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Sarah S. Zaher, Daniel F. Larkin, Andrew J. George; Prolongation of Mouse Corneal Allograft Survival Following Systemic ‘Tranilast’ Administration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1157.
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© ARVO (1962-2015); The Authors (2016-present)
Previously we have shown that indoleamine 2,3-dioxygenase (IDO) and the tryptophan metabolite, 3-hydroxykynurenine (3 HK) can 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 synthetic tryptophan metabolite analogue 3,4-DAA (‘Tranilast’) shares the anthranilic acid core with 3HK and is currently licensed as an anti-allergy drug in Japan. The effect of 3,4-DAA in preventing allogeneic rejection has not been previously investigated. The purpose of this study is to assess whether 3,4-DAA, would extend allograft survival and examine its effect on T cell biology.
In vitro analysis of the effect of -3,4-DAA on T-cell proliferation; T-cell death and T-regulatory cell development as well as its effect on cell cycle progression was carried out. 3,4-DAA was then administered systemically to mice receiving fully MHC mismatched 2.5mm donor corneas or skin transplants.
3,4-DAA significantly inhibited T-lymphocyte proliferation. This inhibition, in contrast to that induced by tryptophan metabolites, was a result of cell cycle arrest rather than T cell death. Cell cycle arrest was mediated by upregulation of the cell cycle-specific inhibitors p21 and p15, and associated with a significant reduction in IL-2 production.Administration of systemic 3,4-DAA to mice receiving a fully mismatched grafts of cornea or skin resulted in significant prolongation of survival (median survival of controls = 12, 13 days respectively, of treated = 24 days and 17 days respectively, p<0.0001 and ≤0.03 respectively).
These data indicate that 3,4-DAA is effective in prolonging allograft survival. We have confirmed that it inhibits T cell proliferation through cell cycle arrest and elucidated a novel mechanism for 3,4-DAA induced T cell anergy. As this is a drug already in clinical use, its oral bioavailability and safe therapeutic profile make it a candidate for the prevention of rejection of transplanted cornea and possibly other tissues.
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