IMMUNE CORTICOTROPIN-RELEASING HORMONE IS PRESENT IN THE EYES OF AND PROMOTES EXPERIMENTAL AUTOIMMUNE UVEORETINITIS IN RODENTS

We examined the presence and potential role of local corticotropin-rel easing hormone (CRH) in experimental uveitis in rodents. This 41-amino acid peptide, originally isolated from the hypothalamus, is also secr eted locally in experimentally induced and natural inflammatory sites, where it exerts autocrine or paracrine proinflammatory effects. Femal e Lewis rats were immunized with the major pathogenic epitope (R16 pep tide) of the interphotoreceptor retinoid-binding protein in complete F reund's adjuvant, monitored daily, and killed 8, 9, 10, 12, 14, or 18 days later, after having developed uveoretinitis. Immunoreactive CRH ( IrCRH) was detected by immunohistochemistry in the uveitic eyes in the cytoplasm of inflammatory cells (macrophages, lymphocytes, and polymo rphonuclear cells) infiltrating the iris, ciliary body, vitreous, reti na, and choroid depending on the stage of the disease. The intensity o f the IrCRH staining was positively correlated with the severity of th e disease based on morphological criteria. The amount of IrCRH measure d by RIA varied between 0.18 +/- 0.03 (mean +/- SE) and 0.79 +/- 0.07 pmol/g wet tissue (8th and 14th day of the disease, respectively). Oph thalmic IrCRH in uveitic rat eyes had similar chromatographic mobility as rat/human CRH-(1-41) by HPLC. Furthermore, female B10.A mice were immunized with interphotoreceptor retinoid-binding protein and treated during the induction (0-7 days) or expression (8-16 days) stages of t he disease with ip injections of the anti-CRH antibody TS-2 or placebo nonimmune rabbit serum The early anti-CRH treatment significantly dec reased the disease intensity compared to that in placebo- or late-trea ted animals (P < 0.05, by analysis of variance). We conclude that IrCR H is present at the site of inflammation in rodent experimental uveiti s and that its expression correlates with the natural history and inte nsity of the disease. Immune CRH appears to play an early pathogenetic role in the induction of experimental uveitis.