Felix Krenzien

A Rationale for Age-Adapted Immunosuppression in Organ Transplantation.

Abstract Demographic changes are associated with a steady increase of older patients with end-stage organ failure in need for transplantation. As a result, the majority of transplant recipients are currently older than 50 years, and organs from elderly donors are more frequently used. Nevertheless, the benefit of transplantation in older patients is well recognized, whereas the most frequent causes of death among older recipients are potentially linked to side effects of their immunosuppressants. Immunosenescence is a physiological part of aging linked to higher rates of diabetes, bacterial infections, and malignancies representing the major causes of death in older patients. These age-related changes impact older transplant candidates and may have significant implications for an age-adapted immunosuppression. For instance, immunosenescence is linked to lower rates of acute rejections in older recipients, whereas the engraftment of older organs has been associated with higher rejection rates. Moreover, new-onset diabetes mellitus after transplantation is more frequent in the elderly, potentially related to corticosteroids, calcineurin inhibitors, and mechanistic target of rapamycin inhibitors. This review presents current knowledge for an age-adapted immunosuppression based on both, experimental and clinical studies in and beyond transplantation. Recommendations of maintenance and induction therapy may help to improve graft function and to design future clinical trials in the elderly.

NAD+ protects against EAE by regulating CD4+ T-cell differentiation.

CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases.

NAD(+) regulates Treg cell fate and promotes allograft survival via a systemic IL-10 production that is CD4(+) CD25(+) Foxp3(+) T cells independent.

CD4+ CD25+ Foxp3+ Tregs have been shown to play a central role in immune homeostasis while preventing from fatal inflammatory responses, while Th17 cells have traditionally been recognized as pro-inflammatory mediators implicated in a myriad of diseases. Studies have shown the potential of Tregs to convert into Th17 cells, and Th17 cells into Tregs. Increasing evidence have pointed out CD25 as a key molecule during this transdifferentiation process, however molecules that allow such development remain unknown. Here, we investigated the impact of NAD+ on the fate of CD4+ CD25+ Foxp3+ Tregs in-depth, dissected their transcriptional signature profile and explored mechanisms underlying their conversion into IL-17A producing cells. Our results demonstrate that NAD+ promotes Treg conversion into Th17 cells in vitro and in vivo via CD25 cell surface marker. Despite the reduced number of Tregs, known to promote homeostasis, and an increased number of pro-inflammatory Th17 cells, NAD+ was able to promote an impressive allograft survival through a robust systemic IL-10 production that was CD4+ CD25+ Foxp3+ independent. Collectively, our study unravels a novel immunoregulatory mechanism of NAD+ that regulates Tregs fate while promoting allograft survival that may have clinical applications in alloimmunity and in a wide spectrum of inflammatory conditions.

CD11c+ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

Background— Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. Methods and Results— Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells augmenting CD4+ and CD8+ T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c+ dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A−/− mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. Conclusions— These results demonstrate a critical role of old donor CD11c+ dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted.

Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly.

Purpose of reviewThis review presents current knowledge of the impact of age on the pharmacokinetics of maintenance immunosuppressants. Recent findingsOver the past decade, there has been a steady increase in older patients on organ transplant waiting lists. As a result, the average age of transplant recipients has significantly increased. The survival and quality-of-life benefits of transplantation in the elderly population have been demonstrated. Advancing age is associated with changes in immune responses, as well as changes in drug handling. Immunosenescence is a physiological part of aging and is linked to reduced rejection rates, but also higher rates of diabetes, infections and malignancies. Physiologic changes associated with age can have a significant impact on the pharmacokinetics of the maintenance immunosuppressive agents. Taken together, these age-related changes impact older transplant candidates and may have significant implications for managing immunosuppression in the elderly. SummaryDespite the lack of formal efficacy, safety and pharmacokinetic studies of individual immunosuppressants in the elderly transplant population, there are enough data available for practitioners to be able to adequately manage their older patients. A proficient understanding of the factors that impact the pharmacokinetics of the immunosuppressants in the elderly is essential to managing these patients successfully.

Mental Status in Patients Before and After Liver Transplantation

BACKGROUND In contrast to the well-described beneficial organic effects of liver transplantation (OLT) in patients with end-stage liver disease, changes in the mental status of patients after OLT remain poorly understood. The current study seeks to evaluate the influence of OLT on anxiety, depression, and dispositional optimism in patients with end-stage liver disease. MATERIAL AND METHODS Questionnaires were sent to patients on the OLT waiting list and patients after OLT. Depression/anxiety and dispositional optimism were assessed using the HADS and LOT-R questionnaires, respectively. These findings were compared to results from the general population. RESULTS The number of returned questionnaires was 292 of 940 (31.1%; 57 patients on the liver transplant waiting list: waiting group, 235 liver transplant recipients: OLT group). Both depression and anxiety scores were significantly higher in the waiting group when compared to the OLT group (p<0.05) and the general population (anxiety: p<0.001, depression: p<0.05), respectively. The OLT group was characterized by significantly higher anxiety scores (p<0.001) compared to the general population. Depression and summation scores did not differ (p>0.05). Dispositional optimism was higher in the OLT group compared to the waiting group (p<0.05) and to the general population (p<0.01). The waiting group had equal values as the general population (p>0.05). CONCLUSIONS Besides beneficial effects on liver function, OLT appears to be associated with significant improvements in depression and anxiety and a more optimistic view of life.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age‐specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon‐γ cytokine production and promote interleukin‐10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin‐2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC‐treated murine and human CD4+ T cells demonstrated an age‐specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC‐treated mice, suggesting that TAC age‐specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age‐specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age‐specific effects when using TAC.

