Inhibition of experimental autoimmune encephalomyelitis by a tyrosine kinase inhibitor

Migration of lymphocytes from the blood into the brain is a critical event in the pathogenesis of experimental autoimmune encephalomyelitis. Lymphocyt e adhesion to brain endothelium is the first step in lymphocyte entry into the central nervous system, leading subsequently to myelin damage and paral ysis. In this paper we show that the tyrosine kinase inhibitor, tyrphostin AG490, prevents binding of freshly isolated mouse lymph node cells and of i n vivo activated lymphocytes to endothelium of inflamed brain in Stamper-Wo odruff adhesion assays. Moreover, AG490 inhibits adhesion of encephalitogen ic T cell lines to purified ICAM-1 and VCAM-1, molecules implicated in T ce ll recruitment into the central nervous system. In contrast, 2-h treatment of T cell lines with high doses of tyrphostin AG490 have no effect on the v iability, intracellular calcium elevation induced by Con A or TCR crosslink ing, proliferation, or TNF production by Ag-stimulated T cell lines. System ic administration of AG490 prevents the accumulation of leukocytes in the b rain and the development of experimental autoimmune encephalomyelitis induc ed by proteolipid protein, peptide 139-151-specific T cell lines in SJL/J m ice. Blood leukocytes isolated from mice treated with tyrphostin AG490 are less adhesive on purified very late Ag-4 ligands compared with adhesion of leukocytes from control animals. Our results suggest that inhibition of sig naling pathways involved in lymphocyte adhesion may represent a novel thera peutic approach for demyelinating diseases.