.
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A major challenge in allogeneic hematopoietic cell transplantation is how to transfer T-cell immunity without causing graft-versus-host disease (GVHD). Effector memory T cells (CD62L−) are a cell subset that can potentially address this challenge because they do not induce GVHD. Here, we investigated how CD62L− T cells contributed to phenotypic and functional T-cell reconstitution after transplantation. On transfer into allogeneic recipients, CD62L− T cells were activated and expressed multiple cytokines and cytotoxic molecules. CD62L− T cells were able to deplete host radioresistant T cells and facilitate hematopoietic engraftment, resulting in enhanced de novo T-cell regeneration. Enhanced functional immune reconstitution was demonstrated in CD62L− T-cell recipients using a tumor and an influenza virus challenge model. Even though CD62L− T cells are able to respond to alloantigens and deplete host radioresistant immune cells in GVHD recipients, alloreactive CD62L− T cells lost the reactivity over time and were eventually tolerant to alloantigens as a result of prolonged antigen exposure, suggesting a mechanism by which CD62L− T cells were able to eliminate host resistance without causing GVHD. These data further highlight the unique characteristics of CD62L− T cells and their potential applications in clinical hematopoietic cell transplantation.
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Bajnok, Anna, Maria Ivanova, János Rigó, and Gergely Toldi. "The Distribution of Activation Markers and Selectins on Peripheral T Lymphocytes in Preeclampsia." Mediators of Inflammation 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8045161.
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Introduction. Impaired maternal immune tolerance resulting in systemic inflammation plays a pivotal role in the pathogenesis of preeclampsia. Phenotypical changes of monocytes and neutrophil granulocytes have already been studied in preeclampsia, and some studies also included T lymphocyte activation markers; however, the results are controversial and a comprehensive analysis of activation markers is lacking. The characteristics of cellular adhesion molecules in preeclampsia are yet to be described.Material and Methods. Peripheral blood samples of 18 preeclamptic patients and 20 healthy pregnant women in the third trimester were evaluated using flow cytometry to characterize the cell surface expression of T lymphocyte activation markers and selectins.Results. We found an elevated ratio of HLA-DR and CD122-, CD62E-, and CD62L-expressing cells among the CD4+ T lymphocytes in PE in comparison to healthy pregnancy. No alterations were found in the prevalence of CD69-, CD25-, and CD62P-expressing lymphocytes and CD11c-expressing monocytes.Conclusions. Our findings support the role of activated T lymphocytes and specific cell adhesion molecules in the pathogenesis of preeclampsia.
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Ito, Yusuke, Fumio Nakahara, Yuki Kagoya, and Mineo Kurokawa. "CD62L Expression Level Dictates the Cell Fate of Myeloid Progenitors in Mice and Humans." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-134753.
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Hematopoietic cells are hierarchically differentiated from hematopoietic stem cells through several progenitors. Recent studies showed that each progenitor population has significant heterogeneity and some of the subsets have skewed differentiation potential. However, it has not been elucidated how and when common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) acquire different fates. We hypothesized that progenitor cells with skewed differentiation potential had acquired a part of gene expression profiles of more differentiated cells. By analyzing publicly available single-cell RNA sequencing data of human and murine CMPs and GMPs, we thoroughly explored surface markers with heterogeneous expression patterns and identified CD62L as a candidate to refine the differentiation potential of CMPs and GMPs. First, at CMP level, we clarified that CD62L-low CMPs had genuine CMP potential, whereas CD62L-high CMPs were mostly restricted to GMP potentials in both mice and humans. CD62L expression on CMPs was widely distributed and when divided into low, middle, and high fraction, colony forming-cell assay showed that murine CD62L-high CMPs mostly differentiated into CD11b-positive granulocytes and macrophages (97.4 ± 1.7%), whereas CD62L-low CMPs produced many erythroid and megakaryocytic colonies (38.7 ± 3.3%), and human CMPs had similar tendency. Also, liquid culture assay showed that murine CD62L-low CMPs differentiated into both GMPs (43.3 ± 4.1%) and megakaryocyte-erythrocyte progenitors (MEPs) (20.6 ± 3.7%), while CD62L-high CMPs mainly produced GMPs (82.8 ± 1.7%) and the proportion of MEPs was only 1.3 ± 0.1%. As for in vivo kinetics, we transplanted CD62L-low and high CMPs from GFP-expressing mice into irradiated wild-type mice, thus donor-derived platelets can be detected as GFP-positive. On day 7 after transplantation of each 15,000 cells, GFP-positive platelets from CD62L-low CMPs accounted for 9.8 ± 2.7% of all platelets, meanwhile CD62L-high CMPs accounted for only 0.20 ± 0.14%, which reinforced our hypothesis. Moreover, we performed transcriptome analysis using data of murine and human CMPs and focused on several transcription factors. Gata1, Klf1, Tal1 and Gfi1b are important transcription factors for erythroid and megakaryocytic differentiation, and these expressions were exclusively high in CD62L-low CMPs. On the other hand, Spi1 and Irf8 are important for differentiation into granulocytes and monocytes, and these expressions were higher in CD62L-high CMPs, which further corroborated the role of CD62L as a marker for refining the differentiation fate of CMPs. Second, at GMP level, we found that part of CD62L-neg GMPs possess remaining CMP potential and CD62L-low GMPs were skewed to granulocyte differentiation. CD62L expression on GMPs was mostly positive, but when we defined lowest 10% of GMPs as CD62L-neg GMPs, colony-forming cell assay in mice showed that part of CD62L-neg GMPs produced erythroid and megakaryocytic colonies (3.9 ± 2.6%), which suggested that this subset still possesses CMP potential. In vivo transplantation experiment using GFP-positive mice showed that CD62L-neg GMPs produced GFP-positive platelets slightly (0.02 ± 0.01%), but no platelets from CD62L-positive GMPs. Also, single-cell RNA-seq data revealed that part of CD62L-neg GMPs had CMP-specific gene expression pattern, suggesting that the bona fide GMPs were restricted to CD62L-positive GMPs. Next, we divided GMPs into CD62L-low and high GMPs, and performed colony-forming cell assay. CD62L-low GMPs produced granulocyte colony (CFU-G) 73.2 ± 6.1% and macrophage colony (CFU-M) 17.4 ± 3.3%, whereas CD62L-high GMPs produced CFU-G 46.6 ± 1.7% and CFU-M 42.9 ± 2.7%, which suggested that CD62L-low GMPs were granulocyte-skewed population. Also, we performed in vivo transplantation assay using Ly5.1 and Ly5.2 mice. On day 5 after transplantation, murine CD62L-low GMPs produced more neutrophils (87.6 ± 3.1%) in spleen than bulk GMPs (78.9 ± 1.9 %), which further confirmed this hypothesis. In summary, our in vitro and in vivo experiment and transcriptome analysis revealed that CMPs and GMPs had high heterogeneity. CD62L expression level refines the definition of CMPs and GMPs in both mice and humans, and elucidates the differentiation mechanism of myeloid cells in more detail. Disclosures Nakahara: Bristol-Myers Squibb Company: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria. Kagoya:NIPPON SHINYAKU CO.,LTD.: Research Funding; Bristol-Myers Squibb Company: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding. Kurokawa:Eisai: Research Funding, Speakers Bureau; Teijin: Research Funding; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Shire Plc: Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau.
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Sopper, Sieghart, Satu Mustjoki, Angelica Loskog, Bjorn T. Gjertsen, Ute Mark, Jens Haenig, Nidas Jurjonas, et al. "Reduced Expression of CD62L Is Associated with Increased ADAM17 Activity and Predicts Molecular Response to Nilotinib Therapy in Patients with Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP)." Blood 124, no. 21 (December 6, 2014): 4522. http://dx.doi.org/10.1182/blood.v124.21.4522.4522.
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Abstract Background: In CML, immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Little is known about potential immune-modulatory effects of nilotinib in vivo. A comprehensive monitoring program to characterize nilotinib-induced immunological changes was set up as a substudy to the ENEST1st study (NCT01061177), which is focused on examining the role of first-line nilotinib therapy in CML-CP. Aims: The identification of immunological changes induced by nilotinib and definition of immunological surrogates for response prediction in newly diagnosed CML-CP patients. Methods: Peripheral blood was taken prior to treatment initiation and after 6 and12 months (mo) from 50 patients treated on the ENEST1st study. Whole blood was phenotyped by 9-color flow cytometry employing 6 panels of antibodies to determine various leukocyte populations and expression of differentiation and activation markers. Soluble factors in plasma were measured by ELISA. Changes in immune parameters were correlated to clinical endpoints. Results: 55% of the patients included in this substudy achieved MMR at 6 mo, 75% at 12 mo and 79% at 24 mo of therapy. MR4.5 was achieved by 5%, 18%, 24% of patients at 6, 12 and 24 mo of therapy, respectively. Expression of L-selectin (CD62L), a known lymph node homing marker, was very low on T cells at baseline (median 5.7%) and the proportion of CD62L-expressing cells among CD4+ and CD8+ T cells negatively correlated with SOKAL score and spleen size. During treatment, CD62L expression on both T cell subsets significantly increased (median 72.3%) to normal levels at mo 6. Moreover, higher proportions of CD62L+ cells among both CD4+ and CD8+ T cells at baseline were negatively associated with lower BCR-ABL1 mRNA burden at 3, 6, 9, 15 and 18 mo. Cumulative response rates for MMR and MR4 were significantly higher in patients with high proportions (cutoff: >25%) of CD62L expressing T cells when compared to patients with low proportions of CD62L+ cells. A detailed characterization of other T cell differentiation marker, such as CD45RA, CD45R0, CD28, CD27 and CD95, did not reveal a reduction of cells usually expressing high CD62L levels, such as naïve T cells. CD62L expression levels on granulocytes were also low at baseline and increased to normal levels during nilotinib therapy. Low levels of CD62L expression were associated with elevated plasma levels of soluble CD62L before treatment initiation. Washing whole blood from treatment naïve patient several times before staining partially restored immunoreactivity for CD62L, and plasma taken at baseline but not after treatment initiation reduced CD62L signal on normal T cells, indicating that interference by increased levels of soluble CD62L with assessment of surface CD62L at least in part contributes to low CD62L expression. Importantly, ADAM17 (TACE, CD156b), the metalloproteinase responsible for CD62L shedding was increased on granulocytes and monocytes but not on T cells of CML patients when compared to normal controls suggesting that reduced levels on CD62L on T cells were mediated by ADAM17 on myeloid cells. Conclusion: We here show for the first time the prognostic impact of reduced CD62L expression levels at baseline for later molecular response to nilotinib in early CML-CP. Decreased expression of CD62L is at least in part due to increased CD62L-cleavage, probably by ADAM17, which is aberrantly expressed on the clonal myeloid cells. One may speculate that decreasing CD62L expression on T cells may interfere with immune surveillance of CML cells and that ADAM17 might be a target for adjunctive therapy. Larger prospective studies are needed to confirm the prognostic relevance of increased soluble CD62L and reduced T cell CD62L expression levels for molecular response in TKI-treated CML-CP. Disclosures Sopper: Novartis: Travel Grants Other. Mustjoki:Novartis: Research Funding. Gjertsen:Novartis: Research Funding. Mark:Novartis: Employment. Haenig:Novartis: Employment. Jurjonas:Novartis: Employment. Giles:Novartis: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding; Ariad: Research Funding; Pfizer: Research Funding. Ossenkoppele:Novartis: Research Funding. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Wolf:Nocartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Chen, Benny J., Xiuyu Cui, Jessica Son, and Nelson J. Chao. "Promotion of Stem Cell-Derived New T Cell Generation by CD62L− Memory T Cells Requires Alloantigen Recognition." Blood 104, no. 11 (November 16, 2004): 3041. http://dx.doi.org/10.1182/blood.v104.11.3041.3041.
