T J Schall

University of Birmingham, Birmingham, England, United Kingdom

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Publications (152)1188.69 Total impact

  • The Journal of allergy and clinical immunology 11/2015; DOI:10.1016/j.jaci.2015.09.029 · 11.48 Impact Factor

  • 11/2015; 3(Suppl 2):P227. DOI:10.1186/2051-1426-3-S2-P227
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    ABSTRACT: While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a −/− mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a −/− mice. In the mdr1a −/− mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.
    Mediators of Inflammation 10/2015; 2015(5):628340. DOI:10.1155/2015/628340 · 3.24 Impact Factor
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    ABSTRACT: Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs. In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18-75 years with proteinuria (first morning void urinary albumin to creatinine ratio [UACR] 100-3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1·73 m(2) or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline UACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1:1:1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in UACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control. This trial is registered with ClinicalTrials.gov, number NCT01447147. The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. UACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0·01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0·08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study. Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy. ChemoCentryx. Copyright © 2015 Elsevier Ltd. All rights reserved.
    08/2015; 3(9). DOI:10.1016/S2213-8587(15)00261-2

  • Cancer Research 08/2015; 75(15 Supplement):CT223-CT223. DOI:10.1158/1538-7445.AM2015-CT223 · 9.33 Impact Factor
  • R. Parker · C. Weston · G. Webb · G. Hirschfield · T. Schall · D. Adams ·

    Journal of Hepatology 04/2015; 62:S486. DOI:10.1016/S0168-8278(15)30670-X · 11.34 Impact Factor
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    ABSTRACT: IntroductionBiological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn¿s disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9 in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA.MethodsCCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-¿ was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted.ResultsCCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-¿ production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues.Conclusion The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA.
    Arthritis Research & Therapy 09/2014; 16(5):445. DOI:10.1186/s13075-014-0445-9 · 3.75 Impact Factor
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    ABSTRACT: Introduction and Aims: To investigate the potential of an oral complement C5 receptor antagonist CCX168 to contribute to disease remission and permit glucocorticoid reduction or avoidance in patients with active ANCA-associated renal vasculitis (AARV) receiving cyclophosphamide (CYC). Methods: This randomised, double-blind, placebo-controlled Phase 2 trial was performed in a stepwise manner. In Step 1 (N=12), CCX168+CYC+low dose prednisone (20 mg/day starting dose) was compared to standard-of-care (SOC) (CYC+high dose prednisone, 60 mg/day starting dose). In Step 2 (N=14), CCX168+CYC and no prednisone was compared to SOC. Eligible patients had GPA, MPA, or renal limited vasculitis, were PR3 or MPO-ANCA positive, and had active renal vasculitis with a GFR >30ml/min. The dose of CCX168 was 30 mg BID PO for 12 weeks and the dose of CYC was 15 mg/kg IV q2-3 wks. Results: Baseline characteristics and efficacy results at Week 12 are shown in the table. Groups were relatively well balanced at baseline. The number of steroid rescue events was not higher in the CCX168 groups compared to SOC. The incidence of renal remission was higher in the CCX168 groups compared to the SOC control group. The percent decrease from baseline in BVAS, urinary ACR and urinary MCP-1/creatinine was higher in the CCX168 groups compared to SOC. Renal function, as measured by eGFR, increased in all 3 groups, with the largest increase (6.8 mL/min/1.73 m2) in the CCX168+low dose steroids group. CCX168 appeared to be well tolerated. No unexpected serious adverse reactions were observed with CCX168 use. There was one early withdrawal from study, in the control, SOC, group. Conclusions: CCX168 plus CYC appear to be at least as effective, if not more effective, as full dose steroids plus CYC in treatment of patients with an ANCA associated renal vasculitis flare. View this table: In this window In a new window
    Nephrology Dialysis Transplantation 05/2014; 29(suppl 3):iii27-iii29. DOI:10.1093/ndt/gfu120 · 3.58 Impact Factor

  • Journal of Hepatology 04/2014; 60(1):S149. DOI:10.1016/S0168-8278(14)60413-X · 11.34 Impact Factor

