Ex Vivo Expanded Donor Alloreactive Regulatory T Cells Lose Immunoregulatory, Proliferation, and Antiapoptotic Markers After Infusion Into ATG-lymphodepleted, Nonhuman Primate Heart Allograft Recipients.

BACKGROUND: Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS: darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS: darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS: Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.

Extracorporeal Support During Bilateral Sequential Lung Transplantation in Patients With Pulmonary Hypertension: Risk Factors and Outcomes.

OBJECTIVE: To identify preoperative predictors of extracorporeal support in patients with pulmonary hypertension (PH) undergoing bilateral sequential lung transplantation (LTx), and to examine outcomes associated with the use of extracorporeal support. DESIGN: Retrospective, observational study. SETTING: Single organ transplantation and tertiary care university medical center. PARTICIPANTS: Adults with PH (preoperative mean pulmonary artery pressure (mPAP)≥25 mmHg) who underwent primary bilateral sequential LTx during 2007 to 2013. MEASUREMENTS AND MAIN RESULTS: Of 262 patients with PH undergoing LTx, extracorporeal support was initiated intraoperatively in 149 (57%). Preoperative severe right ventricle (RV) dysfunction and moderate or severe tricuspid regurgitation (TR) were associated with extracorporeal support. In the remaining 208 patients without those factors, increasing preoperative oxygen requirement (odds ratio [OR] 1.30 per 1 L/min, 95% confidence intervals [CI] 1.11-1.52, p = 0.001), presence of RV dilation (OR 2.77, 95% CI 1.28-6.02, p = 0.010), and mPAP (OR 1.33 per 5-mmHg increase in mPAP, 95% CI 1.04-1.70, p = 0.021) were associated independently with extracorporeal support in the multivariable model. Analysis of 49 propensity-matched pairs showed longer intensive care unit (5 v 14 days, p = 0.006) and hospital stays (27 v 39 days, p = 0.016) and increased need for tracheostomy (16% v 41%, p = 0.017) in patients exposed to extracorporeal support but no differences in 30-day mortality, stroke, myocardial infarction, or dialysis. CONCLUSIONS: Severity of RV dysfunction, TR, RV dilatation, increasing oxygen requirement, and increasing mPAP showed significant associations with the need for extracorporeal support during LTX in patients with PH. Extracorporeal support was associated with increased length of stay and tracheostomy but not with mortality or other complications. © 2016 Elsevier Inc. All rights reserved.

Surgical Strategy for Lung Transplantation in Adults With Small Chests: Lobar Transplant Versus a Pediatric Donor.

BACKGROUND: Adult lung transplant recipients with small chests have traditionally received lungs from pediatric donors, placing an additional strain on the already restricted pediatric donor pool. Performing lobar lung transplantation (LLT) can circumvent issues with donor-recipient size mismatch; however, LLT imparts additional risks. Here, we review our experience using LLT and standard lung transplantation using a pediatric donor (PDLT) for adults with small chests. METHODS: We retrospectively reviewed consecutive patients with end-stage lung disease and a height of 65 inches or less who underwent LLT (n = 15) or PDLT (n = 15) between 2006 and 2012 at our institution, a high-volume lung transplant center. RESULTS: Lobar lung transplantation recipients were older (54 ± 10 vs 48 ± 8 years) and had higher pulmonary pressure (57 ± 11 vs 52 ± 27 mmHg) and higher lung allocation scores (70 ± 9 vs 51 ± 8) than PDLT recipients (all P < 0.05). Mean waiting time was 62 days for PDLT and 9 days for LLT. Postoperatively, the incidence of severe primary graft dysfunction and the incidence of acute renal insufficiency were higher, and the mean intensive care unit stay was longer in the LLT group, but the incidence of bronchial anastomotic complications was higher in the PDLT group because of significant size discrepancy in the main bronchus (P < 0.05). Interestingly, long-term functional outcomes and survival rates were similar between the groups. CONCLUSIONS: Both LLT and PDLT are viable surgical options for adult patients with small chests. Because of the potential impact on posttransplant outcomes, the technical complexity of transplantation, decisions regarding the best surgical approach should be made by experienced surgeons.

Long-term patient and allograft outcomes of renal transplant recipients undergoing cardiac surgery.

OBJECTIVES: Cardiovascular complications are a major cause of morbidity and mortality among renal transplant recipients. This study assessed perioperative risk factors for mortality and long-term outcomes in renal transplant recipients who underwent cardiac surgery. METHODS: From 1999 to 2010, 92 renal transplant recipients with a functioning allograft underwent cardiac surgery at our institution. Cardiac procedures included coronary artery bypass grafting (43 patients, 46%), isolated valve surgery (17 patients, 18%), combined coronary artery bypass grafting and valve surgery (18 patients, 19%), and aortic procedures (7 patients, 7%). RESULTS: Transient renal failure requiring dialysis occurred in 20 of 92 patients (21%), with 3 not recovering renal function and returning to a permanent dialysis regimen while in the hospital. After cardiac surgery 30-day, 1-year, 5-year, and 8-year survival rates were 89%, 72%, 47%, and 30%, respectively. Freedom from dialysis was 90% after 1 year, 66% after 5 years, and 49% after 8 years. Risk factors for 30-day mortality were age > 65 years, left ventricle ejection fraction < 35%, and a combined cardiac procedure. Pulmonary hypertension and diabetes were risk factors for death from a cardiac cause after discharge. Diabetes, dyslipidemia, preoperative use of an intra-aortic balloon pump, postoperative creatinine > 2 mg/dL, and transient renal failure requiring dialysis were associated with a permanent dialysis requirement after cardiac surgery. CONCLUSIONS: Cardiac surgery in patients receiving renal transplant who have functioning allograft has acceptable outcomes. If combined procedures are required, patients should be carefully considered. Transient postoperative renal impairment, even if resolved at discharge, increases the risk for allograft failure during long-term follow-up.