E. Dahlen et al., Inhibition of autoimmune disease by the immunomodulator linomide correlates with the ability to activate macrophages, AUTOIMMUN, 32(3), 2000, pp. 199-211
Linomide is a potent immunomodulator that has been shown to inhibit autoimm
unity in several animal models of autoimmune disease, including experimenta
l autoimmune encephalomyelitis (EAE). Linomide's mechanism of action is unk
nown, however, it has been suggested to modulate the function of antigen pr
esenting cells (APC) and that this may account for the inhibition of autoim
mune disease.
In this study we have been able to show that Linomide treatment of SJL/N mi
ce upregulates the cell surface expression of several activation markers on
macrophages and B cells. Thus, we found the following markers, expressed a
s a % of control, to be significantly upregulated following Linomide treatm
ent; MHC class II (260%), Ly-6A/E (520%), CD11a (280%), CD54 (190%) and CD8
0 (200%) on macrophages and Ly-6A/E (250%) and CD11a (150%) on B cells. The
duration and dosage of Linomide required to obtain these effects is simila
r to those required for EAE inhibition. Several Linomide analogues were mad
e by the introduction of structural modifications into the Linomide molecul
e, resulting in a number of compounds with varying effects on EAE. We found
a linear relationship between the compound's ability to inhibit EAE and it
s ability to upregulate MHC class II on macrophages (p<0.001), such that co
mpounds which were able to inhibit EAE also upregulated MHC class II expres
sion, whereas those that did not inhibit EAE were unable to do so. These re
sults suggest that drug-mediated activation of distinct APC functions may b
e protective in autoimmunity.