The Experts below are selected from a list of 97272 Experts worldwide ranked by ideXlab platform
Gunnar Nilsson - One of the best experts on this subject based on the ideXlab platform.
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Selective CCL5/RANTES-induced mast cell migration through interactions with chemokine receptors CCR1 and CCR4
Biochemical and Biophysical Research Communications, 2002Co-Authors: Mikael Juremalm, Niclas Olsson, Gunnar NilssonAbstract:Mast cells (MCs) accumulate at sites of allergic mucosal inflammation where they act as central effector and regulatory cells. Because chemokines are of vital importance in directing inflammatory leukocytes to the sites of inflammations, we have investigated the expression and function of CC-chemokine receptor (CCR) on human MCs. Two previously unrecognized MC-chemokine receptors, CCR1 and CCR4, could be identified on cord blood-derived MCs (CBMCs). CCR1 and CCR4 expressed on CBMCs exhibited a unique response profile. Of seven CCR1 and CCR4 agonists tested, only CCL5/RANTES act as an agonist inducing chemotaxis. The migration could be partially blocked by specific antibodies against CCR1 or CCR4, while a complete inhibition was achieved when both CCR1 and CCR4 were blocked. These results demonstrate that both CCR1 and CCR4 are functional receptors on human mast cells with capacity to mediate migration towards CCL5.
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selective ccl5 rantes induced mast cell migration through interactions with chemokine receptors ccr1 and CCR4
Biochemical and Biophysical Research Communications, 2002Co-Authors: Mikael Juremalm, Niclas Olsson, Gunnar NilssonAbstract:Mast cells (MCs) accumulate at sites of allergic mucosal inflammation where they act as central effector and regulatory cells. Because chemokines are of vital importance in directing inflammatory leukocytes to the sites of inflammations, we have investigated the expression and function of CC-chemokine receptor (CCR) on human MCs. Two previously unrecognized MC-chemokine receptors, CCR1 and CCR4, could be identified on cord blood-derived MCs (CBMCs). CCR1 and CCR4 expressed on CBMCs exhibited a unique response profile. Of seven CCR1 and CCR4 agonists tested, only CCL5/RANTES act as an agonist inducing chemotaxis. The migration could be partially blocked by specific antibodies against CCR1 or CCR4, while a complete inhibition was achieved when both CCR1 and CCR4 were blocked. These results demonstrate that both CCR1 and CCR4 are functional receptors on human mast cells with capacity to mediate migration towards CCL5.
Mikael Juremalm - One of the best experts on this subject based on the ideXlab platform.
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Selective CCL5/RANTES-induced mast cell migration through interactions with chemokine receptors CCR1 and CCR4
Biochemical and Biophysical Research Communications, 2002Co-Authors: Mikael Juremalm, Niclas Olsson, Gunnar NilssonAbstract:Mast cells (MCs) accumulate at sites of allergic mucosal inflammation where they act as central effector and regulatory cells. Because chemokines are of vital importance in directing inflammatory leukocytes to the sites of inflammations, we have investigated the expression and function of CC-chemokine receptor (CCR) on human MCs. Two previously unrecognized MC-chemokine receptors, CCR1 and CCR4, could be identified on cord blood-derived MCs (CBMCs). CCR1 and CCR4 expressed on CBMCs exhibited a unique response profile. Of seven CCR1 and CCR4 agonists tested, only CCL5/RANTES act as an agonist inducing chemotaxis. The migration could be partially blocked by specific antibodies against CCR1 or CCR4, while a complete inhibition was achieved when both CCR1 and CCR4 were blocked. These results demonstrate that both CCR1 and CCR4 are functional receptors on human mast cells with capacity to mediate migration towards CCL5.
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selective ccl5 rantes induced mast cell migration through interactions with chemokine receptors ccr1 and CCR4
Biochemical and Biophysical Research Communications, 2002Co-Authors: Mikael Juremalm, Niclas Olsson, Gunnar NilssonAbstract:Mast cells (MCs) accumulate at sites of allergic mucosal inflammation where they act as central effector and regulatory cells. Because chemokines are of vital importance in directing inflammatory leukocytes to the sites of inflammations, we have investigated the expression and function of CC-chemokine receptor (CCR) on human MCs. Two previously unrecognized MC-chemokine receptors, CCR1 and CCR4, could be identified on cord blood-derived MCs (CBMCs). CCR1 and CCR4 expressed on CBMCs exhibited a unique response profile. Of seven CCR1 and CCR4 agonists tested, only CCL5/RANTES act as an agonist inducing chemotaxis. The migration could be partially blocked by specific antibodies against CCR1 or CCR4, while a complete inhibition was achieved when both CCR1 and CCR4 were blocked. These results demonstrate that both CCR1 and CCR4 are functional receptors on human mast cells with capacity to mediate migration towards CCL5.
