Oral Abstracts10 MONDAY with Rapa showed stronger ex-vivo reactivity to donor DC than cells from naïve animals, confi rming that Rapa permits T cell priming but promotes anergy induction and/or conversion to Foxp3 expression. Additionally, CD4 T cells isolated from untreated recipients showed a signifi cant degree of "resistance" to in vitro suppression of proliferation by titrated numbers of Treg. Such "resistance" was not evident in T cells from Rapa-treated recipients. Moreover, Rapa treatment prevented allograft T cell infi ltration, and elevation of serum IL-6 (responsible for the observed T cell "resistance" to Treg suppression). Finally, preliminary results indicate the capacity of Rapa to signifi cantly reduce the proliferative capacity of in vitro-generated memory T cells, whose contribution to transplant rejection has been well demonstrated. Conclusion: Rapa contributes to tolerance induction at multiple levels. It lowers circulating T cells by reducing thymocyte development and favors Treg ontogeny. In transplant recipients, Rapa causes additional T cell decreases that correlate with its ability to favor activation-induced cell death (AICD). The increased proportion of splenic Foxp3 + cells correlates with both the Tregsparing properties of Rapa and its reported induction of Foxp3 in T cells. Finally, Rapa exerts signifi cant anti-infl ammatory activity that favors Treg suppressive function, even at the level of memory T cell regulation. 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 the production of kynurenines which act directly on T cells. We have therefore investigated the role of the kynurenines in corneal graft rejection. In order to assess the effect of kynurenines on T cell responses, the molecules were added into both mixed lymphocyte reactions and anti-CD3/CD28 bead stimulation of T cells. In both human and mouse 3-Hydroxykynurenine (3-HK) and 3-Hydroxyanthranilic acid (3-HAA). but not L-Kynurenine or Quinolinic acid, inhibited T cell proliferation. This was accompanied by signifi cant cell T cell death. There is no evidence of induction of regulatory T cells as shown in the mouse by failure to induce FoxP3 expression. Neither 3-HK nor 3-HAA has a major effect on dendritic cell function, nor do they affect apoptosis or the activation status of corneal endothelial cells. In order to determine if these agents can prolong graft survival we carried out corneal allografts in a murine model. Administration of 3-HK on a daily basis to BALB/c mice receiving a C3H corneal graft resulted in considerable prolongation of graft survival (MST of controls = 12 days, of treated = 19 days). This was seen when the 3-HK was given between day 1-7, 7-14 or 1-14. Chronic administration of 3-HK resulted in no signifi cant alteration in CD4, CD8 or FoxP3 positive splenic T cells. These data therefore indicate that one mechanism by which IDO prolongs corneal graft survival is by the produ...

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