Publications by authors named "Pius Loetscher"

20 Publications

  • Page 1 of 1

Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A Hydrolase.

J Med Chem 2021 02 16;64(4):1889-1903. Epub 2021 Feb 16.

The cytosolic metalloenzyme leukotriene A hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B (LTB). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB generation at low exposures , LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01955DOI Listing
February 2021

Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay.

J Med Chem 2020 08 30;63(15):8276-8295. Epub 2020 Jul 30.

Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, United States.

Inappropriate activation of endosomal TLR7 and TLR8 occurs in several autoimmune diseases, in particular systemic lupus erythematosus (SLE). Herein, the development of a TLR8 antagonist competition assay and its application for hit generation of dual TLR7/8 antagonists are reported. The structure-guided optimization of the pyridone hit using this biochemical assay in combination with cellular and TLR8 cocrystal structural data resulted in the identification of a highly potent and selective TLR7/8 antagonist () with efficacy. The two key steps for optimization were (i) a core morph guided by a TLR7 sequence alignment to achieve a dual TLR7/8 antagonism profile and (ii) introduction of a fluorine in the piperidine ring to reduce its basicity, resulting in attractive oral pharmacokinetic (PK) properties and improved TLR8 binding affinity.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00130DOI Listing
August 2020

The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells.

iScience 2020 Feb 17;23(2):100848. Epub 2020 Jan 17.

Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC 27834, USA; Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address:

GPR4 is a pH-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and can be activated by protons in the inflamed tissue microenvironment. Herein, we report that acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the G/Rho GTPase signaling pathway. Evaluation of GPR4 in the inflammatory response using the acute hindlimb ischemia-reperfusion mouse model revealed that GPR4 mediates tissue edema, inflammatory exudate formation, endothelial adhesion molecule expression, and leukocyte infiltration in the inflamed tissue. Genetic knockout and pharmacologic inhibition of GPR4 alleviate tissue inflammation. These results suggest GPR4 is a pro-inflammatory receptor and could be targeted for therapeutic intervention.
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http://dx.doi.org/10.1016/j.isci.2020.100848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997876PMC
February 2020

Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model.

Eur J Pharmacol 2019 Jun 28;852:218-230. Epub 2019 Mar 28.

Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA. Electronic address:

Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE-52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.
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http://dx.doi.org/10.1016/j.ejphar.2019.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526936PMC
June 2019

Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis.

Bioorg Med Chem 2017 08 29;25(16):4512-4525. Epub 2017 Jun 29.

Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.

GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.
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http://dx.doi.org/10.1016/j.bmc.2017.06.050DOI Listing
August 2017

Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis.

J Med Chem 2017 05 26;60(9):3672-3683. Epub 2017 Apr 26.

Global Discovery Chemistry, ‡Autoimmunity Transplantation Inflammation, §Musculoskeletal, ∥Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.

A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01703DOI Listing
May 2017

Pharmacological Blockade of the Chemokine Receptor CCR1 Protects Mice from Systemic Candidiasis of Hematogenous Origin.

Antimicrob Agents Chemother 2017 03 23;61(3). Epub 2017 Feb 23.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in -infected mice. Here, we found that treatment of immunocompetent -infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury.
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http://dx.doi.org/10.1128/AAC.02365-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328547PMC
March 2017

CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice.

J Immunol 2014 Feb 23;192(3):886-96. Epub 2013 Dec 23.

Université Paris-Sud, Laboratoire "Cytokines, Chimiokines et Immunopathologie," Unité Mixte de Recherche S996, 92140 Clamart, France;

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4(+) T cells, Ly6C(+) monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.
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http://dx.doi.org/10.4049/jimmunol.1300123DOI Listing
February 2014

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model.

Proc Natl Acad Sci U S A 2010 Jul 29;107(29):13063-8. Epub 2010 Jun 29.

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CC-chemokine ligands CCL9 and CCL15, respectively, and recruit CD34(+) Gr-1(-) immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.
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http://dx.doi.org/10.1073/pnas.1002372107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919974PMC
July 2010

Microinjection of Cre recombinase protein into zygotes enables specific deletion of two eukaryotic selection cassettes and enhances the expression of a DsRed2 reporter gene in Ccr2/Ccr5 double-deficient mice.