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Abstract We recently demonstrated that non-GVHD-inducing CD62L− memory T cells promote T cell regeneration from hematopoietic stem/progenitor cells in the C57BL/6 (H2b) to BALB/c (H2d) bone marrow transplantation model (BLOOD 2004,103:1534). In this model, 1×107 T cell depleted bone marrow from C57BL/6, CD45.2, Thy1.2 mice and 1×106 CD62L− T cells from C57BL/6, CD45.1, Thy1.1 mice are used and the recipient mice are lethally irradiated. This animal model allows us to differentiate the T cells of different origin by flow cytometry. In the current study, we further investigated how CD62L− T cells promote new T cell generation and whether there is any functional relevance using the same model. Previous data suggest that the promoting effect of CD62L− T cells on stem cell-derived new T cell generation is associated with the facilitation of engraftment because host radioresisdant T cells were depleted in CD62L− T cell recipients but not in the T cell-depleted bone marrow control mice. To determine whether CD62L− T cells promote new T cell generation by overcoming T cell-mediated host resistance, we performed the experiment using SCID mice as recipients. SCID mice lack both T and B cells. In consistent with the previous results, serial peripheral blood T cell counts following bone marrow transplantation demonstrated that the promoting effect of CD62L− T cells were dramatically decreased in the SCID recipients, indicating that CD62L− T cell promote new T cell regeneration by overcoming host resistance. To examine whether CD62L− T cells overcome host resistance by “veto effect”, we performed the experiment using CD62L− T cells from (BALB/cxC57BL/6)F1 mice. T cells from F1 mice do not recognize the parental recipient as non-self and can not initiate classical T cell response against the parental antigens. It was previously reported by other investigators that T cells from F1 mice preserve “veto effect”. However, no promoting effect was observed in the recipients of CD62L− T cells from the F1 mice, demonstrating that “veto effect” is not involved. Rather, alloantigen recognition by donor CD62L− T cells is required for the promoting effect. In agreement with the hypothesis that CD62L− T cells promote new T cell generation by enhancing engraftment through overcoming host resistance, both white cell and platelet recovery in peripheral blood was accelerated in CD62L− T cell recipients comparing with that in the control T cell-depleted bone marrow recipients. Finally, we sought to determine whether these findings have any functional relevance in vivo. We evaluated the functional immune recovery by measuring the ability to inhibit the growth of a recipient-type leukemia/lymphoma cell line called BCL1 cells injected intravenously into the transplantation recipients on day +7. While six out of eight T cell-depleted bone marrow control mice developed tumor and died within 30 days after bone marrow transplantation, none of the CD62L− T cell recipients (n=12) developed tumor and all survived more than 60 days after transplantation. As expected, none of the CD62L− T cell recipients developed graft-versus-host disease. Our data indicate that CD62L− T cells promote new T cell generation by enhancing engraftment through overcoming host resistance. This promoting effect requires alloantigen recognition and is not mediated by “veto effect”. Our current focus is trying to determine how allogeneic CD62L− T cells overcome host resistance without causing graft-versus-host disease.
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Sopper, Sieghart, Satu Mustjoki, Deborah White, Timothy Hughes, Peter Valent, Andreas Burchert, Bjørn T. Gjertsen, et al. "Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia." Journal of Clinical Oncology 35, no. 2 (January 10, 2017): 175–84. http://dx.doi.org/10.1200/jco.2016.67.0893.
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Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.
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Suzuki, Shoji, Makoto Ishii, Takanori Asakura, Ho Namkoong, Satoshi Okamori, Kazuma Yagi, Hirofumi Kamata, et al. "ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 6 (June 1, 2020): L1172—L1182. http://dx.doi.org/10.1152/ajplung.00214.2019.
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Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre ( Adam17ΔMx1) mice (8–10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.
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Voortman, Margarete Maria, Paul Greiner, Daniel Moser, Martin Helmut Stradner, Winfried Graninger, Adrian Moser, Bernd Haditsch, et al. "The effect of disease modifying therapies on CD62L expression in multiple sclerosis." Multiple Sclerosis Journal - Experimental, Translational and Clinical 4, no. 3 (July 2018): 205521731880081. http://dx.doi.org/10.1177/2055217318800810.
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Background The increasing armamentarium of disease-modifying therapies in multiple sclerosis is accompanied by potentially severe adverse effects. The cell-adhesion molecule CD62L, which facilitates leukocyte extravasation, has been proposed as a predictive marker for treatment tolerability. However, pre-analytical procedures might impact test results, thereby limiting its clinical usability. Whether the immediate analysis of CD62L expression of peripheral blood mononuclear cells can aid treatment decision making is yet unclear. Objective To investigate the effect of various disease-modifying therapies in multiple sclerosis on CD62L expression of CD3+CD4+ peripheral blood mononuclear cells in freshly collected blood samples. Methods We collected peripheral blood samples from patients with clinically isolated syndrome and multiple sclerosis (baseline/follow up n = 234/ n = 98) and healthy controls ( n = 51). CD62L+CD3+CD4+ expression was analysed within 1 hour by fluorescence-activated cell sorting. Results CD62L+CD3+CD4+ expression was significantly decreased in patients treated with natalizumab ( n = 26) and fingolimod ( n = 20) and increased with dimethyl-fumarate ( n = 15) compared to patients receiving interferon/glatiramer acetate ( n = 90/30) or no disease-modifying therapies ( n = 53) and controls ( n = 51) ( p<0.001). CD62L expression showed temporal stability during unchanged disease-modifying therapy usage, but increased after natalizumab withdrawal and decreased upon fingolimod introduction. Conclusion CD62L+CD3+CD4+ expression is altered in patients treated with different disease-modifying therapies when measured in freshly collected samples. The clinical meaning of CD62L changes under disease-modifying therapies warrants further investigation.
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Hossain, Mohammad, Andrew T. Gewirtz, John D. Roback, and Edmund K. Waller. "Flagellin, a TLR5 Agonist, Down-Regulate CD62L on Donor T Cells and Limit GvHD in Allogeneic Hematopoietic Stem Cell Transplantation." Blood 112, no. 11 (November 16, 2008): 3521. http://dx.doi.org/10.1182/blood.v112.11.3521.3521.
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Abstract Bacground: Graft-vs-host disease (GvHD) is a major complication in allogeneic Hematopoietic Stem Cell Transplant (HSCT) recipients. Flagellin is a bacterial protein and a TLR5 agonist that showed diverse immunological responses in both human and animal including both activation of dendritic cells and immuno-suppression. We recently observed that prophylactic use of flagellin protected allogeneic HSCT recipient from GvHD without affecting host immune reconstitution. Acute GvHD has been reported to be mediated by allo-reactive CD62L+ T cells, and over 80% of murine naïve splenic CD4+ and CD8+ T cells express CD62L. In order to test the effect of flagellin on GvHD mediated by the CD62L+ CD4+ and CD62L+CD8+ donor T cells, we investigated clinical manifestation of GvHD as well as the in vivo expression of CD62L on donor T cells in flagellin treated versus control treated allogeneic HSCT recipients. Methods: We established a parent →F1 MHC major mismatched model (C57BL/6 → C57BL/6 × BALB/c) for allogeneic HSCT for which GvHD is the major complication. Recipient mice received 5 × 10^6 T cell depleted (TCD) bone marrow cells and 5×10^6 or 10×10^6 CFSE labeled donor splenocytes from naïve C57Bl/6 congenic donors. 50 μg flagellin per recipient was administered intraperitoneally 3 hours before irradiation and 24 hours after allogeneic HSCT (treated). CB6F1 recipients that received no flagellin (untreated) and recipients of syngeneic HSCT were used as control. Recipients were sacrificed on day 66+ transplant and the numbers of CD62L+ T cells and foxp3+CD4+CD25+ T cells were determined by FACS. Recipients of CFSE treated donor splenocytes were sacrificed on day 4 post HSCT, splenocytes were harvested and analyzed for CD62L expression on T cell subsets undergone in vivo cell division by Flow cytometry. 5 mice were used per group. Results: Flagellin treated recipients did not have GvHD and had no mortality. Untreated control recipients had 87% survival at 30 days post transplant and had signs of chronic GvHD. While total cell number and also donor spleen- and BM-derived CD4+ and CD8+ T cells per spleen in untreated recipients were significantly lower compared to flagellin treated recipients (p=0.0006) on day 66 post transplant, persistent of donor spleen-derived CD62L+CD4+ T cells and CD62L+CD8+ T cells per spleen were not significantly different (p=0.13 and p=0.07, respectively). Moreover, higher number of foxp3+CD25+CD4+ regulatory T cells were found in the spleen and thymus in treated recipients compared to untreated recipients. Within day 4 post transplant, the number of CD4+ T cells per spleen of treated and untreated recipients increased significantly compared to syngeneic recipients (p=0.001 and p=0.03, respectively). Although equivalent numbers of CD62L+CD4+ T cells were observed in both treated and untreated recipients (p=0.3), significantly increased numbers of CD62L+CD8+ T cells was found in treated recipients compare to untreated recipients (p=0.02). Moreover, significantly higher numbers of divided (far left CFSE staining population) CD62L+CD4+ and CD62L+CD8+ T cells were found in recipients of treated splenocytes within day 4 post transplant followed by down regulation of CD62L surface marker compared to untreated recipients (p=0.02 and p=0.01, respectively). Conclusion: Flagellin treated recipients had limited GvHD and had rapid increased divided CD4+CD62L+ T cells followed by CD62L-ve activated CD4+ T cells per spleen in treated recipients compared to untreated recipients may be one of the major affect mediated by flagellin. Flagellin-TLR5 receptor agonistic effect may reduce production of biological factor(s) essential to generate allo-reactive T cells or directly stimulate CD62L+CD4+ and CD62L+CD8+ T cells in different activation status other than allo-reactive T cells; maintain a balanced immune reconstitution in lymphoid organs by producing regulatory T cells through their thymus. Therefore, use of flagellin may be a novel therapeutic approach to treat blood cancer patients with allogeneic HSCT without GvHD and toxicity.
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Schwab, Nicholas, Tilman Schneider-Hohendorf, Béatrice Pignolet, Michela Spadaro, Dennis Görlich, Ingrid Meinl, Susanne Windhagen, et al. "PML risk stratification using anti-JCV antibody index and L-selectin." Multiple Sclerosis Journal 22, no. 8 (October 2, 2015): 1048–60. http://dx.doi.org/10.1177/1352458515607651.
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Background: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters. Objective: This study aimed at verifying and integrating both parameters into one algorithm for risk stratification. Methods: Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients). Results: CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor “CD62L low” increasing a patient’s relative risk 55-fold ( p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group. Conclusions: Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.
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Ermann, Joerg, Petra Hoffmann, Matthias Edinger, Suparna Dutt, Francis G. Blankenberg, John P. Higgins, Robert S. Negrin, C. Garrison Fathman, and Samuel Strober. "Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD." Blood 105, no. 5 (March 1, 2005): 2220–26. http://dx.doi.org/10.1182/blood-2004-05-2044.
