Experimental autoimmune uveoretinitis (EAU) is a T helper type 1 cell-mediated
autoimmune disease, which serves as a model of human chronic
uveitis. In this model, cells of a monocyte/macrophage lineage and
retinal antigen (Ag)-specific T cells infiltrate into the retina and cause inflammatory lesion, where proinflammatory
cytokines and various stimuli activate a transcriptional factor,
nuclear factor-kappaB (
NF-kappaB), which modulates
inflammation and enhances immune responses. In the present study, the
therapeutic effect of administration of a
NF-kappaB inhibitor,
pyrrolidine dithiocarbamate (
PDTC), was examined in a murine EAU model. It was shown that
PDTC ameliorated the clinical symptoms of EAU mice and significantly reduced the histopathological score compared with those in untreated mice.
mRNA expressions of
tumor necrosis factor alpha and
interleukin-1beta were suppressed in eyes of
PDTC-treated EAU mice. However, when T cells from
PDTC-treated EAU mice, Ag-presenting cells (APC), and the
retinal Ag
peptides were cocultured, these T cells showed the same level of proliferation as those from control mice. Furthermore, addition of
PDTC in the culture of T cells from EAU mice, Ag, and APC completely abrogated the T cell-proliferative response and
cytokine production. Pretreatment of Ag-primed T cells or APC with
PDTC in vitro also reduced these responses. These results indicate that the inhibitory effect of
PDTC is attributed mainly to the suppression of effector-phase responses including
inflammation but not to the inhibition of T cell priming. Regulation of
NF-kappaB pathway in the lesion could be a novel target for the successful control of uveoretinitis.