  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB129. DOI:10.1016/j.jaci.2013.12.481 · 11.48 Impact Factor
  • J. C. Jaen · D. Dairaghi · M. Leleti · J. P. Powers · Y. Wang · P. Zhang · T. J. Schall ·
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    ABSTRACT: Background Chemokines are key regulators of leukocyte activation and recruitment to sites of inflammation. Of particular relevance in rheumatoid arthritis (RA), the chemokine receptors CCR1 and CCR6 are thought to drive monocyte/macrophage and Th17 cell recruitment, respectively, into RA joints. We recently demonstrated the clinical benefit of our first-generation CCR1 antagonist (CCX354) in a Phase 2 trial in RA patients (Tak et al., 2012). To date, no therapeutic agents targeting CCR6 have progressed into clinical evaluation. Objectives To identify orally active small molecules that selectively target either CCR1 or CCR6 and possess overall profiles suitable for clinical development. Key selection criteria include their potency on CCR1 or CCR6-expressing primary human cells, their selectivity, and their ability to prevent chemotaxis of freshly isolated human blood leukocytes towards RA synovial fluid samples. Methods The in vitro potency of CCX486 (CCR1 antagonist) was assessed by inhibition of CCL15-mediated chemotaxis of THP-1 cells and human blood monocytes. The in vitro potency of C0339589 (CCR6 antagonist) was assessed by inhibition of CCL20-mediated chemotaxis and binding using a human NK cell line and CCR6+ enriched human PBMC. CCX486 and C0339589 were assessed for their ability to block the CCR1 and CCR6-mediated chemotaxis, respectively, of human blood leukocytes towards RA synovial fluids. Results CCX486 potently blocks CCL15-mediated chemotaxis with an IC50 of 0.61 nM (THP-1 cells). In 100% human serum, CCX486 blocks CCL15-mediated chemotaxis with an IC50 of 1.0 nM (THP-1 cells) and 1.8 nM (human monocytes). CCX486 also completely blocks the monocyte-chemotactic activity displayed by human RA synovial fluid samples. C0339589 potently blocks CCL20-mediated chemotaxis of CCR6+ enriched human PBMC (IC50: 38 nM). C0339589 also blocks the lymphocyte-chemotactic activity displayed by human RA synovial fluid samples (IC50 ~ 10-30 nM). Both CCX486 and C0339589 are highly selective for CCR1 and CCR6, respectively, when tested against a wide screen of chemokine and chemoattractant receptors. Conclusions CCR1: A second-generation CCR1 antagonist (CCX486) was designed de novo using existing knowledge from several other CCR1 programs that have previously advanced into clinical evaluation. This compound, which shares very little structural similarity to first-generation molecule CCX354, is nevertheless equally selective for CCR1 and orally bioavailable in preclinical species (Dairaghi et al., 2011). CCX486 is about 20 times more potent on human CCR1 than CCX354. CCX486 was shown to block CCR1-mediated chemotaxis of human blood monocytes towards RA synovial fluid samples. CCR6: Several chemical lead series were identified using a proprietary high-throughput screening format. Optimization of one of these series resulted in advanced molecules such as C0339589. This molecule is highly potent on human and mouse CCR6 and displays properties conducive to its use for the treatment of diseases such as RA, psoriasis and multiple sclerosis. References Disclosure of Interest J. Jaen Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, D. Dairaghi Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, M. Leleti Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, J. Powers Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Y. Wang Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, P. Zhang Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, T. Schall Shareholder of: ChemoCentryx, Employee of: ChemoCentryx
    Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A369-A369. DOI:10.1136/annrheumdis-2013-eular.1130 · 10.38 Impact Factor
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    ABSTRACT: Background The C5a receptor (C5aR) is expressed by cells of the innate immune system and is thought to play a key role in numerous autoimmune diseases, such as anti-neutrophil cytoplasmic antibody (ANCA) vasculitis and rheumatoid arthritis (RA). CCX168 is an orally active antagonist of C5aR that has completed Phase 1 evaluation and is currently in a Phase 2 trial for induction of remission in patients with ANCA-associated renal vasculitis (AARV). Objectives To evaluate CCX168 in preclinical and clinical studies to determine safety, pharmacokinetic, and pharmacodynamics properties, and integrate these properties into a PK/PD relationship predictive of receptor coverage required for effective use in treating C5aR-mediated autoimmune diseases in humans. Methods The in vitro potency of CCX168 against C5aR was assessed by [125I]-C5a binding and chemotaxis assays. Inhibition of C5a-induced leukopenia by CCX168 was determined in multiple species. In the Phase 1 program, ex vivo analysis of C5aR coverage on blood neutrophils was performed based on C5a-induced chemotaxis and CD11b expression. A similar PD assay was performed on blood samples from human C5aR knock-in mice dosed orally with CCX168. PK/PD requirements were defined for inhibition of C5aR-mediated neutrophil activation and prevention of anti-MPO IgG induced glomerulonephritis by CCX168 in these mice. Results CCX168 potently blocks [125I]-C5a binding to human C5aR with an IC50 of 0.62 nM, C5a-mediated chemotaxis with an IC50 of 0.25 nM (U937 cells), and C5a-mediated Ca2+ mobilization with an IC50 of 0.2 nM in human neutrophils. In human whole blood, CCX168 blocks C5a-mediated chemotaxis of neutrophils (IC50 1.7 nM) and CD11b upregulation (IC50 4 nM), and also blocks the granulocyte chemotactic activity displayed by human synovial fluid samples (IC50 ∼5 nM). In human C5aR knock-in mice, CCX168 inhibited C5a-induced leukopenia with an ED50 of ∼0.03 mg/kg, and oral dosing to these mice markedly suppressed the induction of glomerulonephritis by anti-MPO IgG. The lowest dose that produced near-maximal therapeutic benefit in this model was 4 mg/kg bid. CCX168 was well tolerated with excellent oral bioavailability and dose-proportional exposure in a Phase 1 study in healthy volunteers, and plasma levels of CCX168 of 197 ng/mL (∼400 nM) were reached after a 100 mg dose, far exceeding the levels required in the anti-MPO mouse model for near-maximal prevention of glomerulonephritis. Twelve hours following a 100 mg single dose of CCX168, there was a 94% reduction in C5a-induced CD11b upregulation on blood neutrophils (ex vivo PD assay). The combined clinical and preclinical PK/PD results indicate a 30 mg bid dosing regimen in humans should result in >90% receptor coverage on human blood leukocytes at all times. Conclusions CCX168 is a highly potent, orally active, antagonist of C5aR which was well tolerated in Phase 1. The PK/PD data from preclinical and human Phase 1 studies indicate that 30 mg CCX168 bid in humans should result in >90% coverage of C5aR in blood at all times, considered optimal for C5aR antagonism in patients with autoimmune diseases such as vasculitis and RA. A Phase 2 trial of CCX168 in patients with AARV is currently underway. Disclosure of Interest J. Powers Employee of: ChemoCentryx, P. Bekker Employee of: ChemoCentryx, D. Dairaghi Employee of: ChemoCentryx, J. Jennette: None Declared, D. Johnson Employee of: ChemoCentryx, M. Leleti Employee of: ChemoCentryx, S. Miao Employee of: ChemoCentryx, L. Seitz Employee of: ChemoCentryx, Y. Wang Employee of: ChemoCentryx, H. Xiao: None Declared, T. Schall Employee of: ChemoCentryx, J. Jaen Employee of: ChemoCentryx
    Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):124-124. DOI:10.1136/annrheumdis-2012-eular.1887 · 10.38 Impact Factor
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    ABSTRACT: Background: In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed. Methods: We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. Results: CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs. Conclusions: These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.
    British Journal of Cancer 01/2014; 110(5). DOI:10.1038/bjc.2013.830 · 4.84 Impact Factor
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    ABSTRACT: The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor CXCR4. Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in Apoe(-/-) mice fed a high fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe(-/-) mice by FPLC. Uptake of DiI-labeled VLDL to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand, CCX771, to Apoe(-/-) mice inhibited lesion formation and ameliorated hyperlipidemia following vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating VLDL levels, but not LDL or HDL levels, and increased uptake of VLDL into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced Angptl4 expression in adipose tissue. CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected cholesterol-lowering effect of CXCR7 is beneficial for atherosclerotic vascular diseases presumably by ameliorating hyperlipidemia-induced monocytosis and can be augmented using a synthetic CXCR7 ligand.
    Circulation 12/2013; 129(11). DOI:10.1161/CIRCULATIONAHA.113.006840 · 14.43 Impact Factor
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    ABSTRACT: Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.
    Journal of the American Society of Nephrology 10/2013; 25(2). DOI:10.1681/ASN.2013020143 · 9.34 Impact Factor
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    ABSTRACT: The concentration of CXCL12/SDF-1 in the bloodstream is tightly regulated, given its central role in leukocyte and stem/progenitor cell egress from bone marrow and recruitment to sites of inflammation or injury. The mechanism responsible for this regulation is unknown. Here we show that both genetic deletion and pharmacological inhibition of CXCR7, a high-affinity CXCL12 receptor, caused pronounced increases in plasma CXCL12 levels. The rise in plasma CXCL12 levels was associated with an impairment in the ability of leukocytes to migrate to a local source of CXCL12. Using a set of complementary and highly-sensitive techniques, we found that CXCR7 protein is expressed at low levels in multiple organs in both humans and mice. In humans, CXCR7 was detected primarily on venule endothelium and arteriole smooth muscle cells. CXCR7 expression on venule endothelium was also documented in immunodeficient mice and CXCR7+/lacZ mice. The vascular expression of CXCR7 thus gives it immediate access to circulating CXCL12. These studies suggest that endothelial CXCR7 regulates circulating CXCL12 levels and that CXCR7 inhibitors might be used to block CXCL12-mediated cell migration for therapeutic purposes. This article is protected by copyright. All rights reserved.
    Immunology 10/2013; 141(1). DOI:10.1111/imm.12176 · 3.80 Impact Factor
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    ABSTRACT: The chemokine receptor CCR2 is central for migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate Phase 2 clinical trials in diabetic nephropathy, was recently shown to reduce hemoglobin A1c and fasting blood glucose levels in Type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has low affinity for mouse CCR2, transgenic human CCR2 knock-in mice were generated and rendered diabetic either with a high-fat diet (DIO) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of DIO mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of HOMA-IR values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.
    AJP Renal Physiology 08/2013; 305(9). DOI:10.1152/ajprenal.00316.2013 · 3.25 Impact Factor

