INHIBITION OF THE IMMUNOMODULATORY ENZYME INDOLEAMINE 2,3–DIOXYGENASE ACCELERATES ALLOGRAFT REJECTION.

Abstract

P1142 Aims: Indoleamine 2,3-dioxygenase (IDO) via tryptophan depletion and the production of proapoptotic metabolites inhibits T-cell proliferation and leads to T-cell anergy. IDO is activated by INF-γ and has been demonstrated to play an essential role in maternal tolerance. The role of IDO in solid organ transplantation has not been clarified yet. Methods: Hearts of C57BL/10 (H-2b) mice were transplanted to C3H/He (H-2k) recipients. Syngeneic transplants and allograft recipients treated with CsA or with the IDO inhibitor 1-methyl tryptophan (1-MT) served as controls. Serum concentrations of kynurenine and tryptophan were analyzed by high performance liquid chromatography (HPLC) 2, 4, 6 and 8 days following transplantation. Kynurenine to tryptophan ratios (kyn/trp) were calculated as an indirect estimate of IDO activity. Intragraft IDO mRNA expression was assessed by quantitative RT-PCR (Taqman technology). Results: Untreated allografts were rejected after 7.3 ± 0.6 days as confirmed by H&E histology. There was an increase of serum kynurenine and a decrease of tryptophan concentrations as reflected by a significant increase of kyn/trp (day 2 post transplant: 18 ± 10; day 4: 21 ± 8; day 6: 43 ± 23; day 8: 37 ± 14) P < 0.05 at each timepoint. Intragraft expression of IDO mRNA was induced up to 100-fold on p.o. days 6 and 8. In contrast, animals receiving a syngeneic heart or allograft recipients treated with CsA did not show changes in kyn/trp (21 ± 5 and 19 ± 3 respectively) and expression profiles of IDO mRNA remained unchanged (syngeneic), or were attenuated by 2.6 ± 0.6 fold (CsA). IDO inhibition with 1-MT resulted in enhanced T-cell activity and was associated with progressive deterioration of the transplant followed by accelerated graft rejection (4.6 ± 0.8 days). Conclusion: Despite its tolerogenic effect in maternal immunity strong expression of IDO in cardiac allografts delays but does not prevent rejection. IDO activity, however, may serve as a novel marker of immune activation and via modulation of tryptophan catabolism offer a potential tool to abrogate the alloimmune response.