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ObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model.DesignInvestigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13).SettingCharité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union).ParticipantsRecipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9).InterventionsCD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48.Main outcome measuresThe primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio.ResultsFor all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire.ConclusionsThe application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies.Trial registrationNCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).

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Introduction Hyperglycemia is associated with negative outcomes in various settings of critical illness; infectious complications, especially, seem to be increased. On the other hand, intensive insulin therapy (IIT) has been shown to improve outcome in clinical trials. Whether normoglycemia itself or the application of insulin is responsible for the observed findings is unknown. We therefore tested the effect of glucose and insulin on various immune functions in vitro.

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker‐guided trial investigated whether in low immunological‐risk kidney transplants without pretransplant DSA and donor‐specific T cells assessed by a standardized IFN‐γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non‐inferior regarding 6‐month BPAR than tacrolimus‐based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E−) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six‐ and 12‐month BPAR rates were higher among LI than SOC/E− (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per‐protocol analyses. Post‐hoc analysis revealed that poor class‐II eplet matching, especially DQ, discriminated E− patients, notably E−/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti‐class‐I (p = .05) and anti‐DQ (p < .001) de novo DSA. Adverse events were similar, but E−/LI developed fewer viral infections, particularly polyoma‐virus‐associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune‐risk stratification and guide immunosuppression decision‐making in kidney transplantation.

Viral infections have a major impact on morbidity and mortality of immunosuppressed solid organ transplant (SOT) patients because of missing or failure of adequate pharmacologic antiviral treatment. Adoptive antiviral T-cell therapy (AVTT), regenerating disturbed endogenous T-cell immunity, emerged as an attractive alternative approach to combat severe viral complications in immunocompromised patients. AVTT is successful in patients after hematopoietic stem cell transplantation where T-cell products (TCPs) are manufactured from healthy donors. In contrast, in the SOT setting TCPs are derived from/applied back to immunosuppressed patients. We and others demonstrated feasibility of TCP generation from SOT patients and first clinical proof-of-concept trials revealing promising data. However, the initial efficacy is frequently lost long-term, because of limited survival of transferred short-lived T-cells indicating a need for next-generation TCPs. Our recent data suggest that Rapamycin treatment during TCP manufacture, conferring partial inhibition of mTOR, might improve its composition. The aim of this study was to confirm these promising observations in a setting closer to clinical challenges and to deeply characterize the next-generation TCPs. Using cytomegalovirus (CMV) as model, our next-generation Rapamycin-treated (Rapa-)TCP showed consistently increased proportions of CD4 + T-cells as well as CD4 + and CD8 + central-memory T-cells (T CM ). In addition, Rapamycin sustained T-cell function despite withdrawal of Rapamycin, showed superior T-cell viability and resistance to apoptosis, stable metabolism upon activation, preferential expansion of T CM , partial conversion of other memory T-cell subsets to T CM and increased clonal diversity. On transcriptome level, we observed a gene expression profile denoting long-lived early memory T-cells with potent effector functions. Furthermore, we successfully applied the novel protocol for the generation of Rapa-TCPs to 19/19 SOT patients in a comparative study, irrespective of their history of CMV reactivation. Moreover, comparison of paired TCPs generated before/after transplantation did not reveal inferiority of the latter despite exposition to maintenance immunosuppression post -SOT. Our data imply that the Rapa-TCPs, exhibiting longevity and sustained T-cell memory, are a reasonable treatment option for SOT patients. Based on our success to manufacture Rapa-TCPs from SOT patients under maintenance immunosuppression, now, we seek ultimate clinical proof of efficacy in a clinical study.

Background Long-term outcomes of the Eurotransplant Senior Program (ESP) are urgently needed to improve selection criteria and allocation policies in the elderly. Methods We analysed patient and allograft outcomes of 244 ESP-kidney transplant recipients (KTRs) between 1999 and 2019 and assessed quality of living compared with 82 ESP-waitlisted dialysis patients using standardized short form-8. Results We observed 1-, 5- and 10-year patient survival of 91.7, 66.3 and 38.0%, respectively. Mortality risk factors included male gender (P = 0.006) and T-cell-mediated rejection (P &lt; 0.001). Median patient survival of male ESP-KTRs was 80 versus 131 months for female ESP-KTRs (P = 0.006). 1-, 5- and 10-year death-censored allograft survival was 93.3, 82.6 and 70.4%. Risk factors included high body mass index (P &lt; 0.001) and T-cell-mediated rejection (P &lt; 0.001). After re-initiation of dialysis median patient survival was 58 months. Change of estimated glomerular filtration rate showed a mean decline of 2.3 and 6.8 mL/min at 5 and 10 years. Median physical and mental component scores of ESP-KTRs were 40.2 and 48.3, significantly higher compared with dialysis patients (P &lt; 0.05). Of ESP-KTRs, 97.5% who underwent transplantation would again do so. Conclusions Long-term outcomes of ESP-KTRs ultimately support the effectiveness of an age-matched allocation system. Our data suggest that the survival advantage of women is maintained after kidney transplantation and calls for gender-specific care.

BackgroundNoninvasive regional cerebral oxygen saturation (rSO2) measurement using near-infrared spectroscopy (NIRS) might inform on extent and duration of cerebral hypoxia during cardiopulmonary resuscitation (CPR). This information may be used to guide resuscitation efforts and may carry relevant early prognostic information.MethodsWe prospectively investigated non-traumatic out-of-hospital cardiac arrest (OHCA) patients on scene. NIRS was started either during CPR or shortly after (<2 min) return of spontaneous circulation (ROSC) by emergency medical service (EMS). Outcome was determined at intensive care unit (ICU) discharge and 6 months after cardiac arrest.ResultsA total of 29 OHCA patients were included. In 23 patients NIRS was started during CPR and in 6 patients immediately after ROSC. 18 (62.1 %) patients did not reach ROSC. Initial rSO2 during CPR was very low (<50 % in all 23 patients, < 30 % in 19 of 23 patients) with no significant difference between patients achieving ROSC and those who did not. Of five patients with ROSC, in whom NIRS was recorded during CPR, two reached a good six-months outcome (initial rSO2 22 %) and three died during the ICU stay (initial rSO2 15, 16 and 46 %). In six patients with NIRS started immediately after ROSC (<2 min), rSO2 was substantially higher (54–85 %) than in patients during CPR (p = 0.006).Discussion and conclusionInitial frontal brain rSO2 determined by NIRS during CPR was generally very low and recovered rapidly after ROSC. Very low initial rSO2 during CPR was compatible with good neurological outcome in our limited cohort of patients. Further studies are needed to assess in larger cohorts and more detail the implications of very low initial rSO2 during CPR on scene.