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P.B. Williams, D.A. Fellner, F.A. Lattanzio, Jr., J.D. Sheppard, Jr.; Primate Model for Penetrating Keratoplasty . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1392.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Eliminating corneal rejection following penetrating keratoplasty (PK) is highly cost effective. Current studies use rodent models to develop surgical and/or therapeutic protocols. Primates are genetically and anatomically more similar to humans. ISIS 2302 is an anti-sense molecule that inhibits the expression of ICAM-1, an intracellular adhesion molecule, which diminishes the inflammatory response. This study establishes the parameters of the primate model and investigates the protective effect of pretreatment with ISIS 2302 on human corneas transplanted into primates. Methods: Corneas, obtained from the Lions Eye Bank, were transplanted into anesthetized primates (Macaque). Donor corneas were randomized to incubation in either Optisol with ISIS 2302 (400 ug), or Optisol alone (control) for 24 hr before transplantation. By slit lamp, rejection criteria included cornea opacity, neovascularization (CNV), keratitic precipitates (KP) and conjunctival inflammation. Intraocular pressures were also monitored. Confocal microscopy was used to document epithelial, stromal and endothelial changes in vivo. Results: PK was performed on 10 primates. Corneas treated with either ISIS 2302 (n=5) or Optisol alone (n=5) showed early signs of post-operative inflammation that quickly resolved within 7 days. By slit lamp examination eyes were quiet clinically for the first 4 weeks. However, evidence of rejection was already apparent by confocal microscopy 1 week post PK. At 5 weeks corneas from 5 primates were harvested for microscopic evaluation. The remaining primates were studied until rejection occurred. By 8 weeks, 4 of 5 transplanted corneas met the rejection criteria by slit lamp examination. The order of rejection criteria was opacity followed by CNV with little KP or conjunctival inflammation. Conclusion: This study of human corneal tissue xenografted to primate recipient eyes establishes the utility of this model. The earliest signs of rejection were observed by confocal microscopy weeks before positive detection by slit lamp. Compared to the relatively rapid rejection (e.g. days) in the rat model, the primate model takes up to 8 weeks for rejection criteria to be met. In the rapid rejection rat model, ISIS prolonged graft survival 25%. Beneficial effects of ISIS to inhibit ICAM expression are likely manifested shortly after PK and may have been obscured by the longer duration of the rejection in the primate model. A high risk rejection model such as PK after initial graft failure or CNV, may be more a appropriate test system to evaluate the acute effects of these agents.
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