Genesis 2009 Aug;47(8):545-58

Klinikum der Universität München, Campus Innenstadt, Medizinische Poliklinik, Arbeitsgruppe Klinische Biochemie, D-80336 Munich, Germany.

The chemokine receptors CCR2 and CCR5 represent potential novel therapeutic targets to treat important inflammatory and infectious diseases, including atherosclerosis and HIV infection. To study the functions of both receptors in vivo, we aimed to generate Ccr2/Ccr5 double-deficient mice. As these genes are separated by <20 kb, they were inactivated consecutively by two rounds of gene targeting in embryonic stem (ES) cells. Thereby neomycin and hygromycin selection cassettes flanked by four identical loxP recognition sequences for Cre recombinase were integrated into the ES cell genome together with EGFP and DsRed2 reporter genes. Both selection cassettes could be deleted in vitro by transiently transfecting ES cells with Cre expression vectors. However, after blastocyst microinjection these cells yielded only weak chimeras, and germline transmission was not achieved. Therefore, Ccr2/Ccr5 double-deficient mice were generated from ES cells still carrying both selection cassettes. Microinjection of zygotes with a recombinant fusion protein consisting of maltose-binding protein and Cre (MBP-Cre) allowed the selective deletion of both cassettes. All sequences in between and both reporter genes were left intact. Deletion of both selection cassettes resulted in enhanced DsRed2 reporter gene expression. Cre protein microinjection of zygotes represents a novel approach to perform complex recombination tasks.
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http://dx.doi.org/10.1002/dvg.20531DOI Listing
August 2009

The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice.

Am J Pathol 2007 Apr;170(4):1267-76

Medizinische Poliklinik, Klinikum der Universität München-Innenstadt, Pettenkoferstr. 8a, 80336 Munchen, Germany.

Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
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http://dx.doi.org/10.2353/ajpath.2007.060937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829460PMC
April 2007

A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis.

Arthritis Rheum 2006 Aug;54(8):2387-92

Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objective: Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a key role in leukocyte migration and are potential targets in the treatment of chronic inflammatory disorders. The objective of this study was to evaluate the effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in patients with rheumatoid arthritis (RA).

Methods: Patients with active RA were enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial tissue. Immunohistochemistry and digital image analysis were used to characterize biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic analysis and immunotypic studies of peripheral blood mononuclear cells. To assess the clinical effects of treatment with ABN912, an additional 21 patients were treated with the highest dose tolerated.

Results: The total study population comprised 45 patients: 33 patients received ABN912, and 12 patients received placebo. ABN912 treatment was well tolerated. Unexpectedly, there was a dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral blood, up to 2,000-fold. There was no detectable clinical benefit of ABN912 compared with placebo, nor did treatment with the study drug result in a significant change in the levels of biomarkers in synovial tissue and peripheral blood.

Conclusion: ABN912 treatment did not result in clinical or immunohistologic improvement and may have been associated with worsening of RA in patients treated with the highest dose. The results might be related to the greatly increased level of total CCL2/MCP-1 in serum that was observed following treatment with ABN912. This observation may be relevant for a variety of antibody-based therapies.
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http://dx.doi.org/10.1002/art.21975DOI Listing
August 2006

Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis.

Bioorg Med Chem Lett 2005 Dec 28;15(23):5160-4. Epub 2005 Sep 28.

Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Autoimmunity and Transplantation, CH-4002 Basel, Switzerland.

Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.
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http://dx.doi.org/10.1016/j.bmcl.2005.08.057DOI Listing
December 2005

Human polymorphonuclear neutrophils are recruited by porcine chemokines acting on CXC chemokine receptor 2, and platelet-activating factor.

Transplantation 2005 May;79(10):1324-31

Laboratory for Transplantation Immunology, Department for Internal Medicine, University Hospital Zurich, Zurich, Switzerland.