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AbstractCD4+CD25+ regulatory T (Treg) cells are potent modulators of alloimmune responses. In murine models of allogeneic bone marrow transplantation, adoptive transfer of donor CD4+CD25+ Treg cells protects recipient mice from lethal acute graft-versus-host disease (aGVHD) induced by donor CD4+CD25- T cells. Here we examined the differential effect of CD62L+ and CD62L- subsets of CD4+CD25+ Treg cells on aGVHD-related mortality. Both subpopulations showed the characteristic features of CD4+CD25+ Treg cells in vitro and did not induce aGVHD in vivo. However, in cotransfer with donor CD4+CD25- T cells, only the CD62L+ subset of CD4+CD25+ Treg cells prevented severe tissue damage to the colon and protected recipients from lethal aGVHD. Early after transplantation, a higher number of donor-type Treg cells accumulated in host mesenteric lymph node (LN) and spleen when CD4+CD25+CD62L+ Treg cells were transferred compared with the CD62L- subset. Subsequently, CD4+CD25+CD62L+ Treg cells showed a significantly higher capacity than their CD62L- counterpart to inhibit the expansion of donor CD4+CD25- T cells. The ability of Treg cells to efficiently enter the priming sites of pathogenic allo-reactive T cells appears to be a prerequisite for their protective function in aGVHD.
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Barbarash, L., I. Kudryavtsev, N. Rutkovskaya, and A. Golovkin. "T Cell Response in Patients with Implanted Biological and Mechanical Prosthetic Heart Valves." Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/1937564.
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The study was aimed at assessing T cell subsets of peripheral blood from recipients of long-term functioning (more than 60 months) biological and mechanical heart valve prostheses. The absolute and relative number of CD4 and CD8 T cell subsets was analyzed: naïve (N, CD45RA+CD62L+), central memory (CM, CD45RA−CD62L+), effector memory (EM, CD45RA−CD62L−), and terminally differentiated CD45RA-positive effector memory (TEMRA, CD45RA+CD62L−) in 25 persons with biological and 7 with mechanical prosthesis compared with 48 apparently healthy volunteers. The relative and absolute number of central memory and naïve CD3+CD8+in patients with biological prosthesis was decreased (p<0.001). Meanwhile the number of CD45RA+CD62L−CD3+CD8+and CD3+CD4+was increased (p<0.001). Patients with mechanical prosthesis had increased absolute and relative number of CD45RA+CD62L−CD3+CD8+cells (p=0.006). Also the relative number of CD3+CD4+cells was reduced (p=0.04). We assume that altered composition of T cell subsets points at development of xenograft rejection reaction against both mechanical and biological heart valve prostheses.
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Carlson, Michael J., Hans E. Siedel, and Jonathan S. Serody. "CD62L Is Not Critical for T Regulatory Cell-Mediated Protection from Lethal Acute GVHD." Blood 110, no. 11 (November 16, 2007): 2178. http://dx.doi.org/10.1182/blood.v110.11.2178.2178.
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Abstract INTRODUCTION: Graft-versus-host disease (GVHD) is a major complication following allogeneic bone marrow transplantation. Despite advances in understanding the etiology of GVHD it remains a formidable obstacle to the widespread application of BMT. T regulatory (Treg) cells have been shown to inhibit GVHD while preserving the beneficial graft-versus-leukemia (GVL) effect. Published studies by numerous groups, including our own, have shown the importance of Treg homing molecule expression in preventing GVHD. Of note, the Treg population that expressed high levels of the adhesion molecule L-Selectin (CD62L) was shown to be capable of promoting BM engraftment and inhibiting lethal acute GVHD, whereas the CD62Llo population was not. While these studies provided evidence that the phenotype of the CD62Lhi Treg population was responsible for inhibition of GVHD they did not directly assess the role of CD62L. METHODS: To investigate the importance of CD62L in Treg mediated protection from GVHD we utilized a well-described parent into F1 model. We transferred Tregs (2×106) from CD62L deficient mice (CD62L−/−) or wild type (WT) C57BL/6 mice with WT naïve T cell effectors (5×106) into lethally irradiated B6D2 recipients. Our results demonstrated similar survival of recipient mice receiving CD62L−/− Tregs (40% survival) compared to those receiving WT Tregs (60% survival: p =0.66). In addition fluorescence microscopy revealed no difference in GFP+ T cell effector migration/accumulation in GVHD target organs (liver, lung, GI tract) or secondary lymphoid organs (spleen, mesenteric lymph node, inguinal lymph node, Peyers Patches) in the presence of CD62L−/− or WT Tregs. Also, we tracked the migration of GFP+ CD62L−/− Tregs in vivo by fluorescence microscopy and found they were able to efficiently migrate to secondary lymphoid organs and GVHD target organs. Surprisingly, GFP+ CD62L−/− Tregs were also able to home to peripheral lymph nodes. CONCLUSIONS: These results suggest CD62L is dispensable for Treg mediated suppression of GVHD and that the function of the L-selectinhi Treg fraction may be due to the difference in the expression of other homing/migration molecules necessary for Treg migration into lymphoid and GVHD target organs. Figure Figure
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Unsoeld, Heike, and Hanspeter Pircher. "Complex Memory T-Cell Phenotypes Revealed by Coexpression of CD62L and CCR7." Journal of Virology 79, no. 7 (April 1, 2005): 4510–13. http://dx.doi.org/10.1128/jvi.79.7.4510-4513.2005.
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ABSTRACT Antigen-experienced T cells have been divided into CD62L+ CCR7+ central memory (TCM) and CD62L− CCR7− effector memory (TEM) cells. Here, we examined coexpression of CD62L and CCR7 in lymphocytic choriomeningitis virus-specific memory CD8 T cells from both lymphoid and nonlymphoid tissues. Three main points emerged: firstly, memory cells frequently expressed a mixed CD62L− CCR7+ phenotype that differed from the phenotypes of classical TEM and TCM cells; secondly, TCM cells were not restricted to lymphoid organs but were also present in significant numbers in nonlymphoid tissues; and thirdly, a major shift from a TCM to TEM phenotype was found in memory cells that had been stimulated repetitively with antigen.
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Lin, Syh-Jae, Ji-Yih Chen, Ming-Ling Kuo, Hsiu-Shan Hsiao, Pei-Tzu Lee, and Jing-Long Huang. "Effect of Interleukin-15 on CD11b, CD54, and CD62L Expression on Natural Killer Cell and Natural Killer T-Like Cells in Systemic Lupus Erythematosus." Mediators of Inflammation 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/9675861.
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Adhesion molecules may play an important role in systemic lupus erythematosus (SLE) pathogenesis. We investigated the effect of interleukin- (IL-) 15 on CD11b, CD54, and CD62L expression on natural killer (NK) cells, T cells, and CD56+CD3+NKT-like cells from SLE subjects and healthy controls. SLE patients had decreased circulating NK cells and NKT-like cells compared to controls. NK cells from SLE patients showed higher CD11b and CD62L expression compared to controls. IL-15 enhanced CD11b and CD54 but downregulated CD62L expression on NK cells from SLE patients. Similar observations were found for T cells and NKT-like cells. NK cells from SLE patients expressed higher CD56 than controls; both could be further enhanced by IL-15. IL-15 also enhanced CD56 expression of NKT-like cells from SLE patients. A greater degree of IL-15 induced downregulation of CD62L on NKT-like cells noted in SLE patients compared to controls. The percentage of CD11b expressing NK cells and the % inhibition of CD62L expression on NKT-like cells by IL-15 correlated with serum anti-dsDNA levels in SLE patients, respectively. Taken together, we demonstrated the dysfunctional NK and NKT-like cells in SLE patients with regard to CD11b and CD62L expression and their response to IL-15.
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Plautz, Gregory, and Li-Xin Wang. "A Novel Subset of CD8+, CD62L-High Tumor Infiltrating Lymphocytes (TIL) Exhibits Regulatory Function." Blood 112, no. 11 (November 16, 2008): 3910. http://dx.doi.org/10.1182/blood.v112.11.3910.3910.
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Abstract Tumor infiltrating lymphocytes (TIL) have demonstrated therapeutic effects in adoptive cell therapy of melanoma, and there is great interest in optimizing this response. However, the role of lymphocytes during tumor initiation and progression is complex and evolves over time. We have identified two distinct subsets of TIL that have divergent effector vs. regulatory function in murine tumor models. These subsets can be efficiently segregated in vitro based on differential expression of L-selectin (CD62L). Although initially present in small numbers, they can be activated in vitro with anti-CD3 mAb and expanded with a combination of IL-2 and IL-7 to provide sufficient numbers for adoptive transfer into secondary hosts with advanced tumors. Our initial studies demonstrated that the TIL CD62L-low subset is a mixture of CD4 and CD8 cells that individually or in combination mediate tumor-specific regression. By contrast, the CD62L-high subset, which is exclusively CD8+, does not have therapeutic efficacy. Moreover, when CD62Lhigh TIL are co-transferred with CD62L-low effector cells they abrogate their therapeutic efficacy, thus they have suppressor function. Because L-selectin is involved in lymphocyte homing to secondary lymphoid tissues, we hypothesized that the CD62L-high TIL cells might preferentially re-circulate into lymph nodes and inhibit primary sensitization of naïve T cells to tumor antigens. Tumor cells were inoculated subcutaneously, alone or with either CD62L-high TIL or CD62L-low TIL. The CD62L-high TIL actually enhanced the growth of subcutaneous tumors whereas the CD62L-low cells prevented tumor growth. More importantly, tumor-draining lymph nodes were harvested twelve days later and activated in vitro with anti-CD3 and IL-2/IL-7 for adoptive cell transfer to secondary tumor-bearing hosts. The presence of TIL suppressor cells during sensitization of tumor-draining lymph node cells partially inhibited the development of tumor-reactive effector cells. This inhibition was not tumor-antigen specific because TIL suppressor cells derived from the MCA205 fibrosarcoma were able to inhibit sensitization of B16/F10 draining lymph node effector cells. These data suggest that tumors acquire a population of CD8 CD62L-high T cells that can inhibit other effector T cells. The suppressor TIL cells also appear to modulate the tumor stroma to promote tumor growth and modulate antigen-presenting cells that migrate to draining lymph nodes thereby dampening the development of effector cells. Studies are ongoing to determine the mechanism of suppressor function.
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Thibault, Sandra, Mélanie R. Tardif, Caroline Gilbert, and Michel J. Tremblay. "Virus-associated host CD62L increases attachment of human immunodeficiency virus type 1 to endothelial cells and enhances trans infection of CD4+ T lymphocytes." Journal of General Virology 88, no. 9 (September 1, 2007): 2568–73. http://dx.doi.org/10.1099/vir.0.83032-0.
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Previous studies have identified several host-derived cell-surface proteins incorporated within emerging human immunodeficiency virus type 1 (HIV-1) particles. Some of these molecules play a role in different steps of the virus life cycle and are often advantageous for the virus. We report here that the leukocyte L-selectin (also called CD62L) remains functional when inserted within the envelope of HIV-1. Indeed, we demonstrate that adsorption of virions to endothelial cells is enhanced upon acquisition of host-derived CD62L. The more important binding of CD62L-bearing HIV-1 particles resulted in a more efficient virus transmission to CD4+ T lymphocytes. Capture and eventual transfer of such CD62L-bearing virions by the endothelium could play a role in the pathogenesis of HIV-1 infection.
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Alhan, Canan, Theresia M. Westers, Claudia Cali, Floortje L. Kessler, Monique Terwijn, Gert J. Ossenkoppele, Sonja Zweegman, and Arjan A. Van de Loosdrecht. "Decreased Expression of CD62L and CD54 Correlates with Poor Cytogenetic Risk Group In Myelodysplastic Syndromes." Blood 116, no. 21 (November 19, 2010): 2915. http://dx.doi.org/10.1182/blood.v116.21.2915.2915.
