Abstract
Chemokines and their receptors play an important role in cell trafficking and recruitment. The CCR6 chemokine receptor, selectively expressed on leukocyte populations, has been shown to play a deleterious role in the pathogenesis of various chronic inflammatory diseases and, as such, may constitute a prime target in the development of immunotherapeutic treatment. However, to date no neutralizing mouse monoclonal antibodies (mAbs) specific for this chemokine receptor have been reported, whereas information on small molecules capable of interfering with the interaction of CCR6 and its ligands is scant. Here, we report the failure to generate neutralizing mouse mAbs specific for human (hu)CCR6. Immunization of mice with peptides mimicking extracellular domains, potentially involved in CCR6 function, failed to induce Abs reactive with the native receptor. Although the use of NIH-3T3 cells expressing huCCR6 resulted in the isolation of mAbs specific for this receptor, they were not able to block the interaction between huCCR6 and huCCL20. Investigation of the anti-huCCR6 mAbs generated in the present study, as well as those commercially available, show that all mAbs invariably recognize a unique, non-neutralizing, immunodominant region in the first part of its N-terminal domain. Together, these results indicate that the generation of potential neutralizing anti-huCCR6 mAbs in the mouse is unlikely to succeed and that alternative techniques, such as the use of other animal species for immunization, might constitute a better approach to generate such a potentially therapeutic tool for the treatment of inflammatory disease.
Highlights
CCR6 (CD196) is a CC chemokine receptor, involved in host defense and inflammation, especially at epithelial surfaces, that has two specific ligands, the chemokine CCL20 and a non-chemokine ligand β-defensin-2, an anti-microbial peptide produced by epithelial cells that line various organs [1,2,3,4,5,6,7,8,9]
There is compelling evidence from experimental mouse models, as well as from clinical studies in human, that the CCR6/CCL20/Th17 axis is involved in the pathogenesis of various chronic inflammatory and autoimmune diseases, which has been well documented for multiple sclerosis and rheumatoid arthritis
Similar results with respect to lymphocyte migration have been obtained in the SKG mouse model of spontaneous experimental arthritis in which a preferential recruitment of Th17 cells to inflamed, CCL20-expressing, synovial joints was observed that could be inhibited with a neutralizing anti-CCR6 antibody [18], whereas polymorphisms in the CCR6 gene were reported to be associated with rheumatoid arthritis susceptibility [19, 20]
Summary
CCR6 (CD196) is a CC chemokine receptor, involved in host defense and inflammation, especially at epithelial surfaces, that has two specific ligands, the chemokine CCL20 and a non-chemokine ligand β-defensin-2, an anti-microbial peptide produced by epithelial cells that line various organs [1,2,3,4,5,6,7,8,9]. There is compelling evidence from experimental mouse models, as well as from clinical studies in human, that the CCR6/CCL20/Th17 axis is involved in the pathogenesis of various chronic inflammatory and autoimmune diseases, which has been well documented for multiple sclerosis and rheumatoid arthritis. Myelin-specific T cell infiltration in the brain was reported to positively correlate with the expression of CCL20 in the choroid plexus of humans with multiple sclerosis or mice with experimental autoimmune encephalitis [16]. Similar results with respect to lymphocyte migration have been obtained in the SKG mouse model of spontaneous experimental arthritis in which a preferential recruitment of Th17 cells to inflamed, CCL20-expressing, synovial joints was observed that could be inhibited with a neutralizing anti-CCR6 antibody [18], whereas polymorphisms in the CCR6 gene were reported to be associated with rheumatoid arthritis susceptibility [19, 20]
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