PloS one, 2011-07, Vol.6 (7), p.e21772
2011
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- Autor(en) / Beteiligte
- Titel
- Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis
- Ist Teil von
- PloS one, 2011-07, Vol.6 (7), p.e21772
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0021772Titel-ID: cdi_plos_journals_1305134996
- Format
- –
- Schlagworte
- Adult, Aged, Aged, 80 and over, Analysis, Antibodies, Antibodies, Neutralizing - immunology, Antibodies, Neutralizing - pharmacology, Antibodies, Neutralizing - therapeutic use, Arthritis, Arthritis, Rheumatoid - drug therapy, Arthritis, Rheumatoid - immunology, Arthritis, Rheumatoid - metabolism, Autoimmune diseases, Biology, Blocking antibodies, Case-Control Studies, CC chemokine receptors, CCR1 protein, CCR2 protein, CCR5 protein, Chemokine CCL2 - metabolism, Chemokine CCL5 - metabolism, Chemokines, Chemotaxis, Chemotaxis - drug effects, Clinical trials, Computational fluid dynamics, Cytokines, Dose-Response Relationship, Drug, Drug dosages, Female, Fluids, High definition television, Human subjects, Humans, Immunoglobulins, Immunology, Inflammation, Inflammatory diseases, Leukocyte migration, Ligands, Male, Medical research, Medicine, Middle Aged, Migration, Monocyte chemoattractant protein 1, Monocytes, Monocytes - cytology, Monocytes - drug effects, Monocytes - immunology, Monocytes - pathology, Patients, Peripheral blood, Pharmaceuticals, Phenylurea Compounds - pharmacology, Phenylurea Compounds - therapeutic use, Piperidines - pharmacology, Piperidines - therapeutic use, RANTES, Receptors, Receptors, CCR - antagonists & inhibitors, Receptors, CCR - immunology, Receptors, CCR1 - antagonists & inhibitors, Receptors, CCR1 - immunology, Receptors, CCR2 - immunology, Receptors, CCR5 - immunology, Rheumatoid arthritis, Rheumatoid factor, Rheumatology, Synovial Fluid - metabolism