G. Constantin et al., TYRPHOSTIN AG490, A TYROSINE KINASE INHIBITOR, BLOCKS ACTIVELY INDUCED EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, European Journal of Immunology, 28(11), 1998, pp. 3523-3529
Migration of lymphocytes from blood into the brain is a critical event
in the pathogenesis of multiple sclerosis and its animal model, exper
imental autoimmune encephalomyelitis (EAE). Previous observations made
in our laboratory showed that protein tyrosine kinase inhibitors were
able to block lymphocyte adhesion to brain endothelium and prevent th
e entry of encephalitogenic T cell lines into the brain of SJL/J mice.
Here we show that systemic administration of the protein tyrosine kin
ase inhibitor, tyrphostin AG490, blocks the development of actively in
duced EAE in a dose-dependent manner. Administration of 1 mg of drug d
aily significantly decreased the severity of the disease, while 3 mg o
f AG 490 daily totally blocked the disease in 62 % of treated animals,
and in those that developed the disease, paralysis was delayed and cl
inical score was significantly reduced. Blood leukocytes isolated from
mice treated with tyrphostin AG490 were less adhesive on VCAM-1 and f
ibronectin, when compared with control animals. AG490 treatment had no
effect on the proliferation by antigen-stimulated peripheral lymph no
des cells. Interestingly, cells obtained from draining lymph nodes in
AG490-treated animals and stimulated with antigen secreted two times m
ore IFN-gamma and four times more IL-10, when compared with control an
imals, whereas no difference was observed in TNF-alpha production. Our
results suggest that tyrphostin AG490 may have therapeutic potential
by blocking tyrosine kinase activities involved in key mechanisms lead
ing to demyelinating diseases of the central nervous system.