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Abstract Abstract 2915 Interactions in the bone marrow (BM) between haematopoietic progenitor cells (HPC) and the BM micro environment are important for the regulation of cell adhesion, proliferation, differentiation and survival. Expression of both CD62L (L-selectin) and CD54 (ICAM-1) on HPC demonstrated to play a role in signal transduction routes for proliferation and growth regulation. Especially CD54 is involved in uncontrolled proliferation and block of apoptosis. Previously, it was described that decreased expression of CD62L in acute myeloid leukemia (AML) was associated with a poor cytogenetic risk profile and an adverse clinical outcome (Graf M et al, Eur J Haematol 2003) Myelodysplastic syndromes are a group of clonal HPC disorders characterized by ineffective hematopoiesis and a propensity to evolve into AML. The International Prognostic Scoring System (IPSS) provides information on both survival and risk of development of an AML. The purpose of our study was to evaluate CD62L and CD54 expression on CD34+ cells in MDS patients by flow cytometry and to assess the value of a CD62L/CD54 ratio for prognostication. Bone marrow samples of 30 newly diagnosed MDS patients (3 RA(RS)/18 RCMD(RS), the <5% blasts group; 5 RAEB-1, 4 RAEB-2, the >5% blasts group), 16 AML patients with prior MDS and 26 healthy volunteers were analyzed for CD62L and CD54 expression on CD34+ cells by using flow cytometry. An adhesion index was calculated as a ratio of the percentage and MFI of CD62L and CD54 positive cells (as was reported by Buccisano et al, Eur J Haematol 2007). The CD62L/CD54 ratio was significantly decreased in MDS with <5% blasts (median 79.09 p<0.0001) as compared to healthy volunteers (median 480.4) and even more decreased in high risk MDS (median 14.67 p<0.0001 and p=0.001 as compared to healthy volunteers and MDS with <5% blasts, respectively) and AML with prior MDS (median 12.54, p<0.0001 and p=0.009 as compared to healthy volunteers and MDS with <5% blasts, respectively). The MDS patients were assigned to the good, intermediate or poor IPSS cytogenetic risk category. Cytogenetics was available for 22 MDS patients. The CD62L/CD54 ratio was significantly lower in the cytogenetic poor risk category compared with the good risk category (median 5.4 and median 70.79 respectively, p=0.018). Moreover, a low CD62L/CD54 ratio correlated significantly with poor cytogenetics, p=0.006. In the group of MDS patients with <5% blasts, 4 developed a refractory anemia with excess of blasts or AML within a follow up period of 12 months. There was a trend for a lower CD62L/CD54 ratio for MDS patients who developed an AML compared with patients who did not. In conclusion, the CD62L/CD54 ratio is significantly decreased in MDS compared with healthy volunteers and even more decreased in AML with prior MDS. Both CD62L and CD54 are involved in regulation of proliferation and apoptosis of the HPC. A decreased adhesion ratio in low risk MDS patients might reflect HPC damage at an early stage of the disease with an increased proliferative capacity and a decreased apoptotic profile. Interestingly, a low CD62L/CD54 ratio showed a significant inverse correlation with the IPSS cytogenetic risk category. Due to an absence of metaphases in a proportion of MDS patients, cytogenetics is not always available. The CD62L/CD54 ratio might serve as a surrogate marker for poor prognosis cytogenetics in case no karyotype is available. Low risk MDS patients who developed an AML within 12 months tended to have a lower CD62L/CD54 ratio. Although these results are promising, sample size and follow up period needs to be extended. The CD62L/CD54 ratio might add to prognostication of MDS patients and might identify MDS patients with <5% blasts who are at risk for development of an AML. Disclosures: Ossenkoppele: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van de Loosdrecht:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Florek, Mareike, Dominik Schneidawind, Jeanette Baker, Antonio Pierini, Dennis B. Leveson-Gower, Yuqiong Pan, Robert S. Negrin, and Everett H. Meyer. "Loss of CD62L Expression in CD4+FoxP3+ Regulatory T Cells Following Freeze-and-Thaw Prevents Protection Against GVHD in Murine Models." Blood 124, no. 21 (December 6, 2014): 2427. http://dx.doi.org/10.1182/blood.v124.21.2427.2427.
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Abstract Backgrounds: CD4+FoxP3+ regulatory T cells (Treg) have been shown in pre-clinical murine models and human clinical trials to protect against acute graft-versus-host (GVHD) disease following hematopoietic cell transplantation (HCT). In murine models, Treg expression of CD62L is required for in vivo protection of GVHD (Strober 2005/Blazer 2004). Certain aspects of Treg isolation and administration could affect CD62L expression, such as the use of G-CSF mobilization or freeze-and-thaw. We hypothesized that freeze-thaw of Tregs could reduce CD62L expression and prevent Tregs from protecting against GVHD. Furthermore, we hypothesized that the loss of CD62L expression is mediated at least in part by metalloproteinases (MP). Methods and Results: We used established protocols of GVHD, in which lethal dose of fractionated total body irradiation was followed by murine bone marrow transplantation across major histocompatibility barriers. We sort-purified CD4+Foxp3+ Tregs based on CD25+(high) expression and measured baseline expression of CD62L. Cells were then gradually frozen in fetal calf serum/10%DMSO, and finally stored in liquid nitrogen for at least 7 days. After thawing Tregs showed an average of 58% of the baseline CD62L expression (CD62L expression fresh vs. frozen p=0.0009, n=5). Binding of frozen Tregs to plate bound L-Selectin ligand Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in vitrowas significantly reduced as compared to fresh Tregs (p=0.0003). To test the potential effect of freeze and thaw in vivo, we used an established murine model in which Tregs are given prior to conventional T cells (Tcon) to protect against GHVD. At the time of transplant conditioned BALB/c donors received 5x10^6 whole bone marrow and 5x10^5 CD4+CD25(high) Tregs (day 0), followed by 1x10^6 Tcon (day +2). Frozen/thawed Tregs and fresh Tregs respectively were given at the same time point at the same quantity of viable cells. Using luciferase-expressing cells (luc+) and BLI imaging we could show that homing of frozen luc+Tregs into pLN at day+5 was impaired as compared to fresh Tregs (p=0.0005). Relative weight loss as an indicator for GVHD was significantly higher and survival was significantly reduced in mice receiving frozen Treg in comparison to mice receiving fresh Treg. To confirm the importance of CD62L expression on Treg function we blocked CD62L in vivo by incubating fresh Tregs with monoclonal blocking antibody Mel14 (120ug/ml) for 1 hour prior to injection. A significantly higher proliferation of luc+ Tcon was observed in mice injected with Mel14-treated Tregs as compared to isotype control-treated Tregs. To test the potential role of metalloproteinases in cleaving CD62L following freeze and thaw, we added various metalloproteinase inhibitors (MPI) during the freezing process. We found that the addition of at least one MPI GM6001 (50nM) can diminish the loss of CD62L. Conclusion: Augmenting or manipulating Tregs of the donor graft is a promising area of cellular therapy that could be used to prevent GVHD in HCT and in potentially many other clinical contexts. We have found that the process of freeze and thaw reduces CD62L expression on Tregs and reduces protection against GVHD. Further, MPs may play role in the loss of CD62L expression and the use of MPIs for frozen products might preserve Treg function. Disclosures No relevant conflicts of interest to declare.
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Foster, Aaron E., Marina Marangolo, Mary M. Sartor, Stephen I. Alexander, Min Hu, Kenneth F. Bradstock, and David J. Gottlieb. "Human CD62L– memory T cells are less responsive to alloantigen stimulation than CD62L+ naive T cells: potential for adoptive immunotherapy and allodepletion." Blood 104, no. 8 (October 15, 2004): 2403–9. http://dx.doi.org/10.1182/blood-2003-12-4431.
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Abstract Selective depletion of alloreactive T cells from allogeneic stem cell grafts can reduce graft-versus-host disease (GVHD) while preserving beneficial effects of T cells including facilitation of engraftment, protection against opportunistic infection, and reduced relapse risk. Memory T cells (CD62L–) represent a population of T cells that have previously encountered pathogens and may contain fewer T cells capable of recognizing neoantigens including recipient allogeneic antigen (aAg). We investigated whether human naive (CD62L+) or memory (CD62L–) T cells had different capacities to respond to aAg by assessing their ability to proliferate in response to and lyse HLA-mismatched Epstein-Barr virus–transformed B cells. Freshly sorted and in vitro expanded CD62L– memory T cells were less responsive to aAg stimulation than were CD62L+ naive T cells but contained higher levels of cytomegalovirus (CMV)–specific T cells. Analysis of T cell receptor (TCR) repertoire showed restricted TCR diversity in the memory T-cell population possibly due to selection associated with chronic exposure to common pathogens. Memory T cells may represent a donor cell subpopulation suitable for enhancing immune reconstitution without increasing the risk of GVHD.
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Meguri, Yusuke, Takeru Asano, Takanori Yoshioka, Haruka Izumi, Yuriko Kishi, Yoshinobu Maeda, Mitsune Tanimoto, and Ken-ichi Matsuoka. "Host Immune Status Determines the Effects of Therapeutic Interleukin-2 Administration: Enhancement of GVL or Induction of Tolerance?" Blood 124, no. 21 (December 6, 2014): 2431. http://dx.doi.org/10.1182/blood.v124.21.2431.2431.
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Abstract Interleukin-2 (IL-2) has a central role in immune tolerance thorough maintaining the homeostasis of CD4+CD25+Foxp3+ regulatory T cell (Treg). We recently reported that administration of low-dose IL-2 could preferentially enhance Treg in vivo and suppress clinical manifestations of chronic GVHD after allogeneic hematopoietic stem cell transplantation (NEJM2011). On the other hand, IL-2 is also necessary for the development of cytotoxic T cell function and has been used for the systemic immune therapy to amplify anti-tumor immunity. Thus, IL-2 administration after transplantation can induce the bipolar effects, namely, enhancement of Graft-versus-Leukemia effect (GVL effect) or prevention of Graft-versus-Host Disease (GVHD). For the appropriate therapeutic use of IL-2 for different purpose, we need to elucidate the factors to predict the effect of IL-2, however, the determinants except for the IL-2 dosage has not been characterized. To address this issue, we explored the impact of the immunological reconstitution after transplant on the effect of IL-2 therapy. First, we examined the in vivo reactivity to exogenous IL-2 in different lymphocyte subsets; CD8+ T cells, CD4+ conventional T cells (Tcon) and CD4+ regulatory T cells (Treg). We purified CD62L+ naïve lymphocytes and CD62L- lymphocytes from B6 spleen by cell-sorting and labeled with CFSE, adaptively transferred cells into irradiated B6 host and subcutaneously administrated 5000 IU of IL-2 or control vehicle from day1 to 5. At day6, spleen cells were harvested and the in vivo proliferation of each lymphocyte were evaluated by CFSE dilution assay. Proliferation of Tcons was just limited but both CD8 T cells and Tregs showed vigorous proliferations in response to IL-2. As expected, IL-2 induced the proliferation of CD62L- activated/memory CD8 T cells more than CD62L+ naïve CD8 T cells. In contrast, oppositely to CD8+ subsets, IL-2 induced the proliferation of CD62L+ naïve Tregs more than CD62L- Tregs, suggesting naïve Treg might be “primed” naturally and be ready to respond to IL-2 without antigenic TCR stimulation. Next, we examined the balance between naïve and memory phenotype in each lymphocyte subsets after allogeneic HSCT using murine BMT model. Lethally irradiated B6D2F1 mice were transplanted with 5x106 spleen cells from the CD45.2 B6 mice together with 5x106 TCD-BM from CD45.1 B6 donors. The balance between graft-derived cells (CD45.2) and BM-derived cells (CD45.1) in CD8+ T cell, CD4+ Tcon and Treg were monitored separately at day7, 14, 21,28 and 35. In the early phase of transplant, graft-derived cells showing CD62- were predominant, peaked at day21 and thereafter decreased in each subset. After day28, BM-derived cells generally emerged in each subset. Using this model, we compared the effects of IL-2 administration in the early phase (Day5-12) and in the late phase (Day35-42). Interestingly, IL-2 administration of daily 5000 IU of IL-2 in the early phase resulted in the dominant expansion of circulating CD62-CD44+ effector/memory CD8 T cell without Treg increase (CD8+T; 162 cells vs 75 cells/uL, P<0.05: Treg; 0.42 cells vs 0.48 cells/uL, NS). In contrast, the same dose of IL-2 administration in the late phase resulted in the vigorous increase of CD62+ Treg without CD8 T cell increase (CD8+T; 205 cells vs 185 cells/uL, NS: Treg; 57.1 cells vs 21.0 cells/uL, P<0.05). GVL experiments using 2.5x104 host-type P815 leukemia cells, that were uniformly lethal to the recipients of syngeneic BMT by day 15 after BMT, showed that IL-2 injection from day5 delayed the leukemia relapse (P<0.05), indicating IL-2 enhanced CD8+ CTL might mediated anti-tumor immunity. In conclusion, these data suggests that not only the dose of IL-2 but also host immune status at IL-2 administration is a critical factor to determine the in vivo effect of IL-2 therapy. From the point of view, the adjusted dose and timing of IL-2 infusion based on the detailed immune monitoring might enable to optimize and personalize this cytokine therapy. Our findings provide important information for developing therapeutic strategies to modulate immune cells in vivo and promote well-balanced immune recovery after transplantation. Disclosures No relevant conflicts of interest to declare.