  • Immunology letters 08/2013; 154(1-2). DOI:10.1016/j.imlet.2013.08.004 · 2.51 Impact Factor
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    ABSTRACT: CCR2 inhibition has produced promising experimental and clinical anti-hyperglycemic effects. These results support the thesis that insulin resistance and Type 2 diabetes (T2D) are associated with chronic unresolved inflammation. The aim of this study was to provide a broad analysis of the various physiological changes occurring in mouse models of T2D in connection with pharmacological CCR2 inhibition. A mouse-active chemical analogue of the clinical candidate CCX140-B was tested in diet-induced obese (DIO) mice and db/db mice. Measurements included: adipose tissue inflammatory macrophage counts; peripheral blood glucose levels at steady-state and after glucose and insulin challenges; peripheral blood insulin and adiponectin levels; 24-h urine output and urinary glucose levels; pancreatic islet number and size; hepatic triglyceride and glycogen content; and hepatic glucose-6-phosphatase levels. In DIO mice, the CCR2 antagonist completely blocked the recruitment of inflammatory macrophages to visceral adipose tissue. The mice exhibited reduced hyperglycemia and insulinemia, improved insulin sensitivity, increased circulating adiponectin levels, decreased pancreatic islet size and increased islet number. It also reduced urine output, glucose excretion, hepatic glycogen and triglyceride content and glucose 6-phosphatase levels. Similar effects were observed in the db/db diabetic mice. These data indicate that pharmacological inhibition of CCR2 in models of T2D can reduce inflammation in adipose tissue, alter hepatic metabolism and ameliorate multiple diabetic parameters. These mechanisms may contribute to the promising anti-diabetic effects seen in humans with at least one CCR2 antagonist.
    Metabolism: clinical and experimental 08/2013; 62(11). DOI:10.1016/j.metabol.2013.06.008 · 3.89 Impact Factor
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    La Presse Médicale 04/2013; 42(4):768-769. DOI:10.1016/j.lpm.2013.02.277 · 1.08 Impact Factor