Background: Pig-to-human xenotransplantation is hampered by strong humoral and cellular immune responses, including acute vascular rejection (AVR). Infiltration of vascular xenografts by recipient polymorphonuclear neutrophils (PMN) is an early feature of AVR. Since little is known about the initiation of PMN recruitment, the present study investigated whether activated porcine endothelial cells (EC) release factors that induce human PMN recruitment.

Methods: Primary and immortalized porcine aortic EC cultures were stimulated with phorbol-myristate acetate/ionomycin, lipopolysaccharide, tumor-necrosis factor-alpha, or interferon-gamma. The interleukin (IL)-8 concentration of porcine EC supernatants was tested by ELISA. Human and porcine PMN were isolated from peripheral blood by Ficoll sedimentation and centrifugation, characterized by morphology and flow cytometry, and analyzed for chemotaxis using Boyden chambers or Transwells. PMN chemokine receptor desensitization was determined by intracellular calcium-flux measurements.

Results: Porcine EC supernatants contained significant amounts of porcine IL-8 and triggered chemotaxis in both human and porcine PMN. Chemotaxis of porcine, but not human, PMN was inhibited by anti-porcine IL-8 antibodies and recombinant porcine IL-8 induced strong chemotaxis only in porcine PMN. Porcine EC supernatants desensitized human PMN CXC-chemokine receptor (CXCR) 2, but not CXCR1, a receptor for human IL-8. Human PMN chemotaxis induced by porcine EC supernatants was significantly inhibited by blocking CXCR2 and platelet-activating factor (PAF).

Conclusions: Both chemokines acting via CXCR2 and PAF are released by porcine EC inducing efficient chemotaxis of human PMN. These mechanisms responsible for the recruitment of human PMN to porcine endothelium during cell-mediated rejection of xenografts represent potential targets for preventive strategies.
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http://dx.doi.org/10.1097/01.tp.0000155429.44902.44DOI Listing
May 2005

A skin-selective homing mechanism for human immune surveillance T cells.

J Exp Med 2004 May;199(9):1265-75

Theodor-Kocher Institute, University of Bern, P.O. Box 99, CH-3000 Bern 9, Switzerland.

Effective immune surveillance is essential for maintaining protection and homeostasis of peripheral tissues. However, mechanisms controlling memory T cell migration to peripheral tissues such as the skin are poorly understood. Here, we show that the majority of human T cells in healthy skin express the chemokine receptor CCR8 and respond to its selective ligand I-309/CCL1. These CCR8(+) T cells are absent in small intestine and colon tissue, and are extremely rare in peripheral blood, suggesting healthy skin as their physiological target site. Cutaneous CCR8(+) T cells are preactivated and secrete proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma, but lack markers of cytolytic T cells. Secretion of interleukin (IL)-4, IL-10, and transforming growth factor-beta was low to undetectable, arguing against a strict association of CCR8 expression with either T helper cell 2 or regulatory T cell subsets. Potential precursors of skin surveillance T cells in peripheral blood may correspond to the minor subset of CCR8(+)CD25(-) T cells. Importantly, CCL1 is constitutively expressed at strategic cutaneous locations, including dermal microvessels and epidermal antigen-presenting cells. For the first time, these findings define a chemokine system for homeostatic T cell traffic in normal human skin.
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http://dx.doi.org/10.1084/jem.20032177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211907PMC
May 2004

Chemokines: multiple levels of leukocyte migration control.

Trends Immunol 2004 Feb;25(2):75-84

Theodor-Kocher Institute, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland.

The surge in interest in chemokines is explained by the recognition that numerous aspects of immunity are intimately related to leukocyte traffic. Chemokines are leukocyte attractants but also contribute to immune processes that do not directly involve leukocyte migration. Recent progress is most evident in the areas of lymphocyte development, immune response initiation and immune pathology. Important observations have also been reported on chemokine-receptor interactions, signal transduction and cellular responses. New insights into the role of chemokines in leukocyte attraction and relocation will be discussed, with emphasis on the distinct levels of leukocyte migration control that ultimately determine the performance of our immune defense system.
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http://dx.doi.org/10.1016/j.it.2003.12.005DOI Listing
February 2004

Rho kinase is required for CCR7-mediated polarization and chemotaxis of T lymphocytes.