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Wickenhauser, Claudia, Beate Schmitz, Stephan Ernst Baldus, Franc Henze, Parvis Farahmand, Semra Frimpong, Jürgen Thiele, and Robert Fischer. "Selectins (CD62L, CD62P) and megakaryocytic glycoproteins (CD41a, CD42b) mediate megakaryocyte–fibroblast interactions in human bone marrow." Leukemia Research 24, no. 12 (December 2000): 1013–21. http://dx.doi.org/10.1016/s0145-2126(00)00063-1.
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Anderson, Britt E., Patricia A. Taylor, Jennifer M. McNiff, Dhanpat Jain, Anthony J. Demetris, Angela Panoskaltsis-Mortari, Ann Ager, Bruce R. Blazar, Warren D. Shlomchik, and Mark J. Shlomchik. "Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells." Blood 111, no. 10 (May 15, 2008): 5242–51. http://dx.doi.org/10.1182/blood-2007-09-107953.
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Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (TEM) do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of TEM to cause GVHD is that TEM lack CD62L and CCR7, which are instrumental in directing naive T cells (TN) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus TEM should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for TN-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on TEM did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that TEM fail to induce GVHD because of inefficient trafficking to LN and PP.
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Chen, Benny J., Xiuyu Cui, Gregory D. Sempowski, Congxiao Liu, and Nelson J. Chao. "Transfer of allogeneic CD62L– memory T cells without graft-versus-host disease." Blood 103, no. 4 (February 15, 2004): 1534–41. http://dx.doi.org/10.1182/blood-2003-08-2987.
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Abstract The major challenge in allogeneic hematopoietic cell transplantation is how to transfer allogeneic T-cell immunity without causing graft-versus-host disease (GVHD). Here we report a novel strategy to selectively prevent GVHD by depleting CD62L+ T cells (naive and a subset of memory T cells). In unprimed mice, CD62L– T cells (a subset of memory T cells) failed to proliferate in response to alloantigens (which the mice have never previously encountered) and were unable to induce GVHD in allogeneic hosts. CD62L– T cells contributed to T-cell reconstitution by peripheral expansion as well as by promoting T-cell regeneration from bone marrow stem/progenitor cells. CD62L– T cells from the animals previously primed with a tumor cell line (BCL1) were able to inhibit the tumor growth in vivo but were unable to induce GVHD in the third-party recipients. This novel technology may allow transfer of allogeneic recall antitumor and antimicrobial immunity without causing GVHD.
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Hossain, Mohammad S., and Ned Waller. "Mechanisms of Migration and Generation of Allo-Reactive Donor T Cells That Cause Organ Specific Acute GvHD in Allogeneic BMT Recipients." Blood 110, no. 11 (November 16, 2007): 3270. http://dx.doi.org/10.1182/blood.v110.11.3270.3270.
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Background: Allo-reactive donor T cells are primarily responsible for GvHD in allogeneic BMT. A number of studies have shown that increased allo-reactivity is found among the CD62L+ subset of donor T-cells, but the mechanisms for organ specific allo-reactivity are poorly defined. Our hypothesis is that rapid proliferation and migration of CD62L+ naive donor CD4+ and CD8+ T cells to specific organs leads to acute GvHD. Methods: We used a parent (C57BL/6) to (C57BL/6 × BALB/c) CB6F1 allogeneic BMT model with a combination of T cell depleted BM (TCD BM) and splenocytes. 30 × 106 congeneic donor splenocytes labeled with CFSE were transplanted with 5 × 106 TCD congeneic BM into lethally irradiated (11Gy) CB6F1 mice. Recipients were sacrificed within 3.5 days of transplant and FACS was used to measure proliferation of CFSE-labeled donor T-cells isolated from blood, spleen, liver, lungs, thymus, BM, lymph nodes, and peritoneal exudates cells (PEC). Syngeneic C57BL/6 recipients served as controls. At least 5 mice per group were used in each experiment. Results: There was increased homing of CFSE-labeled donor T-cells to most organs in allogeneic compared to syngeneic BMT recipients. CD45.1+ donor cells were 4-fold higher in spleen, p=0.01; 9-fold higher in liver, p=0.002; 14-fold higher in PEC, p=0.017; 136-fold higher in lung, p=0.0006; 126-fold higher in BM, P=0.002, 1482-fold higher in thymus p=0.002 compared to syngeneic recipients. Allogeneic and syngeneic recipients had equivalent numbers of donor CFSE-labeled lymphocytes in PBMC and lymph nodes. The tissue specific homing of CD4+ and CD8+ donor T-cells was also found significantly higher in most organs except the PBMC and LNs. Donor splenocytes were 80% CD62L+ before transplant, but the frequency of CD62L+ donor T-cells had declined to 15–16% in BM, 4–10% in liver, 17–30% in spleen and 10 to 25% in the thymus within 3.5 days post-transplant. In syngeneic recipients, 80% of donor T-cells remained CD62L+ within 3.5 days post-transplant. Most donor T-cells that divided rapidly lost expression of CD62L, while non-replicating donor CD4+ and CD8+ T cells remained predominately CD62L+. The expression of CD44 on donor T-cells were the opposite, with CD44+ cells undergoing less, and CD44− cells dividing more in allogeneic transplant recipients. In syngeneic BMT, donor CD4+ and CD8+ T-cells underwent minimal proliferation within the first 3.5 days post-transplant. Intracellular cytokine staining showed that high levels of IFN-g and TNF-a synthesis was seen among CD62L+ CD4+ and CD8+ T cells that had yet to divide (and had un-diluted CFSE staining). Conclusion: Migration of allogeneic donor T cells to tissues and local proliferation occurs rapidly after allogeneic BMT compared to recipients of syngeneic transplants. The dissociation of CD62L expression from lymph node homing suggests lack of the CD62L-receptor expression in lymph node HEV following irradiation, or a dominant effect of other chemokine receptors in directing donor T-cell preferentially to other organs. The marked and preferential homing of donor T-cells to the recipient thymus and bone marrow may play a role in achieving donor hematopoietic and T-cell chimerism in recipients of allogeneic BMT. Tissue specific homing of naive CD62L+ donor T-cells, with a high proliferative capacity, is likely responsible for the initiation of acute GvHD at these sites.
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Chung, Hung-Tao, Yu-Sheng Chang, Sui-Ling Liao, and Shen-Hao Lai. "The effects of corrective surgery on endothelial biomarkers and anthropometric data in children with congenital heart disease." Journal of International Medical Research 45, no. 2 (March 6, 2017): 493–503. http://dx.doi.org/10.1177/0300060516685659.
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Objective To investigate the influence of surgical correction on biomarkers of endothelial dysfunction in children with congenital heart disease and to evaluate anthropometric data. Methods Children with pulmonary hypertension (PH) or Tetralogy of Fallot (TOF) who were scheduled for corrective surgery were enrolled in this prospective study. Age-matched healthy children were included as controls. Demographic, haemodynamic and cardiac ultrasonography data were collected. Blood samples were taken pre-surgery, 24–48 hours post-surgery and again 3–6 months later. Several biomarkers (protein C, soluble platelet selectin [CD62P], soluble endothelium selectin [CD62E], soluble leukocyte selectin [CD62L], plasma von Willebrand Factor [vWF] atrial natriuretic peptide [ANP], brain natriuretic peptide[(BNP] and insulin-like growth factor-1 [IGF-1]) were measured. Results Sixty-three children (32 with PH, 15 with TOF, and 16 controls) were enrolled. No significant differences between the PH and TOF groups were observed in the expression of biomarkers pre- and post-surgery. IGF-1 levels were closely related to anthropometric data, particularly those children with PH. Expression of IGF-1 and weight/height normalized after corrective surgery. Conclusions No significant endothelial dysfunction was observed in children with PH or TOF before or after corrective surgery. Significant retardation of growth, particularly weight, was found before surgery and may be related to IGF-1 suppression.
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Elangbam, C. S., C. W. Qualls, and R. R. Dahlgren. "Cell Adhesion Molecules—Update." Veterinary Pathology 34, no. 1 (January 1997): 61–73. http://dx.doi.org/10.1177/030098589703400113.
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Cell adhesion molecules are glycoproteins expressed on the cell surface and play an important role in inflammatory as well as neoplastic diseases. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. The integrin family has eight subfamilies, designated as β1, through β8. The most widely studied subfamilies are β1 (CD29, very late activation [VLA] members), β2 (leukocyte integrins such as CDlla/CD18, CDllb/CD18, CDllc/CD18, and αdβ2), β3 (CD61, eytoadhesions), and β7 (α4β7 and αEβ7). The immunoglobulin superfamily includes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function antigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The selectin family includes E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L). Cadherins are major cell-cell adhesion molecules and include epithelial (E), placental (P), and neural (N) subclasses. The binding sites (ligands/receptors) are different for each of these cell adhesion molecules (e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell adhesion molecules and their ligands that may be involved in pathologic conditions and potential therapeutie strategies by modulating the expression of these molecules will be discussed.
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Simon, Scott I., Vasilios A. Morikis, Shannon Chase, and John L. Magnani. "Rivipansel (GMI-1070) Inhibits E-Selectin Recognition of Sialyl LewisX Expressed on CD62L (L-selectin) and Blocks Integrin Activation and Arrest of Human Neutrophils." Blood 128, no. 22 (December 2, 2016): 2509. http://dx.doi.org/10.1182/blood.v128.22.2509.2509.
