Activation of antigen presenting cells through the interaction of CD40 with its ligand is a critical co-stimulatory signal for IL-12 production and Th1 differentiation. Tyrphostins are organic molecules that inhibit the phosphorylation of protein tyrosine kinases. We show that tyrphostin A1 inhibits CD40L-stimulated IL-12 production in macrophage cultures and antigen-induced generation of Th1 cells. Our data also show that tyrphostin A1 blocks CD40L-induced translocation of NF-kappaB to the nucleus, and reduces the activation of IL-12 p40 gene. In vivo therapy with A1 leads to decrease in generation of myelin basic protein (MBP) specific encephalitogenic T cells. In addition, treatment of SJL/J mice with A1 results in attenuation of experimental allergic encephalomyelitis (EAE).