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Hiroshi Keino, MD, PhD; Takeshi Kezuka, MD, PhD; Masaru Takeuchi, MD, PhD; Naoyuki Yamakawa, PhD; Takaaki Hattori, MD; Masahiko Usui, MD, PhD

Arch Ophthalmol. 2004;122:1179-1184.

Background  Vasoactive intestinal peptide (VIP), a neuropeptide that is known to be present in lymphoid tissue microenvironments, shows prominent anti-inflammatory actions.

Objective  To examine the potential effect of VIP on the development of experimental autoimmune uveoretinitis (EAU).

Design  We immunized C57BL/6 mice with human interphotoreceptor retinoid-binding protein peptide 1-20 (h-IRBP peptide). Vasoactive intestinal peptide was administered intraperitoneally on alternate days until day 21 after immunization (entire group). In some cases, VIP was injected at different time points after the induction of immunity with h-IRBP peptide (efferent group). In each experiment, a control group of mice was injected with phosphate-buffered saline instead of VIP. Development of EAU was evaluated by means of histological examination on day 21 after immunization. Furthermore, we determined whether intravenous injection of peritoneal exudate cells cultured with VIP overnight in vitro abrogated EAU. We analyzed delayed hypersensitivity for h-IRBP peptide and the occurrence and severity of EAU using evaluation of histopathological sections for inflammatory ocular disease.

Results  Treatment with VIP suppressed the expression of delayed hypersensitivity responses to h-IRBP peptide significantly (positive control vs entire group, P = .02; positive control vs efferent group, P<.001). Mice treated with VIP (n = 10) showed a lower occurrence (40%) and decreased severity of EAU (entire group mean score, 0.3; median score, 0) compared with untreated mice (occurrence, 80%; mean score, 0.85; median score, 0.75), as assessed by histopathological analyses (P = .049). Suppressive effects of VIP on EAU were also observed, even when VIP was administered on days 8 through 20 after immunization (efferent group [n = 9] occurrence, 11%; mean score, 0.1; median score, 0) (P = .003). Moreover, expression of EAU was significantly suppressed when the animals were pretreated with peritoneal exudate cells pulsed with h-IRBP in the presence of VIP (control mean score, 1.2; median score, 1.0; occurrence, 80% [n = 10]) compared with the VIP-treatment group (mean score, 0.3; median score, 0; occurrence, 30% [n = 10]) (P = .004). In addition, VIP-treated peritoneal exudate cells generated regulator T cells in the spleens of recipient mice that were able to interfere with the development of EAU (control group mean score, 0.5; median score, 0.5; occurrence, 63% [n = 8]) compared with the VIP-treatment group (mean score, 0.08; median score, 0; occurrence, 17% [n = 6]) (P = .08).

Conclusion  Treatment with VIP is a highly effective therapy to suppress EAU.

Clinical Relevance  As a result of its efficacy in preventing EAU, VIP might be considered as a novel therapeutic modality for human uveitis.

From the Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan. The authors have no relevant financial interest in this article.

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