The Experts below are selected from a list of 18498 Experts worldwide ranked by ideXlab platform
Si-yi Chen - One of the best experts on this subject based on the ideXlab platform.
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Genetic co-inactivation of macrophage- and T-tropic HIV-1 Chemokine coReceptors CCR-5 and CXCR-4 by intrakines.
Gene therapy, 1998Co-Authors: Bai X, Angang Yang, Torti F, Si-yi ChenAbstract:CC-Chemokine Receptor (CCR)-5 is the principal coReceptor for the entry of macrophage (M)-tropic HIV-1 viruses into a cell, while CXC-Chemokine Receptor (CXCR)-4 is the principal coReceptor for T cell line (T)-tropic HIV-1. In this study, we utilized a novel intracellular Chemokine (intrakine) strategy to co-inactivate genetically both CCR-5 and CXCR-4 in human lymphocytes. The principle of co-inactivation of CCR-5 and CXCR-4 was illustrated by targeting the CC-intrakine and CXC-intrakine to the lumen of the endoplasmic reticulum (ER) for intracellular blockade of the transport of newly synthesized Chemokine coReceptors to the cell surface. The lymphocytes with the phenotypic knock-out of CCR-5 and CXCR-4 were found broadly to resist the infection of M-tropic, T-tropic and dual-tropic HIV-1 viruses. Moreover, the transduced lymphocytes retained normal cell features, including the responsiveness to mitogen and recall antigen stimulation. Thus, this study to our knowledge, is the first to demonstrate that genetic co-inactivation of the M- and T-tropic HIV-1 principal coReceptors in lymphocytes or other cells could be a viable strategy for the long-term control of HIV-1 infection.
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Inactivation of HIV-1 Chemokine co-Receptor CXCR-4 by a novel intrakine strategy.
Nature medicine, 1997Co-Authors: Ji-dai Chen, Xuefan Bai, Angang Yang, Yanping Cong, Si-yi ChenAbstract:CXC-Chemokine Receptor (CXCR)-4/fusin, a newly discovered co-Receptor for T-cell line (T)-tropic HIV-1 virus, plays a critical role in T-tropic virus fusion and entry into permissive cells. The occurrence of T-tropic HIV viruses is associated with CD4-positive cell decline and progression to AIDS, suggesting that the T-tropic HIV-1 contributes to AIDS pathogenesis. In this study, we used a novel strategy to inactivate CXCR-4 by targeting a modified CXC-Chemokine to the endoplasmic reticulum (ER) to block the surface expression of newly synthesized CXCR-4. The genetically modified lymphocytes expressing this intracellular Chemokine, termed "intrakine", are immune to T-tropic virus infection and appear to retain normal biological features. Thus, this genetic intrakine strategy is uniquely targeted at the conserved cellular Receptor for the prevention of HIV-1 entry and may be developed into an effective treatment for HIV-1 infection and AIDS.
Alessandro Antonelli - One of the best experts on this subject based on the ideXlab platform.
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Novel Therapies for Thyroid Autoimmune Diseases.
Expert review of clinical pharmacology, 2016Co-Authors: Poupak Fallahi, Dilia Giuggioli, Clodoveo Ferri, Giusy Elia, Silvia Martina Ferrari, Francesco Nasini, Michele Colaci, Roberto Vita, Salvatore Benvenga, Alessandro AntonelliAbstract:C-X-C Chemokine Receptor (CXCR)3 and its interferon(IFN)γ-dependent Chemokines (CXCL10, CXCL9, CXCL11) are implicated in the immune-pathogenesis of autoimmune thyroiditis (AT), Graves disease (GD) and Graves Ophthalmopathy (GO). In tissue, recruited Th1 lymphocytes produce IFNγ, enhancing the tissue secretion of IFNγ-inducible Chemokines, initiating and perpetuating the autoimmune process. Patients with AT (with hypothyroidism), and with GO and GD, particularly in the active phase, have high IFNγ-inducible Chemokines. Peroxisome proliferator-activated Receptor (PPAR)γ or -α agonists and methimazole exert an immune-modulation on CXCR3 Chemokines in AT, GD and GO. Other studies are ongoing to evaluate new molecules acting as antagonists of CXCR3, or blocking CXCL10, in Hashimoto thyroiditis (HT), GD and GO. Recently, novel molecules targeting the various agents involved in the pathogenesis of GO, such as rituximab, have been proposed as an alternative to corticosteroids. However, randomized and controlled studies are needed to generalize these interesting results.
