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Published online before print March 30, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0805453

Received for publication August 14, 2005.
Revised January 30, 2006.
Accepted for publication February 15, 2006.

Article

Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-B (NF-B), pyrrolidine dithiocarbamate

Hirokuni Kitamei ^*, Kazuya Iwabuchi ^*, Kenichi Namba , Kazuhiko Yoshida , Yoshiki Yanagawa ^*, Nobuyoshi Kitaichi , Mizuki Kitamura ^*, Shigeaki Ohno , and Kazunori Onoé ^*@

*Division of Immunobiology, Institute for Genetic Medicine, and Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

^@ To whom correspondence should be addressed. E-mail: kazunori{at}igm.hokudai.ac.jp.

	Abstract

Experimental autoimmune uveoretinitis (EAU) is a T helper cell 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-B (NF-B), which modulates inflammation and enhances immune responses. In the present study, the therapeutic effect of administration of a NF-B 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 and interleukin-1 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-B pathway in the lesion could be a novel target for the successful control of uveoretinits.

Key Words: inflammation • cytokine • immunomodulation • uveitis

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