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Abstract Introduction: Mechanical force acting on selectin bonds facilitates neutrophil (PMN) rolling and transduction of signals that subsequently activate integrins that support cell arrest under hydrodynamic shear flow. E-selectin upregulated on inflamed endothelium has the unique capacity to bind multiple sialyl Lewisx (sLex) presenting ligands on circulating leukocytes to mediate slow rolling and activation of the β2 integrin- lymphocyte function-associated antigen 1 (LFA-1), which in turn binds ICAM-1 during PMN arrest at sites of inflammation. It was demonstrated in a mouse model that PSGL-1 is the primary E-selectin ligand (ESL) that facilitates cell rolling. L-selectin/PSGL-1 clustering at the site of adhesive contact provides an outside-in signal that in turn activates LFA-1. A fundamental difference between mouse and human PMN with respect to ESL recognition is the biosynthesis of glycosylated ligands. Human L-selectin (CD62L) expresses N- and O- linked sLex that is recognized by the lectin domain of E-selectin, whereas mouse L-selectin is not decorated with sLex. We report that CD62L binding and clustering by E-selectin is necessary and sufficient to transduce signals that activate LFA-1, even in the absence of PSGL-1 engagement. Our study aims to elucidate how sLexexpressed on CD62L is preferentially bound by E-selectin and how tension induced clustering at sites of adhesive contact transduces integrin mediated PMN arrest. Recognition of CD62L can be selectively blocked by rivipansel (GMI-1070), a small molecule glycomimetic pan-selectin antagonist. Materials and Methods: PMN are perfused into a microfluidic device at 2 dynes/cm2 over a glass substrate coated with ICAM-1/E-selectin to mimic the inflamed vasculature and allow for quantification of rolling to arrest. Total internal reflection fluorescence (TIRF) microscopy employing quantitative dynamic footprinting (qDF) enables imaging of a membrane dye in conjunction with fluorescent antibodies to record cell adhesion and ligation of receptors by a molecular substrate. Rivipansel along with antibodies are used to block CD62L and PSGL-1 receptors. Fluorescent antibodies are used to image localization of receptors at the substrate. Immunoprecipitation of PMN lysates by E-selectin in presence or absence of antibody and rivipansel were followed up by Western blot analysis to identify their relative capacity to block recognition of CD62L versusPSGL-1. Results and Discussion: Isolated human PMN rolling to arrest was recorded on a substrate of recombinant human E-selectin/ICAM-1. Rivipansel inhibited PMN rolling at IC50 ~6.5µM, whereas antagonism of β2-integrin activation resulted in tenfold more potent activity with an IC50 ~0.5 μM. Blocking PSGL-1 with antibody did not alter this inhibition, indicating that it is not required for CD62L mediated outside-in signaling of β2-integrin dependent rolling to arrest. Western blots of PMN lysates immunoprecipitated against E- versus P-selectin revealed that rivipansel at 6.5 µM inhibits E-selectin recognition of sLex on CD62L by ~70%, while PSGL-1 binding was unaltered at this concentration. qDF imaging of the distribution of CD62L/PSGL-1 during human PMN rolling on E-selectin/ICAM-1 revealed that PSGL-1 was not necessary for tethering interactions of CD62L on E-selectin, nor signaling of integrin activation and arrest. Conclusions: E-selectin recognition of sLex expressed on CD62L is necessary and sufficient to generate outside-in signaling and activation of LFA-1 dependent arrest on ICAM-1. PSGL-1 contributes to PMN capture and rolling in shear flow, but is not requisite for conversion to arrest. Rivipansel binds tightly to the lectin domain on E-selectin and displaces sLex presented by CD62L, thereby preventing subsequent signal transduction associated with integrin activation and stable bond formation to ICAM-1. Blocking activation and arrest of leukocytes by rivipansel may play a central role in its reported clinical benefit in treatment of vaso-occlusive crisis in sickle cell patients. Disclosures Magnani: GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Mangare, Caroline, Sabine Tischer-Zimmermann, Sebastian B. Riese, Anna C. Dragon, Immo Prinz, Rainer Blasczyk, Britta Maecker-Kolhoff, and Britta Eiz-Vesper. "Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads." International Journal of Molecular Sciences 20, no. 6 (March 20, 2019): 1415. http://dx.doi.org/10.3390/ijms20061415.
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Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (TN) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA−/CD62L− naive T-cell-depleted as well as CD45RA+/CD62L+ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA), and CD62L depletion in loss of central memory T cells (TCM). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3–5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present.
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Burgess, Melinda, Sally Mapp, Roberta Mazzieri, Jonathan Ellis, Catherine Cheung, Lynne Chambers, Stephen Mattarollo, Peter Mollee, Devinder Gill, and Nicholas Saunders. "Emergence of Fc-Gamma-Riib-Dominance Contributes to Resistance to Therapeutic Antibodies in Patients with Chronic Lymphocytic Leukaemia." Blood 126, no. 23 (December 3, 2015): 447. http://dx.doi.org/10.1182/blood.v126.23.447.447.
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Abstract Aim: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Whilst therapeutic antibodies show clinical activity in CLL patients, resistance develops. Thus, identifying mechanisms of antibody resistance and methods to reduce resistance would be valuable in managing CLL. Results: In this study we show that a therapeutic antibody against CD62L is able to induce antibody-dependent cell mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. Significantly, we observed that patients with stable disease retained sensitivity to CD62L-Ab whilst untreated patients, whose disease progressed, became progressively resistant to CD62L-Ab. Using strategies to enrich for monocytes we were able to show that the CD62L-Ab dependent killing was attributable to an FcγR-dependent mechanism within the monocyte derived cell (MDC) fraction of PBMCs. Transcriptomic profiling and marker analysis indicated that the MDCs acquired a macrophage phenotype. Both MDCs from antibody-sensitive or antibody-resistant patients were able to bind Ab-bound CLL cells equally. Moreover, resistance could not be attributed to reduced numbers of monocytes or macrophages or to distinct subtypes of monocytes or macrophages. Using pharmacological inhibitors of the activating pathway of FcγR signaling and the inhibitory FcγRIIB pathway we were able to show that the antibody resistance in MDCs, derived from patients with CLL, was due to the emerging dominance of the FcγRIIb pathway relative to the activating FcγR pathways. We examined whether the differential sensitivity to CD62L-Ab was also evident for anti-CD20 antibodies used clinically for CLL. Rituximab showed only moderate activity in vitro and no clear difference in cytotoxicity was observed between patients who were previously identified as being resistant or sensitive to the CD62L antibody. Obinutuzumab invoked similar differential cell killing in PBMCs from patients sensitive to, or resistant to, CD62L-Ab. Further comparison indicated that CD62L-Ab and obinutuzumab induced similar malignant B cell binding to MDCs and ADP in contrast to rituximab. Finally, similar to anti-CD62L, ADCC/ADP response to obinutuzumab was reduced following treatment of sensitive cultures with a syk or BTK inhibitor and increased in MDCs derived from resistant patients treated with a Ship1 inhibitor. Conclusions: These data establish, for the first time, that MDCs derived from CLL patients may switch from an antibody sensitive phenotype to an antibody-resistant phenotype as disease progresses. Significantly, we show that the resistance to MDC-mediated ADCC/ADP may be reversed by the inhibition of FcγRIIB with pharmacological modifiers. Disclosures Mollee: Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding.
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Sopper, Sieghart, Satu Mustjoki, Angelica Loskog, Bjorn T. Gjertsen, Guenther A. Gastl, Frank Giles, Andreas Hochhaus, Gert J. Ossenkoppele, Kimmo Porkka, and Dominik Wolf. "Increased TACE (Tumor necrosis factor-alpha±-converting enzyme; ADAM17) Activity Associates with Decreased CD62L Expression, Increased Soluble CD62L Plasma Levels and Predicts Molecular Response to Nilotinib Therapy in Patients with Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP): Results from an ENEST1st Substudy." Blood 126, no. 23 (December 3, 2015): 4033. http://dx.doi.org/10.1182/blood.v126.23.4033.4033.
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Abstract Background and Aim: Tyrosine kinase inhibitors (TKI) imatinib and dasatinib modulate immune responses in vitro and in vivo. Immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Moreover, baseline immunological characteristics may be associated with response to TKI therapy. Little is known about potential immune-modulatory effects of nilotinib in vivo. The ENEST1st study (NCT01061177) evaluated the role of first-line nilotinib therapy in CML-CP. The primary endpoint was the MR4 rate at 18 months. A comprehensive immunological monitoring program within this ENEST1st substudy characterized baseline and therapy-induced immunological variables to correlate them with biological disease characteritics and clinical response parameters. Methods: Peripheral blood was taken prior to treatment initiation and after 6 and12 months (mo) from 52 patients. Samples were analyzed by nine colour flow cytometry employing six panels of optimized antibodies to determine various leukocyte populations (e.g. T cell subpopulations including Treg and NKT cells, NK cells, B cells, monocytes, MDSC, dendritic cell subsets). Plasma concentrations of soluble CD62L (sCD62L) and TACE (tumor necrosis factor-α-converting enzyme; ADAM17, CD156b), the metalloproteinase inducing proteolytic cleavage of CD62L from the cell surface, were either measured by ELISA or (in case of the enzymatic activity of TACE) using a fluorogenic assay. Changes in immune cell parameters were correlated to biological disease features and clinical endpoints. Results: The most striking finding of this study is the drastic loss of the lymph-node homing marker CD62L on immune cells (T cell subsets and granulocytes) at baseline (basCD62L), which increased back to normal levels during nilotinib therapy. The proportion of basCD62L+ cells among both CD4+ and CD8+ T cell subsets significantly correlated with Sokal score (both as continous and categorial variable, i.e. high vs. low/int). Low basCD62L expression levels on both T cell subsets correlate with increased spleen size, higher BM and PB blast and WBC counts as well as it correlates to higher BCR-ABL copy numbers at almost all time points during treatment. Similarly, lower basCD62L on either CD4+ or CD8+ T cells is linked to a longer duration to reach the respective molecular endpoint. Patients reaching MR4 at 18 months (primary study endpoint) had significantly higher levels of basCD62L on both CD4+ (p=0.02) and CD8+ (p=0.008) T cells. Consequently, MR4 at 18 months was attained in a significantly higher percentage of patients in the basCD62hi compared to the CD62lo patients (63% vs. 13.0%). Vice versa, patients who reached MR4 at 18 months had significantly higher proportions of basCD62L expressing cells among both CD4+ and CD8+ T cells. Moreover, as depicted by a cumulative response rate, patients with high proportions of basCD62Lhi T cells, achieved MMR and MR4 significantly earlier and in a higher proportion throughout the observation period. A detailed characterization of other T cell differentiation marker (CD45RA, CD45R0, CD28, CD27, and CD95) did not reveal significant baseline T cell subset alterations as explanation for altered CD62L expression. In contrast to low basCD62L surface expression levels, its shed form sCD62L is significantly increased at diagnosis but subsequently drops back during nilotinib therapy. Similar to surface CD62L expression, also sCD62L associates with biological disease features and molecular response to nilotinib. Finally, low CD62L surface expression was associated with elevated sCD62L levels and increased proteolytic activity but not total amount of TACE. Conclusion: At baseline, increased proteolytic activity of TACE sheds CD62L from the immune cell surface. During nilotinib therapy, TACE activity gets normalized leading to re-expression of CD62L on T cells and vice versa a drop of sCD62L. Low baseline T cell expression levels of CD62L and increased sCD62L levels correlate to a more aggressive CML phenotype and are linked to inferior molecular response to nilotinib in early CML-CP. Larger prospective studies including also other TKIs are needed to confirm the prognostic relevance of sCD62L/CD62L expression as response-prediction marker, as this marker is easy to measure by ELISA in plasma samples or flow-cytometry. Disclosures Mustjoki: Finnish Cancer Institute: Research Funding; Sigrid Juselius Foundation: Research Funding; Academy of Finland: Research Funding; the Finnish Cancer Societies: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Signe and Ane Gyllenberg Foundation: Research Funding. Loskog:RePos Pharma AB: Membership on an entity's Board of Directors or advisory committees; Vivolux AB: Membership on an entity's Board of Directors or advisory committees; Lokon Pharma AB: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; NEXTTOBE AB: Membership on an entity's Board of Directors or advisory committees; Alligator Bioscience AB: Patents & Royalties. Gjertsen:Haukeland University Hospital: Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. Ossenkoppele:Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.