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Application of Agents Against Interferon-Gamma-Dependent Chemokines in Immunotherapy
Letters in Drug Design & Discovery, 2015Co-Authors: Poupak Fallahi, Silvia Ferrari, Dilia Giuggioli, Clodoveo Ferri, Alessandro AntonelliAbstract:The CXC Chemokine Receptor (CXCR) 3 and its Chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune disesases. Under the influence of interferon (IFN) \u3b3, the IFN\u3b3-inducible Chemokines are secreted by lymphocytes, and by target cells (fibroblasts, epithelial cells, etc). In target tissues, Th1 lymphocytes are recruited; hence IFN\u3b3 is enhanced, which stimulates IFN\u3b3-inducible Chemokines (CXCL9, CXCL10, CXCL11) secretion reiterating the autoimmune process. Many studies have evaluated if blockade of ..
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Targeting Chemokine (C-X-C motif) Receptor 3 in thyroid autoimmunity.
Recent patents on endocrine metabolic & immune drug discovery, 2014Co-Authors: Poupak Fallahi, Silvia Ferrari, Dilia Giuggioli, Clodoveo Ferri, Alda Corrado, Alessandro AntonelliAbstract:The C-X-C Chemokine Receptor (CXCR)3 and its Chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune thyroiditis (AT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). Under the influence of interferon(IFN)γ, the IFNγ-induced protein 10 (IP-10/CXCL10) is secreted by thyrocytes, orbital fibroblasts and preadipocytes. In tissue, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates CXCL10 secretion reiterating the autoimmune process. The presence of elevated levels of CXCL10 in peripheral liquids is considered a marker of Th1 orientated immune response. High levels of circulating CXCL10 (sCXCL10) have been shown in patients with AT, overall with hypothyroidism. In GD and GO patients high sCXCL10 have been shown particularly in the active disease. A modulatory role of peroxisome proliferator-activated Receptor (PPAR)γ or - α agonists on CXCR3 Chemokines in AT, GD and GO and the immuno-modulatory effect of methimazole on CXCR3 Chemokines in GD have been shown. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied.
Jürgen Bernhagen - One of the best experts on this subject based on the ideXlab platform.
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MIF interacts with CXCR7 to promote Receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015Co-Authors: Setareh Alampour-rajabi, Andreas Schober, Omar El Bounkari, Antal Rot, Gerhard Müller-newen, Françoise Bachelerie, Meinrad Gawaz, Christian Weber, Jürgen BernhagenAbstract:Macrophage migration-inhibitory factor (MIF) is a pleiotropic cytokine with Chemokine-like functions and is a mediator in numerous inflammatory conditions. Depending on the context, MIF signals through 1 or more of its Receptors cluster of differentiation (CD)74, CXC-motif Chemokine Receptor (CXCR)2, and CXCR4. In addition, heteromeric Receptor complexes have been identified. We characterized the atypical Chemokine Receptor CXCR7 as a novel Receptor for MIF. MIF promoted human CXCR7 internalization up to 40%, peaking at 50-400 nM and 30 min, but CXCR7 internalization by MIF was not dependent on CXCR4. Yet, by coimmunoprecipitation, fluorescence microscopy, and a proximity ligation assay, CXCR7 was found to engage in MIF Receptor complexes with CXCR4 and CD74, both after ectopic overexpression and in endogenous conditions in a human B-cell line. Receptor competition binding and coimmunoprecipitation studies combined with sulfo-SBED-biotin-transfer provided evidence for a direct interaction between MIF and CXCR7. Finally, we demonstrated MIF/CXCR7-mediated functional responses. Blockade of CXCR7 suppressed MIF-mediated ERK- and zeta-chain-associated protein kinase (ZAP)-70 activation (from 2.1- to 1.2-fold and from 2.5- to 1.6-fold, respectively) and fully abrogated primary murine B-cell chemotaxis triggered by MIF, but not by CXCL12. B cells from CXCR7(-/-) mice exhibited an ablated transmigration response to MIF, indicating that CXCR7 is essential for MIF-promoted B-cell migration. Our findings provide biochemical and functional evidence that MIF is an alternative ligand of CXCR7 and suggest a functional role of the MIF-CXCR7 axis in B-lymphocyte migration.
