CNI-1493 mediated suppression of dendritic cell activation in vitro and in vivo

The tetravalent guanylhydrazone CNI-1493 (CNI-1493) has been shown to inhibit macrophage activation, reduce systemic inflammation as well as proinflammatory cytokine production. Here we report for the first time that CNI-1493 also influences the biology of dendritic cells (DC). In order to become potent T cell stimulators of DC have to mature. Interestingly, when CNI-1493 was added to the maturation stimulus the expression of a typical DC-maturation marker i.e. CD83 was reduced. Subsequent functional in vitro analyses showed that DC-mediated T-cell stimulation was clearly reduced in CNI-1493-treated DC, underlining the functional impact that CNI-1493 on DC biology. Furthermore, the effect of CNI-1493 was analyzed in vivo using the experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice. Interestingly, in a prophylactic treatment regimen CNI-1493 prevented the paralysis associated with EAE almost completely. In addition, when applied in an early therapeutic setting CNI-1493 also reduced the clinical EAE symptoms. In summary, we show for the first time, that in addition to the earlier reported effects on macrophages, CNI-1493 also influences the function and biology of DC. Since DC are the only antigen-presenting cells (APC) known today to be able to prime naive T cells, the findings reported herein are highly relevant for the therapeutic application of CNI-1493.