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https://hdl.handle.net/2440/45248
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Type: | Journal article |
Title: | Antagonism of the chemokine receptors CXCR3 and CXCR4 reduces the pathology of experimental autoimmune encephalomyelitis |
Author: | Kohler, R. Comerford, I. Townley, S. Haylock-Jacobs, S. Clark-Lewis, I. McColl, S. |
Citation: | Brain Pathology, 2008; 18(4):504-516 |
Publisher: | Int Soc Neuropathology |
Issue Date: | 2008 |
ISSN: | 1015-6305 1750-3639 |
Abstract: | Chemokines regulate lymphocyte trafficking under physiologic and pathologic conditions. In this study, we have investigated the role of CXCR3 and CXCR4 in the activation of T lymphocytes and their migration to the central nervous system (CNS) using novel mutant chemokines to antagonize CXCR3 and CXCR4 specifically. A series of truncation mutants of CXCL11, which has the highest affinity for CXCR3, were synthesized, and an antagonist, CXCL11((4-79)), was obtained. CXCL11((4-79)) strongly inhibited the migration of activated mouse T cells in response to all three high-affinity CXCR3 ligands, CXCL9, 10 and 11. CXCL12((P2G2)), while exhibiting minimal agonistic activity, potently inhibited the migration of activated mouse T cells in response to CXCL12. Interfering with the action of CXCR3 and CXCR4 with these synthetic receptor antagonists inhibited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis and reduced the accumulation of CD4(+) T cells in the CNS. Further investigation demonstrated that CXCL12((P2G2)) inhibited the sensitization phase, whereas CXCL11((4-79)) inhibited the effector phase of the immune response. Our data suggest that simultaneous targeting of CXCR4 and CXCR3 may be of benefit in the treatment of the CNS autoimmune disease. |
Keywords: | Central Nervous System T-Lymphocytes Cells, Cultured Animals Mice Encephalomyelitis, Autoimmune, Experimental Disease Models, Animal Peptides Receptors, CXCR4 Chemokines Immunologic Factors Treatment Outcome Adoptive Transfer Chemotaxis, Leukocyte Sequence Homology, Amino Acid Molecular Sequence Data Female Receptors, CXCR3 Chemokine CXCL11 Chemokine CXCL12 Immunosuppression Therapy |
Description: | The definitive version may be found at www.wiley.com |
Provenance: | Published early online by Blackwell. |
DOI: | 10.1111/j.1750-3639.2008.00154.x |
Published version: | http://www3.interscience.wiley.com/journal/120123944/abstract |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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