MIP-1-ALPHA AND MCP-1 DIFFERENTIALLY REGULATE ACUTE AND RELAPSING AUTOIMMUNE ENCEPHALOMYELITIS AS WELL AS TH1 TH2 LYMPHOCTYE DIFFERENTIATION/

Chemokines are a family of small-molecular-weight cytokines that induc e chemotaxis and chemokinesis of leukocytes. These molecules are ligan ds for seven-transmembrane, G-protein-linked receptors and are known t o activate integrins on the surface of leukocytes and other cells as w ell as induce a number of signaling events, They play a significant ro le in the migration of leukocytes from blood into tissue during inflam matory processes, We tested the role of chemokines in experimental aut oimmune encephalomyelitis (EAE) and found that macrophage inflammatory protein-1 alpha (MIP-1 alpha) correlated with acute disease developme nt, whereas monocyte chemotactic protein-1 (MCP-1) did not, In contras t, MCP-1 production in the central nervous system correlated with rela psing EAE development, Moreover, anti-MIP-1 alpha, but not anti-MCP-1, inhibited development of acute but not relapsing EAE, whereas anti-MC P-1 significantly reduced the severity of relapsing EAE, To test the e ffects of chemokines on the differentiation of naive T cells, TCR tran sgenic splenic T cells (Tg(+) T cells) from D011.10 OVA TCR transgenic mice were used as a source of Th0 cells and were stimulated with spec ific anti-clonotypic monoclonal antibodies in the presence of MIP-1 al pha, MCP-1, or controls, MIP-1 alpha drove Th0 cells to differentiate to Th1, whereas MCP-1 drove Th0 cells to differentiate to Th2. Similar ly MCP-1, but not MIP-1 alpha significantly inhibited the adoptive tra nsfer of EAE when included in in vitro activation cultures, further su ggesting a regulatory anti-inflammatory property These results suggest a differential role for CC chemokines in the development and activati on of T cells during autoimmune inflammatory diseases.