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S. S. Zaher, D. F. P. Larkin, A. J. T. George; Prolongation of Mouse Corneal Allograft Survival Following Systemic and Topical 3-Hydroxykynurenine (3HK) Administration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1548.
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© ARVO (1962-2015); The Authors (2016-present)
Indoleamine 2,3-dioxygenase (IDO) has been shown to prolong corneal graft survival. IDO modulates the immune response by depletion of the essential amino acid tryptophan and by breakdown to kynurenines, which themselves act directly on T lymphocytes. The effect of kynurenines on corneal allograft survival is unknown.
IDO and kynurenines are potential targets for preventing allograft rejection. We investigated the role of kynurenine administration on corneal graft survival to determine whether this was the mechanism by which IDO delays rejection.
In vitro analysis of the effect of kynurenines on T-cell proliferation; T-cell death; T-regulatory cell development; dendritic cell function, phenotype and viability was carried out. Two exogenous kynurenines were then administered systemically and topically to inbred mice receiving fully MHC mismatched 2.5mm donor corneas.
T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3-HK and 3-Hydroxyanthranilic acid (3-HAA). This was accompanied by significant T- cell death. Neither 3-HK nor 3-HAA altered dendritic cell function, nor did they affect apoptosis or pathogenicity to corneal endothelial cells.Administration of systemic and topical 3-HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of controls = 12 days, of treated = 19 days and 15 days respectively, p<0.0003).
These data therefore indicate that one mechanism by which IDO prolongs corneal graft survival is by the production of kynurenines, in particular 3-HK and 3-HAA. In addition it highlights the potential of these molecules as agents for preventing allograft rejection in patients at high rejection risk.
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