Expression of CC chemokines and their receptors in the eye in autoimmune anterior uveitis associated with EAE

PURPOSE. To determine the pattern of expression of CC chemokines and their receptors in the eyes of Lewis rats and to establish their role in autoimmu ne anterior uveitis (AU) associated with experimental autoimmune encephalom yelitis (EAE). METHODS. EAE/AU was induced in Lewis rats with myelin basic protein in comp lete Freund's adjuvant (CFA). The rats were scored for the development of c linical EAE and AU. The expression of CCL5/regulated on activation normal T -cell expressed and secreted (RANTES), CCL2/monocyte chemotactic protein (M CP)-1, CCL3/macrophage inflammatory protein (MIP)-1 alpha, and CCL4/MIP-1 b eta and their receptors was examined at the preclinical stage. onset, peak, and recovery by RT-PCR and ELISA. EAE/AU rats were treated with neutralizi ng polyclonal antibodies against CCL3/MIP-1 alpha, CCL4/MIP-1 beta, CCL2/MC P-1, and CCL5/RANTES and tested for the suppression of onset of clinical AU and EAE. The control group received normal rabbit IgG at the same dose. RESULTS. The gene expression of those chemokines was up-regulated concurren tly with symptom onset of EAE/AU and correlated with the intensity of infla mmatory changes in the eye and central nervous system (CNS). The highest ex pression of CCL4/RANTES, CCL2/MCP-1, and CCL3/MIP-1 alpha in the eye was de tected at onset of clinical uveitis, whereas CCL4/MIP-1 beta was elevated a t the peak of AU. The expression of chemokine receptors associated with T-h elper (Th)1-type response, CCR1 and CCR5, correlated with their appropriate ligands and was the highest at the peak of AU, whereas CCR2, the receptor for CCL2/MCP-1, was present before the onset of the disease. Treatment of a nti-MIP-1 beta and anti-MCP-1 significantly delayed the onset and shortened the duration of AU and EAE. Anti-MIP-1 alpha treatment had no effect on cl inical EAE but inhibited the clinical signs of AU. Although CCL5/RANTES exp ression was observed during the entire course of the disease, anti-RANTES t reatment had no effect on clinical disease progression. CONCLUSIONS. The data suggest that CCL2/MCP-1, CCL3/MIP-1 alpha, and CCL4/M IP-beta contribute to the recruitment of inflammatory cells into the eve an d CNS and to disease activity.