Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent

We have shown that macrophages and microglia present within demyelinating p laques of patients with multiple sclerosis (MS) are immunoreactive for the chemokine receptor CCR1 and its ligand, macrophage inflammatory protein-icc . To test the importance of CCR1 to the pathogenesis of MS, we studied the progression of experimental allergic encephalomyelitis (EAE) in CCR1(+/+) v s. CCR1(+/+) mice. After immunization with myelin oligodendrocyte glycoprot ein (MOG) 35-55 peptide, nearly all CCR1(+/+) mice developed EAE (95% incid ence, 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-d initrofluorobenzene, suggesting that CCR1(-/-) mice were not systemically i mmunosuppressed. These data demonstrate that deletion of a chemokine recept or is at least partially protective in EAE, and suggest that targeting of C CR1 may be of therapeutic significance clinically.