Daniel C. Baumgart - One of the best experts on this subject based on the ideXlab platform.
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Targeting leukocyte migration and adhesion in Crohn’s disease and ulcerative colitis
Inflammopharmacology, 2012Co-Authors: Saskia Thomas, Daniel C. BaumgartAbstract:Crohn’s disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4^+ T-cells, CD8^+ T-cells, T_REG, T_H1, T_H17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [α4β7 (LPAM-1), α_Eβ_7 (HML1 Human Mucosal Lymphocyte Antigen 1), α_4β_1 (VLA-4)_, α_Lβ_7, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-α_4, Tysabri^®, Antegren^®), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-EN™) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety.
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targeting leukocyte migration and adhesion in crohn s disease and ulcerative colitis
Inflammopharmacology, 2012Co-Authors: Saskia Thomas, Daniel C. BaumgartAbstract:Crohn’s disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4+ T-cells, CD8+ T-cells, TREG, TH1, TH17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [α4β7 (LPAM-1), αEβ7 (HML1 Human Mucosal Lymphocyte Antigen 1), α4β1 (VLA-4), αLβ7, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-α4, Tysabri®, Antegren®), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-EN™) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety.
Rodrigo Guabiraba - One of the best experts on this subject based on the ideXlab platform.
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role of the chemokine receptors ccr1 ccr2 and CCR4 in the pathogenesis of experimental dengue infection in mice
PLOS ONE, 2010Co-Authors: Rodrigo Guabiraba, Rafael Elias Marques, Annegaelle Besnard, Caio T Fagundes, Danielle G. Souza, Bernhard Ryffel, Mauro M TeixeiraAbstract:Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different chemokines in plasma and severity of dengue. We evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2 infection in mice. Infection of mice induced evident clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, lymphopenia, increased levels of transaminases and pro-inflammatory cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of chemokines CCL2/JE, CCL3/MIP-1α and CCL5/RANTES in spleen and liver. CCR1-/- mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2-/- mice, lethality, liver damage, levels of IL-6 and IFN-γ, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice. Infection enhanced levels of CCL17/TARC, a CCR4 ligand. In CCR4-/- mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of chemokine receptors has discrete roles in the pathogenesis of dengue infection. These studies suggest that the chemokine storm that follows severe primary dengue infection associates mostly to development of disease rather than protection.
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CC chemokine receptors play different roles in the pathogenesis of dengue virus infection in mice
2010Co-Authors: Rodrigo GuabirabaAbstract:Introduction: Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in Brazil and other tropical regions. Infection is characterized by a systemic inflammatory response and hematological alterations that may evolve with shock and death in severe cases. Chemokines and their receptors are important molecules involved in leukocyte recruitment and activation in many viral infections. Recent clinical data have shown an association between components of the chemokine network and severity of Dengue. However, the function of the chemokine system in the context of dengue infection is not known. Here we evaluated the role of CC chemokine receptors CCR1, CCR2, CCR4 and CCR5 in an experimental model of DENV-2 infection using mice genetically deficient for each chemokine receptor. Chemokine receptor antagonists were used to confirm major findings and evaluate potential therapeutic benefit of targeting the system. Methods: C57/BL6 (WT) and gene deficient mice were inoculated i.p. with 1 or 10 LD50 of a mouse adapted DENV-2 strain. Survival, MPO (as a marker of neutrophil accumulation), cytokines, histological analysis and viral titration in spleen and liver were evaluated. Hematocrit, platelet numbers and levels of cytokines and transaminases (TGO/TGP) were also evaluated in blood. Protocol CETEA/UFMG: 113/2009. Results: WT animals infected with DENV-2 died around day 7 after infection. At day 6, there was evidence of clinical disease and tissue damage, as shown by thrombocytopenia, hemoconcentration, increased levels of transaminases, neutrophil accumulation in tissues and elevated levels of cytokines (TNF-α, IFN-γ, IL-6, IL-12p40, CXCL1/KC). CCR1-/- mice were similar to WT mice with similar disease pattern and mortality, but slightly increased neutrophil accumulation and levels of IL-6, IFN- γ and KC in spleen, liver or serum. Lethality was decreased in CCR2-/- mice (p=0.03), tissue injury was slightly increased and systemic parameters of inflammation were similar to those of infected WT mice, although IFN- γ and IL-6 are reduced in liver. Infection enhanced levels of CCL17/TARC, a ligand for CCR4. More importantly, lethality rate, tissue injury and systemic inflammation were decreased in CCR4-/- mice. The phenotype of CCR5-/- mice was qualitatively similar to that of CCR4-/- mice but protection was much more pronounced in the former animals. Indeed, infected CCR5-/- mice did not die after infection and showed no hematological alterations or evidence of tissue injury or systemic inflammation. Importantly, viral load was greatly reduced in CCR5-/- mice (< 3 Log reduction). Finally, treatment with a CCR1/5 antagonist, MetRANTES (10 μg/mouse/day), was associated with decreased clinical disease, systemic inflammation and lethality after DENV-2 infection. Discussion: This study shows that the chemokine system plays a major role in the context of experimental dengue infection. Although CCR1 appears to play a minor role, CCR2 seems to be important for liver-associated pathology and CCR4 and CCR5 contributed markedly to tissue and systemic inflammatory changes associated with the experimental infection. CC chemokine receptor blockade, especially CCR5, may represent an interesting therapeutic approach for the treatment of dengue infection.