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Elkhouly, E. A., W. M. Radwan, M. A. Soliman, and S. Swelim. "CD62L expression in chronic lymphocytic leukemia patients." Annals of Oncology 29 (September 2018): vi5. http://dx.doi.org/10.1093/annonc/mdy317.007.
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Vlad, Amalia, Pierre-Antoine Deglesne, Remi Letestu, Nathalie Chevallier, Fanny Baran-Marszak, Nadine Varin-Blank, Florence Cymbalista, and Dominique Ledoux. "CXCR4 and CD62L Down-Regulation Following B-Cell Receptor Ligation Is Restricted to Progressive Chronic Lymphocytic Leukemia (CLL) Cases." Blood 110, no. 11 (November 16, 2007): 1122. http://dx.doi.org/10.1182/blood.v110.11.1122.1122.
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Abstract B cell receptor (BCR) mediated survival plays a central role in disease progression of CLL. We have previously shown that BCR engagement allowed the identification of two groups of patients with a strong correlation between in vitro cell survival response capacity and clinical stage or prognostic factors. The aim of this study was to determine the implication of BCR stimulation in the accumulation of CLL cells in the enlarged lymph nodes of progressive cases. Therefore, we investigated the in vitro migratory capacity of CLL cells and the level of expression of microenvironment interacting molecules upon BCR stimulation. Surface expression of two membrane proteins: CXCR4 and CD62L were dramatically reduced in 40% of CLL cases after BCR engagement. CXCR4/CXCL12 axis and the L-selectin (CD62L) are critical for trafficking of B cells into lymph node, germinal center organization as well as lymphocyte exit from the lymph node. Peripheral blood mononuclear cells obtained from 27 untreated patients were purified and stimulated with immobilized anti-IgM for 48h. Presence of CXCR4 and CD62L at the cell surface was then measured by flow cytometry in CD19-positive cells. The CXCL12-dependant migratory capacity of B-CLL cells was analysed using a Transwell chemotaxis assay before and after BCR stimulation. BCR stimulation induced over 90% decrease of both CXCR4 and CD62L membrane expression in 11/27 cases. Importantly, this strong down-regulation of CXCR4 and CD62L was restricted to progressive cases with lymphadenopathy and unfavourable prognostic markers (unmutated IgVH, expression of ZAP70, high level of proliferation markers). These cases also showed marked increase of in vitro cell survival upon BCR engagement. Conversely, in the 6/27 cases corresponding to stable stage A patients with favourable prognostic markers, and absence of BCR mediated in vitro survival enhancement, no decrease of CXCR4/CD62L expression upon BCR stimulation was observed. We demonstrated that the down-regulation of CXCR4 from cell surface was associated with the internalization of the receptor mainly through clathrin-mediated endocytosis. CXCR4 down-regulation was associated with a reduced capacity of the cells to migrate in response to CXCL12 gradient. Indeed, migration was not affected in the 6 stable cases. Finally, the 10/27 remaining cases exhibited an intermediate down-regulation of CXCR4 and CD62L. The remaining level of expression of CXCR4 was strikingly correlated to CD62L level in all cases(y= 0.99x + 4.44; R2=0.893). This matching variation of both surface molecules reflects the cellular heterogeneity of response to BCR engagement in a given patient. In conclusion, our results show that BCR engagement induces a strong down-regulation of CXCR4 and CD62L, and the subsequent decrease of migratory capacity of the cells in progressive CLL cases only. These experiments strongly suggest that BCR signalling capacity is linked to the down-regulation of cell surface markers that favour a reduced lymphocyte trafficking and the maintenance of a proliferative cellular pool within the lymph nodes.
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Brophy, Sarah, Paul Browne, Elisabeth A. Vandenberghe, David O'Brien, and Anthony M. McElligott. "Microenvironmental-Mediated Regulation of L-Selectin in Chronic Lymphocytic Leukaemia." Blood 126, no. 23 (December 3, 2015): 4133. http://dx.doi.org/10.1182/blood.v126.23.4133.4133.
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Abstract Chronic Lymphocytic Leukaemia (CLL) is characterized by the accumulation of CD5/19+ve B cells in the blood, bone marrow and lymph nodes. The tumour microenvironment of the bone marrow and secondary lymphoid organs promotes cell proliferation, survival and protection from drug induced apoptosis. Selectins, integrins and chemokines mediate the trafficking of CLL cells to these protective niches. An important adhesion molecule in this process is L-selectin (CD62L) which is involved in initial tethering and rolling of CLL cells in the high endothelial venules, allowing migration between the blood and the secondary lymphoid organs. It has been shown that CLL cell expression of CD62L increases during in vitro culture and blocking antibodies cause an increase in apoptosis, suggesting a role for CD62L in cell survival (Burgess et al., Clin Cancer Res. 2013). The B-cell receptor (BCR) signalling pathway is the most important pathway involved in micro-environmental crosstalk and CLL cell survival, and has recently been shown to interact with the STAT3 signalling pathway (Rozovski et al., Blood 2014). In this study, Hs5 Bone Marrow Stromal Cell (BMSC), Human Umbilical Vein Endothelial cells (HUVEC) and patient derived BMSC co-cultures were used to mimic pro-survival microenvironmental signals and investigate the effect on the expression of a panel of cell surface adhesion molecules. These coculture models resulted in a significant increase in CD62L positive CLL cells (p<0.01, n=7). Stimulation of the BCR using immunoglobulin F(ab´)2fragments induced tyrosine phosphorylation of STAT3 and resulted in a significant increase in CD62L expression, which was abrogated by pre-treatment with the Bruton tyrosine kinase (btk) inhibitor Ibrutinib prior to BCR stimulation. (p<0.05, n=5). siRNA mediated STAT3 knockdown and treatment with STAT3 inhibitors, including Cucurbitacin I, resulted in a significant decrease in CD62L positive CLL cells (p<0.0001, n=14). Co-culture with Hs5 cells, HUVECs, patient derived BMSC or BCR stimulation did not overcome Cucurbitacin I induced downregulation of CD62L. The effect of STAT3 inhibition on CLL cell adhesion and chemotaxis was also investigated. A microfluidic system including a neMESYS Low Pressure syringe pump system (Cetoni GmbH) and Cellix Vena8Endothelial+biochips coated with Human Umbilical Vein Endothelial cells (HUVECs) or Human Dermal Lymphatic Endothelial cells (HDLEC) was utilised to investigate CLL cell adhesion under fluid shear flow conditions. Flow rates of0.5 dynes/cm2 for the HUVEC-coated biochips and 0.08 dynes/cm2 for the HDLEC coated biochips were used to model the fluid shear of blood and lymphatic flow respectively. Treatment with Cucurbitacin I resulted in a mean decrease of 50% in CLL cell adhesion to HUVEC but not HDLEC in this system (p<0.05, n=3). Chemotaxis of CLL cells was investigated using Neuroprobe 96-well ChemoTx plates. Treatment with Cucurbitacin I resulted in a mean decrease of 87% of CLL cells migrated in response to the chemokine CXCL12 compared to control (p<0.0001, n=4). In conclusion, this study shows microenvironmental signals mediate the expression of CD62L in CLL cells. Our data suggest that the STAT3 pathway regulates the expression of CD62L and the adhesion and chemotaxis of CLL cells. The down-regulation of CD62L expression through inhibition of BCR signalling or direct inhibition of STAT3 may have implications for the trafficking of CLL cells and treatment of CLL. Disclosures No relevant conflicts of interest to declare.
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Stockfelt, Marit, Karin Christenson, Anders Andersson, Lena Björkman, Médea Padra, Bettina Brundin, Koustav Ganguly, et al. "Increased CD11b and Decreased CD62L in Blood and Airway Neutrophils from Long-Term Smokers with and without COPD." Journal of Innate Immunity 12, no. 6 (2020): 480–89. http://dx.doi.org/10.1159/000509715.
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There is incomplete mechanistic understanding of the mobilization of neutrophils in the systemic and local compartment in smokers with chronic obstructive pulmonary disease (COPD). In this pilot study, we characterized how the adhesion molecules CD11b and CD62L, surface markers indicative of priming, are altered as neutrophils extravasate, and whether surface density of CD11b and CD62L differs between long-term tobacco smokers (LTS) with and without COPD compared with healthy never-smokers (HNS). Unstimulated blood neutrophils from LTS with (<i>n</i> = 5) and without (<i>n</i> = 9) COPD displayed lower surface density of CD62L compared with HNS (<i>n</i> = 8). In addition, surface density of CD11b was higher in bronchoalveolar lavage (BAL) neutrophils from LTS without COPD compared with those with COPD and HNS. Moreover, in BAL neutrophils from all study groups, CD62L was lower compared with matched blood neutrophils. In addition, BAL neutrophils responded with a further decrease in CD62L to ex vivo TNF stimulation. Thus, neutrophils in the airway lumen display a higher state of priming than systemic neutrophils and bear the potential to be further primed by local cytokines even with no smoking or the presence of COPD, findings that may represent a universal host defense mechanism against local bacteria. Moreover, systemic neutrophils are primed in LTS regardless of COPD. Further studies in larger materials are warranted to determine whether the priming of neutrophils is protective against COPD or merely preceding it.
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Loschi, Michael, Régis Peffault de Latour, Raphael Porcher, Valerie Vanneaux, Marie Robin, Alienor Xhaard, Jerome Larghero, and Gérard Socié. "High Numbers Of Memory T Cells Are Associated With Higher Risk Of Grade II-IV Acute Gvhd After Human Allogeneic Transplantation." Blood 122, no. 21 (November 15, 2013): 2061. http://dx.doi.org/10.1182/blood.v122.21.2061.2061.
