Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-kappaB (NF-kappaB), pyrrolidine dithiocarbamate.
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.
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Hirokuni
H
Kitamei
Kazuya
K
Iwabuchi
Kenichi
K
Namba
Kazuhiko
K
Yoshida
Yoshiki
Y
Yanagawa
Nobuyoshi
N
Kitaichi
Mizuki
M
Kitamura
Shigeaki
S
Ohno
Kazunori
K
Onoé
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003433:Crosses, Genetic; D004353:Drug Evaluation, Preclinical; D005136:Eye Proteins / Q000737:chemistry / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020721:Nervous System Autoimmune Disease, Experimental / Q000188:drug therapy*; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D021381:Protein Transport / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D012173:Retinitis / Q000188:drug therapy*; D012177:Retinol-Binding Proteins / Q000737:chemistry / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000032:analysis / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014605:Uveitis / Q000188:drug therapy*; D000099214:Retinol-Binding Proteins, Interstitial
D001324:Autoantigens; D005136:Eye Proteins; D007375:Interleukin-1; D007378:Interleukins; D016328:NF-kappa B; D010446:Peptide Fragments; D011759:Pyrrolidines; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099214:Retinol-Binding Proteins, Interstitial; C498144:Rela protein, mouse; C020972:pyrrolidine dithiocarbamic acid