Treatment of experimental autoimmune encephalomyelitis with the chemokine receptor antagonist Met-RANTES.
Specific chemokines and chemokine receptors have been implicated in inflammatory demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Amino-terminal modifications of chemokines can alter receptor interactions, converting agonists to specific antagonists. To examine the function in EAE of murine types 1 and 5 CC chemokine receptors (CCR1 and CCR5), we used Met-RANTES, a peptide that blocks both receptors; controls received heat-inactivated peptide. There was no effect of active treatment on acute-monophasic EAE, regardless whether compound was given at onset or in a pre-treatment regimen. Administered at disease onset, Met-RANTES modestly but significantly ameliorated fixed neurological disability at the endpoint of chronic-relapsing EAE. Met-RANTES treatment did not reduce CNS cellular infiltrates or up-regulation of CCR1 and CCR5 in affected CNS tissues. Analysis of a subset of mice suggested a trend towards reduced axonal pathology in those receiving active treatment. These data indicate that chemokine receptor blockade with Met-RANTES does not affect leukocyte trafficking in chronic-relapsing EAE. Further analysis of the effects of chemokine receptor blockade may need to focus on leukocyte activation within the affected CNS as well as trafficking events.
Matsui
Masaru
M
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Weaver
Jennifer
J
Proudfoot
Amanda E I
AE
Wujek
Jerome R
JR
Wei
Tao
T
Richer
Edward
E
Trapp
Bruce D
BD
Rao
Ashwin
A
Ransohoff
Richard M
RM
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000235:genetics; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017211:Treatment Failure
C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D018925:Chemokines; C108335:RANTES, Met-; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases