Antagonism of the chemokine receptors CXCR3 and CXCR4 reduces the pathology of experimental autoimmune encephalomyelitis.
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.
Kohler
Rachel E
RE
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia.
Comerford
Iain
I
Townley
Scott
S
Haylock-Jacobs
Sarah
S
Clark-Lewis
Ian
I
McColl
Shaun R
SR
D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D054371:Chemokine CXCL11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000819:agonists / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007165:Immunosuppression Therapy / Q000379:methods; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
C514936:CXCR4 protein, mouse; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D018925:Chemokines; C515203:Cxcl11 protein, mouse; C515256:Cxcl12 protein, mouse; C515188:Cxcr3 protein, mouse; D007155:Immunologic Factors; D010455:Peptides; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4