Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent.
We have shown that macrophages and microglia present within demyelinating plaques of patients with multiple sclerosis (MS) are immunoreactive for the chemokine receptor CCR1 and its ligand, macrophage inflammatory protein-1alpha. To test the importance of CCR1 to the pathogenesis of MS, we studied the progression of experimental allergic encephalomyelitis (EAE) in CCR1(+/+) vs. CCR1(-/-) mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, nearly all CCR1(+/+) mice developed EAE (95% incidence, severity 2.5+/-0.1), whereas CCR1(-/-) mice had less severe disease (55% incidence, p<0.001; severity 1. 2+/-0.2, p<0.001). CCR1(+/+) mice showed elevated brain mRNA for the chemokines immune protein (IP)-10, RANTES and monocyte chemoattractant protein-1 prior to disease onset, whereas only IP-10 mRNA was elevated in CCR1(-/-) mice. Both groups of mice had comparable in vitro lymphocyte proliferation and cytokine production upon stimulation with MOG peptide, and similar cutaneous hypersensitivity responses to 2,4-dinitrofluorobenzene, suggesting that CCR1(-/-) mice were not systemically immunosuppressed. These data demonstrate that deletion of a chemokine receptor is at least partially protective in EAE, and suggest that targeting of CCR1 may be of therapeutic significance clinically.
Rottman
J B
JB
LeukoSite, Inc., Cambridge, MA, USA. jrottman@mpi.com
Slavin
A J
AJ
Silva
R
R
Weiner
H L
HL
Gerard
C G
CG
Hancock
W W
WW
D000818:Animals; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000235:genetics; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000628:therapy; D007114:Immunization; D007962:Leukocytes / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000502:physiology*; D012867:Skin / Q000276:immunology
C515301:Ccr1 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine