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F.A. Lattanzio, N. Alvarez-Chedzoy, J.D. Sheppard, Jr., T. Parker, A. Fateh; Early Signs of Corneal Rejection Detected by in vivo Confocal Microscopy: Effect of Anti-ICAM-1 Corneal Oligonucleotides . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3662.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: ISIS 9125, an antisense oligonucleotide, inhibits expression of ICAM-1, an intracellular adhesion molecule essential to the rejection reaction. To monitor inflammation in uveitis patients, in vivo confocal microscopy (CFM) is superior to slit lamp biomicroscopy (SLB). Likewise, the goal here is to evaluate whether in vivo CFM provides early detection of corneal rejection as well as whether ISIS 9125 retards corneal rejection. Methods: Corneal allografts (3mm), from anesthetized donor ACI rats, were transplanted to anesthetized Lewis rats. Recipients were randomized to receive a cornea incubated with either ISIS 9125 (400 ug) or vehicle alone (control) for 24 hr before transplantation. SLB rejection criteria included corneal opacity and edema, neovascularization, keratic precipitates and conjunctival and iris inflammation. CFM was used to document epithelial, stromal and endothelial changes in vivo. Results: Incubation with ISIS 9125 increased days to rejection by 25% over vehicle alone. By CFM subtle signs of rejection were apparent within 1 d after transplantation, but were not apparent by SLB until day 3. By SLB, the ISIS 9125 group was had 50% less corneal opacity and neovascularization, but had more corneal edema than the control group. A graded CFM scale showed a significant reduction in leukocyte infiltration in the ISIS 9124 group. Confocal image analysis revealed a statistically significant improvement in inflammation of corneas treated with ISIS 9125, with more ISIS treated corneas in the least inflamed class (P=0.005.) and no ISIS treated corneas in the most inflamed class (P=0.013). Conclusions: SLB provided indirect evidence regarding the onset and intensity of the corneal rejection process. By comparison, in vivo CFM detected and quantified actual leucocyte infiltration of the stroma, endothelium and anterior chamber. ISIS 9125 inhibits ICAM receptor expression, resulting in decreased leucocyte adhesion and subsequent infiltration. Thus, in vivo CFM can provide earlier detection of rejection and thereby a more direct measure of drug effect. In vivo CFM indicated that corneas without ISIS pretreatment were more inflamed and infiltrated. Pretreatment with ISIS 9125 may reduce the incidence of or delay the onset of the rejection reaction, as well as decrease the inflammation associated with rejection reactions.
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