Autoimmune intervention by CD154 blockade prevents T cell retention and effector function in the target organ

The CD40-CD154 interaction is an attractive target for therapeutic interven tion in many autoimmune disorders, including multiple sclerosis, Previously , we showed that CD154 blockade both inhibited the onset of experimental au toimmune encephalomyelitis and blocked clinical disease progression (relaps es) in mice with established disease. The mechanism of this protection is p oorly understood. Because CD154 plays a role in Th1 development, its blocka de has been thought to promote anti-inflammatory Th2 responses. However, th ese conclusions have primarily been based on extrapolated data from in vitr o experiments, which may not accurately reflect the more complex events occ urring in vivo. In this paper we determine how the immune response develops under the influence of therapeutic CD154 blockade in vivo. We demonstrate that anti-CD154 treatment does not alter the early expansion of Ag-specific T cells in secondary lymphoid organs or result in deviation to a Th2-domin ant response. Interestingly, the late expansion and retention of Th1 cells in the lymph nodes were markedly reduced following immunization of Ab-treat ed mice, and this coincided with a recompartmentalization of these cells to the spleen. Most importantly, anti-CD154 treatment eliminated the retentio n/expansion of encephalitogenic Th1 cells, but not their entry into the CNS , These data indicate that a major mechanism by which CD154 blockade protec ts against autoimmune disease is by controlling the amplitude of acute phas e Th1 responses in the draining lymph nodes and by preventing the sustained expansion of effector cells within the target organ.