Richard Horuk - One of the best experts on this subject based on the ideXlab platform.
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why ccr2 and ccr5 blockade failed and why ccr1 blockade might still be effective in the treatment of rheumatoid arthritis
PLOS ONE, 2011Co-Authors: M C Lebre, Richard Horuk, Clarissa E Vergunst, I Y Choi, Saida Aarrass, Ana S F Oliveira, Tim Wyant, Kris A ReedquistAbstract:The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model. Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis. The RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo
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mip 1α utilizes both ccr1 and ccr5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells
Experimental Hematology, 2005Co-Authors: Lori A Ehrlich, Ho Yeon Chung, Natalie Callander, Diane F Jelinek, Richard Horuk, Sun Jin Choi, David G RoodmanAbstract:Objectives Macrophage inflammatory protein-1α (MIP-1α), an osteoclast (OCL) stimulatory factor produced by primary multiple myeloma (MM) cells, increases bone destruction and tumor burden in murine models of MM. Several chemokine receptors (CCR1, CCR5, and CCR9) mediate the effects of MIP-1α. In this study, we determined which of these mediates the effects of MIP-1α on human OCL formation and myeloma cells. Methods We employed RT-PCR analysis, neutralizing antibodies to CCR1 and CCR5 as well as a CCR1-specific antagonist and OCL formation assays to identify the MIP-1α receptors involved in MIP-1α's effects on myeloma cells and OCL formation. Results RT-PCR analysis demonstrated that both CCR1 and CCR5 were expressed by highly purified human OCL precursors, myeloma cell lines, and purified marrow plasma cells from MM patients. Neutralizing antibodies to CCR1 or CCR5 inhibited MIP-1α-induced OCL formation. Furthermore, monocyte chemotactic protein-3 (MCP-3), which binds CCR1 but not CCR5 and the CCR1-specific antagonist, BX471, markedly inhibited OCL formation stimulated with MIP-1α. Anti-CCR1, anti-CCR5, or BX471 also inhibited the upregulation of β 1 integrin mRNA in myeloma cells induced by MIP-1α, as well as the adherence of myeloma cells to stromal cells and IL-6 production by stromal cells in response to myeloma cells. Conclusion These data demonstrate that MIP-1α utilizes either CCR1 or CCR5 for its effects on OCL formation and myeloma cells, and that blocking either CCR1 or CCR5 inhibits OCL formation and myeloma cell adhesion to stromal cells.
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late onset of treatment with a chemokine receptor ccr1 antagonist prevents progression of lupus nephritis in mrl fas lpr mice
Journal of The American Society of Nephrology, 2004Co-Authors: Hans-joachim Anders, Stephan Segerer, Guillermo Perez De Lema, Emilia Belemezova, Volker Vielhauer, Clemens D Cohen, Richard Horuk, Michael Frink, Matthias Kretzler, Kelly L HudkinsAbstract:ABSTRACT. Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL lpr/lpr mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a week from week 20 to 24 of age. BX471 improved blood urea nitrogen levels (BX471, 35.1 ± 5.3; vehicle, 73.1 ± 39.6 mg/dl; P lpr/lpr mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-β. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL lpr/lpr mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.