FEBS Lett 2003 May;542(1-3):79-83

Theodor Kocher Institute, P.O. Box, CH-3000 9 Bern, Switzerland.

We studied the role of Rho kinase and extracellular signal-regulated kinase (ERK)-2 in the polarization and migration of T lymphocytes in response to the CCR7 ligands EBI1 ligand chemokine (ELC; CCL19) and secondary lymphoid-tissue chemokine (SLC; CCL21). Both Rho kinase protein isoforms are expressed in T lymphocytes. Inhibition of the Rho kinases with Y-27632 strongly inhibited SLC- and ELC-induced polarized morphology and chemotaxis of T lymphocytes. Although the chemokines induced ERK-2 activation, the blockade of this signaling pathway showed no effect on polarization and migration. This study indicates an important role of Rho kinase in CCR7-mediated polarization and migration of T lymphocytes, whereas ERK-2 is not involved in these processes.
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http://dx.doi.org/10.1016/s0014-5793(03)00351-xDOI Listing
May 2003

Structure-function relationship between the human chemokine receptor CXCR3 and its ligands.

J Biol Chem 2003 Jan 1;278(1):289-95. Epub 2002 Nov 1.

Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

I-TAC, IP10, and Mig are interferon-gamma inducible CXC chemokines that share the same G-protein-coupled receptor CXCR3, which is preferentially expressed on Th1 lymphocytes. We have explored the structure-function relationship of the CXCR3 ligands, in particular of I-TAC, which has highest affinity for CXCR3 and is the most potent agonist. A potent antagonist for CXCR3 was obtained by NH(2)-terminal truncation of I-TAC. I-TAC (4-73), which lacks the first three residues, has no agonistic activity but competes for the binding of I-TAC to CXCR3-bearing cells and inhibits migration and Ca(2+) changes in such cells in response to stimulation with I-TAC, IP10, and Mig. It does also not induce internalization of CXCR3, which is in support of the lack of agonistic effects. Hybrid chemokines between I-TAC and IP10 were used to identify regions responsible for the higher activity of I-TAC. I-TAC-like IP10 analogs are obtained by substituting the NH(2) terminus (residues 1-8) or N-loop region (residues 12-17) of IP10 with those of I-TAC, suggesting that the differences in function of the CXCR3 ligands can be assigned to distinct regions and that these regions are interchangeable. Structure-activity studies with Mig showed that the extended basic COOH-terminal region, which is not present in I-TAC and IP10, is important for binding and activity.
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http://dx.doi.org/10.1074/jbc.M209470200DOI Listing
January 2003

Homing chemokines in rheumatoid arthritis.

Arthritis Res 2002 31;4(4):233-6. Epub 2002 Jan 31.

Theodor-Kocher Institute, University of Bern, Switzerland.

In about 20% of patients with rheumatoid arthritis, B and T lymphocytes recruited into the inflamed synovium are organized into complex microstructures, which resemble secondary lymphoid organs. The development of such lymphoid aggregates with germinal centers appears to contribute to the pathogenesis of the disease. Growing evidence indicates that chemokines and their receptors control the recruitment and positioning of leukocytes as well as their organization into node-like lymphoid structures. Here, we comment on recent studies highlighting the importance of chemokines in rheumatoid arthritis, in particular of B-cell-activating chemokine-1 in lymphoid neogenesis in the inflamed synovium.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC128928PMC
http://dx.doi.org/10.1186/ar412DOI Listing
December 2002

CXCR5(+) T cells: follicular homing takes center stage in T-helper-cell responses.

Trends Immunol 2002 May;23(5):250-4

Theodor-Kocher Institute, University of Bern, Freiestrasse 1, 3000 Bern 9, Switzerland.

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http://dx.doi.org/10.1016/s1471-4906(02)02218-4DOI Listing
May 2002