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mif interacts with CXCR7 to promote Receptor internalization erk1 2 and zap 70 signaling and lymphocyte chemotaxis
The FASEB Journal, 2015Co-Authors: Setareh Alampourrajabi, Jürgen Bernhagen, Andreas Schober, Omar El Bounkari, Antal Rot, Françoise Bachelerie, Meinrad Gawaz, Christian Weber, Gerhard MullernewenAbstract:Macrophage migration-inhibitory factor (MIF) is a pleiotropic cytokine with Chemokine-like functions and is a mediator in numerous inflammatory conditions. Depending on the context, MIF signals through 1 or more of its Receptors cluster of differentiation (CD)74, CXC-motif Chemokine Receptor (CXCR)2, and CXCR4. In addition, heteromeric Receptor complexes have been identified. We characterized the atypical Chemokine Receptor CXCR7 as a novel Receptor for MIF. MIF promoted human CXCR7 internalization up to 40%, peaking at 50-400 nM and 30 min, but CXCR7 internalization by MIF was not dependent on CXCR4. Yet, by coimmunoprecipitation, fluorescence microscopy, and a proximity ligation assay, CXCR7 was found to engage in MIF Receptor complexes with CXCR4 and CD74, both after ectopic overexpression and in endogenous conditions in a human B-cell line. Receptor competition binding and coimmunoprecipitation studies combined with sulfo-SBED-biotin-transfer provided evidence for a direct interaction between MIF and CXCR7. Finally, we demonstrated MIF/CXCR7-mediated functional responses. Blockade of CXCR7 suppressed MIF-mediated ERK- and zeta-chain-associated protein kinase (ZAP)-70 activation (from 2.1- to 1.2-fold and from 2.5- to 1.6-fold, respectively) and fully abrogated primary murine B-cell chemotaxis triggered by MIF, but not by CXCL12. B cells from CXCR7(-/-) mice exhibited an ablated transmigration response to MIF, indicating that CXCR7 is essential for MIF-promoted B-cell migration. Our findings provide biochemical and functional evidence that MIF is an alternative ligand of CXCR7 and suggest a functional role of the MIF-CXCR7 axis in B-lymphocyte migration.
Laura J Frishman - One of the best experts on this subject based on the ideXlab platform.
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critical role of the cxcl10 c x c Chemokine Receptor 3 axis in promoting leukocyte recruitment and neuronal injury during traumatic optic neuropathy induced by optic nerve crush
American Journal of Pathology, 2017Co-Authors: Hua Liu, Wei Liu, Shuang Zhu, Jared Nathanson, Rakez Kayed, Bradford D Loucas, Jiaren Sun, Laura J Frishman, Massoud Motamedi, Wenbo ZhangAbstract:Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a Chemokine that recruits leukocytes after binding to its Receptor C-X-C Chemokine Receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death.
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Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush.
The American journal of pathology, 2016Co-Authors: Hua Liu, Wei Liu, Shuang Zhu, Jared Nathanson, Rakez Kayed, Bradford D Loucas, Jiaren Sun, Laura J FrishmanAbstract:Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a Chemokine that recruits leukocytes after binding to its Receptor C-X-C Chemokine Receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death.
Shiranee Sriskandan - One of the best experts on this subject based on the ideXlab platform.
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Streptococcal superantigen-induced expansion of human tonsil T cells leads to altered T follicular helper cell phenotype, B cell death and reduced immunoglobulin release.
Clinical and Experimental Immunology, 2019Co-Authors: Frances Davies, Carl Olme, Nicola N. Lynskey, Claire E. Turner, Shiranee SriskandanAbstract:: Streptococcal pyrogenic exotoxin (Spe) A expression is epidemiologically linked to streptococcal tonsillo-pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantage to Streptococcus pyogenes are unclear. S. pyogenes is an exclusively human pathogen. As the leucocyte profile of tonsil is unique, the impact of SpeA production on human tonsil cell function was investigated. Human tonsil cells from routine tonsillectomy were co-incubated with purified streptococcal superantigens or culture supernatants from isogenic streptococcal isolates, differing only in superantigen production. Tonsil cell proliferation was quantified by tritiated thymidine incorporation, and cell surface characteristics assessed by flow cytometry. Soluble mediators including immunoglobulin were measured using enzyme-linked immunosorbent assay. Tonsil T cells proliferated in response to SpeA and demonstrated typical release of proinflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7 days. In contrast, marked B cell apoptosis and abrogation of total immunoglobulin (Ig)A, IgM, and IgG production occurred in the presence of SpeA and other superantigens. In SpeA-stimulated cultures, T follicular helper (Tfh) cells showed a reduction in C-X-C Chemokine Receptor (CXCR)5 (CD185) expression, but up-regulation of OX40 (CD134) and inducible T cell co-stimulator (ICOS) (CD278) expression. The phenotypical change in the Tfh population was associated with impaired chemotactic response to CXCL13. SpeA and other superantigens cause dysregulated tonsil immune function, driving T cells from Tfh to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen-producing bacteria with a probable survival advantage.