Selective CB2 receptor agonist Gp1a attenuates EAE through modulating CD4 T cell differentiation and immune cell infiltration in the CNS (BA8P.131)

Abstract

Abstract CB2 agonists have beneficial effects in experimental autoimmune encephalomyelitis (EAE). Our previous studies showed that the CB2 selective agonist O-1966 inhibited EAE development and leukocyte rolling and adhesion to CNS microvasculature. Here we report that Gp1a, a highly selective CB2 agonist, inhibits EAE development following early treatment and improves recovery following late treatment. Gp1a treatment resulted in lower levels of demyelination, axonal loss, and immune cell infiltration. Our results indicate that early Gp1a treatment inhibits Th1 and Th17 and promotes Th2 and Treg differentiation both in vivo and in vitro. We confirmed that Gp1a inhibited Th1 and Th17 differentiation both in non-polarizing and polarizing conditions. Following later treatment, Gp1a reduced the accumulation of pathogenic immune cells in the CNS, which was associated with reductions in the expression of CNS chemokines and adhesion molecules and of chemokine receptors in T cells. We concluded that at least two mechanisms were involved in the beneficial effects of Gp1a in EAE, an early effect on Th1/Th17 differentiation and a later effect on the accumulation of pathogenic immune cells in the CNS. The combined effect of CB2 agonists on Th17 differentiation and immune cell accumulation into the CNS, suggest the CB2 receptors are potential therapeutic targets in neuroinflammation.