title: Small molecule antagonists of CCR8 inhibit eosinophil and T cell migration.
abstract: In this study, we demonstrate that in addition to T lymphocytes, human naïve eosinophils and the differentiated eosinophil-like cell line, AML14.3D10 express CCR8 and respond to CCL1 through CCR8 engagement. The responsiveness of cells was dependent on maturation stage, since CCL1 induced pronounced chemotaxis only in differentiated CCR8 positive AML14.3D10 cells. Despite the low CCR8 surface expression, human naïve eosinophils respond with a chemotaxis to high concentration CCL1. We further describe that Th2 clones in a maturation dependent fashion produce autocrine CCL1, which renders them unresponsive to further stimulation. An innovative method to enrich primary CCR8 reactive T cells was developed which demonstrates that primary peripheral CCR8 expressing T cells respond significantly to CCL1. We have developed novel small molecule CCR8 antagonists that are effective in inhibiting calcium mobilization and chemotaxis in differentiated AML cells as well as in human primary CCR8 positive T cells. Importantly, we demonstrate that the compounds can be divided into two subgroups: (i) compounds that are functional agonists for calcium mobilization and chemotaxis (ii) compounds that are pure antagonists. We demonstrate that agonism of these compounds does not correlate with their antagonistic potency. Taken together, we have identified a novel set of CCR8 compounds with antagonistic properties that inhibit CCL1 driven chemotaxis in both CCR8 expressing eosinophils as well as primary human T cells.
authors: AstraZeneca R&D Lund, Sweden.
authors: Anna K C
authors: AK
authors: Karlsson
authors: Katarina
authors: K
authors: Walles
authors: Håkan
authors: H
authors: Bladh
authors: Stephen
authors: S
authors: Connolly
authors: Marco
authors: M
authors: Skrinjar
authors: Alexander
authors: A
authors: Rosendahl
mesh_terms: D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002460:Cell Line; D002469:Cell Separation; D054402:Chemokine CCL1 / Q000037:antagonists & inhibitors; D002633:Chemotaxis / Q000187:drug effects* / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology; D057166:High-Throughput Screening Assays; D006801:Humans; D054401:Receptors, CCR8 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D018927:Anti-Asthmatic Agents; D054402:Chemokine CCL1; D054401:Receptors, CCR8; D054852:Small Molecule Libraries