Defective CD8 Signaling Pathways Delay Rejection in Older Recipients.

Abstract CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8+ T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+CD44highCD62Llow effector/memory T cells and a reduced systemic IFN&ggr; production. When reconstituting young CBA Rag-1−/− mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2Kb T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFN&ggr; levels observed in old recipients had been linked to a compromised expression of the IL-2R &bgr; subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFN&ggr; production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8+ T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c+ cells. Collectively, our study demonstrated that aging delays allograft rejection. CD8+ T cells play a critical role in this process linked to a compromised production of IFN&ggr;, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8+ T cells and dendritic cells.

Risk Stratification of Ruptured Abdominal Aortic Aneurysms in Patients Treated by Open Surgical Repair

OBJECTIVE The present study tested scoring models for ruptured abdominal aortic aneurysms (rAAAs) in patients treated by open surgical repair (OSR). Scores were tested in a European population to validate their applicability for predicting outcome. METHODS Between 2002 and 2013, 92 patients with rAAAs underwent OSR and medical records were reviewed retrospectively. The Edinburgh Rupture Aneurysm Score (ERAS), Vascular Study Group of New England (VSGNE) rAAA risk score, Hardman Index, and Glasgow Aneurysm Score (GAS) were calculated and analyzed according to in hospital mortality. The discriminatory power and calibration of all models were assessed by applying the receiver operating characteristic and the Hosmer-Lemeshow test χ(2). RESULTS An ERAS ≤ 1 (n = 55), 2 (n = 15) and 3 (n = 16) was associated with a mortality of 27%, 47%, and 69%, respectively. The calibration was the best of all tested scores (χ(2) = 0.44; p = .81) and the area under the curve (AUC) was 0.71 (95% CI 0.6-0.82; p = .001). A VSGNE rAAA risk score = 0 (n = 19), 1 (n = 15), 2 (n = 19), 3 (n = 25), and ≥ 4 (n = 9) was associated with a mortality of 11%, 20%, 32%, 72%, and 56%, and an AUC of 0.76 (95% CI 0.66-0.87; p = .001). The calibration was reduced (χ(2) = 6.9; p = .08). The GAS and Hardman Index increased stepwise with increasing in hospital mortality, but were inferior to ERAS and the VSGNE rAAA risk score. The Hardman Index showed the smallest AUC (0.68; 95% CI 0.56-0.80; p = .011) and demonstrated a lack of fit (χ(2) = 8.2; p = .04). The GAS showed good discrimination (AUC = 0.75; 95% CI 0.64-0.85; p < .001) and calibration (χ(2) = 0.85; p = .66); however, the parametric scale of GAS limits its use to classifying patients according to their risk. CONCLUSION The present study revealed remarkable differences in survival between subgroups (10-70%) and underscores the need for risk stratification. The ERAS was favorable with striking ease of use and high accuracy in predicting outcome.

Alternative treatment of symptomatic pancreatic fistula

BACKGROUND The management of symptomatic pancreatic fistula after pancreaticoduodenectomy is complex and associated with increased morbidity and mortality. We here report continuous irrigation and drainage of the pancreatic remnant to be a feasible and safe alternative to total pancreatectomy. MATERIALS AND METHODS Between 2005 and 2011, patients were analyzed, in which pancreaticojejunal anastomosis was disconnected because of grade C fistula, and catheters for continuous irrigation and drainage were placed close to the pancreatic remnant. Clinical data were monitored and quality of life was evaluated. RESULTS A total of 13 of 202 patients undergoing pancreaticoduodenectomy required reoperation due to symptomatic pancreatic fistula. Ninety-day mortality of these patients was 15.3%. Median length of stay on the intensive care unit and total length of stay was 18 d (range 3-45) and 46 d (range 33-96), respectively. Patients with early reoperation (<10 d) had significantly decreased length of stay on the intensive care unit and operation time (P < 0.05). Global health status after a median time of 22 mo (range 6-66) was nearly identical, when compared with that of a healthy control group. Mean follow-up was 44.4 mo (±27.2). Four patients (36.6 %) died during the follow-up period; two patients from tumor recurrence, one patient from pneumonia, and one patient for unknown reasons. CONCLUSIONS Treatment of pancreatic fistula by continuous irrigation and drainage of the preserved pancreatic remnant is a simple and feasible alternative to total pancreatectomy. This technique maintains a sufficient endocrine function and is associated with low mortality and reasonable quality of life.