Publication Stats

19k Citations
1,188.69 Total Impact Points


  • 2014
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 1998-2014
    • ChemoCentryx
      Mountain View, California, United States
    • Neurocrine Biosciences, Inc.
      San Diego, California, United States
    • University of Washington Seattle
      • Department of Laboratory Medicine
      Seattle, Washington, United States
  • 1995-2008
    • Palo Alto Institute for Research and Education
      Palo Alto, California, United States
    • The Heart Lung Center
      Londinium, England, United Kingdom
    • University of Toronto
      Toronto, Ontario, Canada
  • 2002
    • University of California, Davis
      • Center for Comparative Medicine
      Davis, California, United States
  • 1997
    • University of Oxford
      • Sir William Dunn School of Pathology
      Oxford, England, United Kingdom
  • 1996
    • National Institutes of Health
      • Branch of Surgery
      Bethesda, MD, United States
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1994
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • McMaster University
      • Department of Pathology and Molecular Medicine
      Hamilton, Ontario, Canada
  • 1993
    • SUNY Ulster
      Кингстон, New York, United States
    • Centre d'enseignement et de recherche en foresterie de Sainte-Foy
      Québec, Quebec, Canada
  • 1992
    • Université du Québec
      Québec, Quebec, Canada
  • 1990
    • University of California, Irvine
      • Department of Molecular Biology and Biochemistry
      Irvine, California, United States