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Abstract Introduction Acute graft versus host disease is a frequent and life threatening complication following HSCT. Some predictive factors have been identified in the last decades. Experimental studies in mice suggest that the naïve cytotoxic T cells (CD3+/CD8+/CD45RA+/CD62L+) are the major mediators of acute GVHD and that removing this subset of the donor T cells, called ‘naïve T cells’, before transplant may reduce the frequency and intensity of GVHD. Detailed immunophenotyping of the graft including naïve and memory (CD3+/CD8+/CD45RA-/CD62L- ; CD3+/CD8+/CD45RA+/CD62L- ; CD3+/CD8+/CD45RA-/CD62L+ ) T-cell contents have never been explored in human GVHD. We studied the correlation between memory and naive T cell in bone marrow and peripheral blood grafts and development of acute GVHD after hematopoietic stem cell transplant. Methods We analyzed by detailed immunophenotyping, the grafts of a cohort of 210 patients among 402 patients who received an allogeneic stem cell transplantation from bone marrow and peripheral blood between January 2009 and June 2012 at a single center. There were no differences between the 210 studied patients and the other 192 in whom grafts were not studied. Characteristics of patients investigated for naïve and memory T cells were compared using Wilcoxon rank-sum tests and Fisher’s exact tests. The main outcome was occurrence of acute GVHD grade II – IV. Cumulating incidence of acute GVHD was estimated using usual methods and compared according to tertiles of T cytotoxic lymphocytes subpopulations using Gray’s test. Adjusted analyses were performed using Fine- Gray proportional hazards models. All tests were two - sided and p-values ≤ 0.05 were considered as indicating significant association. T cytotoxic lymphocytes were typed in all 210 grafts using CD3, CD8, CD45 RA and CD62L four colors immuphenotyping. Clinical and histological characteristics of patients were recorded. Including age, gender, ABO group and rhesus, viral serology of both the donor and the patient, characteristic of the grafts including HLA compatibility, bone marrow or peripheral blood, lymphocytes and nucleated cell and CD34 numeration, conditioning regimens, GVHD prophylaxis, characteristics of GVHD (date of onset, organs involved, stage and grade). Results Median follow up from transplant was 18 months. Cumulative incidence of acute GVHD was 59% (95% CI range 45 to 59) overall, and 49% (95% CI 42 to 56) at 100 days. In univariate analysis increased absolute counts of memory T cell subtypes were significantly correlated with the onset of an acute GVHD grade II – IV. Risk factors for acute GVHD (multivariate analysis) were use of an unrelated donor, positive CMV donor for a negative recipient, and use of TBI 12Gy. In a multivariate analysis the subtype CD3+/CD8+/CD45 RA-/CD62L- was associated with the onset of acute GVHD grade II-IV (adjusted Hazard Ratio = 1.26 and 1.98, p=0.02). Adjusting analysis on the total number of total nucleated cells infused did not affect the results. Restricting analyses to patients receiving peripheral blood stem cells also provided same conclusions. Conclusion This first study on the relation between rate of memory T cell and GVHD revealed that CD3+/CD8+/CD45 RA-/CD62 L- T-cells numbers and percentage were associated with acute GVHD grade II – IV. In contrast to murine models we did not find evidence for a link between naïve T-cells and GVHD risk Disclosures: Robin: novartis: Research Funding.
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Chudilova, G. A., I. V. Nesterova, S. V. Kovaleva, and L. V. Lomtatidze. "Regulatory cytokine effects in vitro on the phenotype of subpopulations CD62L+CD63-, CD62L+CD63+ and microbicidal activity of neutrophilic granulocytes in patients with colorectal cancer." RUDN Journal of Medicine 24, no. 4 (December 15, 2020): 304–14. http://dx.doi.org/10.22363/2313-0245-2020-24-4-304-314.
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Relevance. Neutrophilic granulocytes (NG) are the first cells of the immune system to migrate to the tumor and are actively involved in the implementation of a full-fledged antitumor response through the mechanisms of direct killing of tumor cells, extracellular lysis (NET), and through the activation of antibody-dependent cellular cytotoxicity (ADCC), inhibition of angiogenesis, initiation of other cells with antitumor activity. The aim of the study was to study the effect of cytokines IFN, IFN, G-CSF on the CD62L+CD63- and CD62L+CD63+ subsets and the microbicidal activity of NGs in patients with colorectal cancer (CRC) in vitro. Materials and methods. We studied samples of peripheral blood (PB) of 10 patients of both sexes 38-70 years old with newly diagnosed untreated CRC stage II-III (study group) and 10 healthy volunteers (comparison group). The subsets CD62L+CD63+ NG, CD62L+CD63- NG were assessed by flow cytometry (CYTOMICS FC500, Beckman Coulter, USA), the microbicidal functions of NG were tested by cytochemical methods: activity of NADPH - oxidases, myeloperoxidase (MP), level of cationic protein (CP) in spontaneous tests and under additional stress of S. aureus . The effect of IFN, IFN, G-CSF cytokines on subsets and the microbicidal activity of NG in vitro was studied in both study groups. Microsoft Exel 2016 and StatPlus 2010 were used for statistical processing of the obtained data using nonparametric tests: Me (Q1; Q3), Mann-Whitney U-test and Wilcoxon test . Results . The features of transformation of CD62L+ CD63-NG and CD62L+ CD63+ NG subsets of PB in CRC have been established, that allows to get an idea of the NG ability to roll and readiness to activate the microbicidal arsenal, various defects of spontaneous and induced microbicidal activity of oxygendependent and oxygen-independent mechanisms of NG. The effects of cytokine influence on NG in CRC in vitro have been shown, which indicates the possibility of regulating the receptor and microbicidal functions of NG, and, on the other hand, suggests defects in NG perception of regulatory stimuli, that is confirmed by the progression of tumor growth.
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Martins, Sergio L. R., Lisa S. St. John, and Krishna V. Komanduri. "Naïve and Memory CD4+ T Cells Proliferate and Contribute to Cytokine Production in the Human Alloreactive T Cell Response in Vitro." Blood 104, no. 11 (November 16, 2004): 4983. http://dx.doi.org/10.1182/blood.v104.11.4983.4983.
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Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in the setting of allogeneic stem cell transplantation (SCT). We recently developed a cytokine flow cytometry (CFC)-based assay to assess alloreactivity (Martins, et al., Blood 2004). This approach utilizes CFC to facilitate the simultaneous assessment of effector cytokine production and the surface phenotype of responding alloreactive T cells. Recently, studies in murine models have suggested that GVHD may be mediated primarily by naïve T cells and not by memory T cells, raising the possibility that naïve T cell depletion may limit clinical GVHD after human SCT. We sought to assess the independent capability of human naïve and memory T cells to respond functionally to alloantigenic stimulation by CFC. To do this, we purified naive CD4 T cells (CD45RA+CD62L+), memory CD4 T cells (CD4+CD45RA-CD62L+) or naïve-depleted CD4+ T cells (consisting of both CD4+CD45RA-CD62L+ and CD4+CD45RA-CD62L- cells) from fresh healthy donor PBMC using cell sorting. Purified populations were recombined with autologous monocytes and then stimulated with pooled, irradiated mismatched allogeneic stimulator cells, irradiated autologous cells or media. Purified responder cell subpopulations were also labeled with CFSE to facilitate assessment of functional activation and proliferation in the CFSE-marked subsets. Following three and seven day stimulation periods, responder T cells were harvested and incubated in the presence of brefeldin A for 6 hr to facilitate the accumulation of intracellular TNFα, an effector cytokine important in GVHD pathogenesis. We then analyzed the frequencies of responding CFSE-low CD4+ T cells expressing surface differentiation and activation markers, and assessed the co-expression of intracellular TNFα using CFC. We assessed a wide range of T cell surface markers (e.g., CD25, CD38, CD58, CD122, CD45RO, CD62L, and CCR7). By day seven, we consistently observed alloreactive T cell activation in the naïve CD4+ T cell (i.e., CD45RA+CD62L+) compartment. However, purified populations of memory CD4+ T cells also responded to alloreactive stimulation, as assessed by both decreased CFSE staining intensity and by intracellular TNFα production. Amongst cells that were naïve in phenotype prior to stimulation (CD45RA+CD62L+), we observed that those cells that were CFSE-low after stimulation (proliferating cells) downregulated CD45RA and CD62L, consistent with maturation to a memory phenotype. Surprisingly, the expression of the chemokine receptor CCR7, a marker of naïve and central memory T cells also known to be important in lymphoid homing, was altered following allogeneic activation in proliferating (CFSE-low) cells that were originally naïve in phenotype. CCR7 expression increased on a subpopulation of alloreactive cells but decreased on a distinct subset of these cells. Similarly, increases in CCR7 expression were also demonstrated in memory CD4+ T cells following functional activation with alloantigens. In summary, these experiments demonstrate that both naive and memory human T cells responding to allogeneic stimulation are capable of proliferation and effector cytokine production in vitro. Additionally, responding naïve CD4+ T cells lose CD45RA and CD62L expression, consistent with memory maturation, while distinct subsets of these cells increase and decrease their expression of CCR7.
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Gondois-Rey, Françoise, Angelique Biancotto, Marcelo Antonio Fernandez, Lise Bettendroffer, Jana Blazkova, Katerina Trejbalova, Marjorie Pion, and Ivan Hirsch. "R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L− CD4+ T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors." Journal of Virology 80, no. 2 (January 15, 2006): 854–65. http://dx.doi.org/10.1128/jvi.80.2.854-865.2006.
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ABSTRACT The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4+ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4+ T cells on the predominance of R5 and X4 HIV-1 variants in different subsets of CD4+ T cells in ex vivo-infected human lymphoid tissues and peripheral blood mononuclear cells (PBMCs). In these cell systems, we examined the sensitivity of HIV replication to reverse transcriptase inhibitors. We demonstrate that R5 HIV-1 variants preferentially produced productive infection in HLA-DR− CD62L− CD4+ T cells. These cells were mostly in the G1b phase of the cell cycle, divided slowly, and expressed high levels of CCR5. In contrast, X4 HIV-1 variants preferentially produced productive infection in activated HLA-DR+ CD62L+ CD4+ T cells, which expressed high levels of CXCR4. The abilities of the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine to stop HIV-1 replication were 20 times greater in activated T cells than in slowly dividing HLA-DR− CD62L− CD4+ T cells. This result, demonstrated both in a highly physiologically relevant ex vivo lymphoid tissue model and in PBMCs, correlated with higher levels of thymidine kinase mRNA in activated than in slowly dividing HLA-DR− CD62L− CD4+ T cells. The non-NRTI nevirapine was equally efficient in both cell subsets. The lymphoid tissue and PBMC-derived cell systems represent well-defined models which could be used as new tools for the study of the mechanism of resistance to HIV-1 inhibitors in HLA-DR− CD62L− CD4+ T cells.
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Timganova, Valeria, Maria Bochkova, Pavel Khramtsov, Sofia Kochurova, Mikhail Rayev, and Svetlana Zamorina. "Effects of pregnancy-specific β-1-glycoprotein on the helper T-cell response." Archives of Biological Sciences 71, no. 2 (2019): 369–78. http://dx.doi.org/10.2298/abs190122019t.
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Pregnancy-specific ?-1-glycoproteins (PSGs) are capable of regulating innate and adaptive immunity. As fetal antigens circulate in the blood of pregnant women, it is of particular interest to reveal the effects of PSGs on the differentiation of memory T cells in the context of maternal-fetal tolerance formation. We studied if, native PSG preparation affects helper T-cell proliferation, the frequencies of CD4+CD45R0+, CD4+CD45RA+, CD4+CD45RA+CD45R0+cells, naive CD45RA+CD45R0-CD62L+ cells (NAIVE), central memory CD45RA-CD45R0+CD62L+ cells (TCM), effector memory helper T cells (CD45RA-CD45R0+CD62L- (TEM) and CD45RA+CD45R0-CD62L- cells (TEMRA), together with IL-4 and IFN-? production by all ?D4+ T cells. The suppressive effect of PSG on helper T-cell proliferation was established. It was found that PSG does not influence the frequencies of CD45RA+ and CD45R0+ cells, while it decreased the percentage of CD45RA+CD45R0+ cells. PSG increased the percentage of NAIVE cells in culture, and prevented the conversion of these cells into TEMRA, without affecting the levels of TCM and TEM. In addition, PSG lowered the amount of IL-4 and IFN-? in the supernatants of helper T-cell cultures. As TEMRA exhibit cytotoxic activity that is unfavorable during pregnancy, the revealed PSG effects may play a fetoprotective role in vivo.