IDO and regulatory T cell support are critical for cytotoxic T lymphocyte-associated Ag-4 Ig-mediated long-term solid organ allograft survival.

Costimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig upregulates expression of the immunoregulatory enzyme IDO in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. In this study, we studied whether concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor-specific transfusion showed indefinite graft survival (>100 d) without signs of chronic rejection or donor specific Ab formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared with rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-dl-tryptophan, either at transplant or at postoperative day 50, abrogated CTLA4Ig + DST-induced long-term graft survival. Importantly, IDO1 knockout recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of regulatory T cells (Tregs) resulted in decreased IDO activity and again prevented CTLA4Ig + DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this costimulatory blocker.

Major risk stratification models do not predict perioperative outcome after coronary artery bypass grafting in patients with previous percutaneous intervention.

OBJECTIVE: To investigate whether common risk stratification models in cardiac surgery predict perioperative outcome of coronary artery bypass grafting (CABG) in patients with previous percutaneous coronary interventions (PCIs). METHODS: We retrospectively analyzed the perioperative mortality and morbidity of 367 patients with prior elective PCI versus 2361 patients without prior PCI, who underwent first-time isolated CABG between 2001 and 2009 at our institution. Receiver operating characteristics (ROC) were used to describe the performance and accuracy of the European System for Cardiac Operative Risk Evaluation (EuroSCORE) and the Society of Thoracic Surgeons (STS) risk model in predicting mortality and morbidity. RESULTS: Both groups were comparable concerning preoperative logistic EuroSCORE (PCI: 4.9 ± 6.57, non-PCI: 4.60 ± 5.45, p=0.51). Patients with previous elective PCI had increased perioperative mortality (PCI: 3.8% vs non-PCI: 2.1%, p=0.01) and higher rates of major adverse cardiac events (8.4% vs 4.5% respectively, p=0.003). Discriminatory power for 30-day mortality was higher in the non-PCI group (EuroSCORE area under the curve (AUC): 0.875 vs 0.552 in the PCI group). Logistic EuroSCORE predicted 30-day mortality in the non-PCI group (confidence interval (CI)=0.806-0.934, p=0.0004) but not in the PCI group (CI=0.301-0.765, p=0.8). Discriminatory power for morbidity or mortality (M&M) was lower in the PCI group (AUC: 0.980 vs 0.713 for the non-PCI group). The STS risk model had a lower discriminatory power for predicting M&M in PCI patients (AUC: 0.611 vs 0.686 for the non-PCI group, p<0.001). CONCLUSIONS: The EuroSCORE and the STS risk model were inaccurate in predicting perioperative mortality after CABG in patients with history of elective PCI. There is a need for modification of risk models to improve risk assessment for surgical candidates with prior PCI.