Utilization of hepatitis B virus surface antigen positive grafts in liver transplantation: A matched study based on a national registry cohort.

BACKGROUND AND AIM: Donor shortage has become worldwide limitation in liver transplantation (LT). Use of hepatitis B virus surface antigen positive (HBsAg+) donors could be an alternative source of donor organs. This study aims to investigate the safety and efficacy of LT using HBsAg+ liver grafts and associated long-term outcome. METHODS: This was a retrospective study of adults LT registered in the database of the China Liver Transplant Registry between January 2015 and September 2018. By propensity score matching (1:1), 503 eligible patients who received HBsAg+ liver grafts were compared with 503 matched patients who received HBsAg- liver grafts. RESULTS: The 1-, 3-, and 5-year patient survival rates were 81.52%, 72.04%, and 66.65% in HBsAg+ donor group, which were comparable with 83.93%, 77.27%, and 65.73% in HBsAg- donor group (P = 0.222). The 1-, 3-, and 5-year graft survival rates were also comparable between the two groups (81.49%, 71.45%, and 67.26% vs 83.62%, 77.11%, and 65.81%, respectively, P = 0.243). Most main complications were not increased in HBsAg+ donor group except for the retaining of HBsAg positivity after LT. Furthermore, transplanting HBsAg+ liver grafts did not result in inferior outcomes either in HBsAg+ or HBsAg- recipients. The risk of tumor recurrence after LT was not increased in hepatocellular carcinoma patients. CONCLUSIONS: The outcomes of using HBsAg+ liver grafts were comparable with those of HBsAg- liver grafts. Our study provided strong evidence for the safe use of HBsAg+ grafts in LT to expand the donor liver pool.

Comparison and development of advanced machine learning tools to predict nonalcoholic fatty liver disease: An extended study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a public health challenge and significant cause of morbidity and mortality worldwide. Early identification is crucial for disease intervention. We recently proposed a nomogram-based NAFLD prediction model from a large population cohort. We aimed to explore machine learning tools in predicting NAFLD. METHODS: A retrospective cross-sectional study was performed on 15 315 Chinese subjects (10 373 training and 4942 testing sets). Selected clinical and biochemical factors were evaluated by different types of machine learning algorithms to develop and validate seven predictive models. Nine evaluation indicators including area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), accuracy, positive predictive value, sensitivity, F1 score, Matthews correlation coefficient (MCC), specificity and negative prognostic value were applied to compare the performance among the models. The selected clinical and biochemical factors were ranked according to the importance in prediction ability. RESULTS: Totally 4018/10 373 (38.74%) and 1860/4942 (37.64%) subjects had ultrasound-proven NAFLD in the training and testing sets, respectively. Seven machine learning based models were developed and demonstrated good performance in predicting NAFLD. Among these models, the XGBoost model revealed the highest AUROC (0.873), AUPRC (0.810), accuracy (0.795), positive predictive value (0.806), F1 score (0.695), MCC (0.557), specificity (0.909), demonstrating the best prediction ability among the built models. Body mass index was the most valuable indicator to predict NAFLD according to the feature ranking scores. CONCLUSIONS: The XGBoost model has the best overall prediction ability for diagnosing NAFLD. The novel machine learning tools provide considerable beneficial potential in NAFLD screening.

A high frequency of CD8+CD28- T-suppressor cells contributes to maintaining stable graft function and reducing immunosuppressant dosage after liver transplantation.

CD8+CD28-T cells (CD8Ts) exert immunosuppressive effects in various autoimmune diseases. The current study was designed to investigate the role of defects in CD8Ts in liver transplantation (LT). The proportion of CD8Ts in peripheral blood was determined by flow cytometry. The mean proportion of CD8Ts was 23.39% in recipients with stable graft function and 16.64% in those with graft dysfunction following LT compared with 19.86% in the healthy cohort. After receiving enhanced immunosuppressive therapy, patients in the rejection group who achieved recovery of graft function showed an increase in the proportion of CD8Ts (from 17.39% to 25.55%), but those in the group with refractory graft dysfunction showed no significant change (12.49% to 10.30%). Furthermore, in the first year after LT, recipients longer removed in time from the LT date exhibited a higher proportion of CD8Ts. Patients benefited most from tacrolimus concentrations of 5-10 ng/ml in the first year after LT and 0-5 ng/ml thereafter. Moreover, the change in the proportion of CD8Ts (ΔCD8Ts) was significantly higher in recipients with stable graft function than in those with graft dysfunction. These results suggest that a high frequency of CD8Ts prevents rejection and contributes to reduce immunosuppressant dosage and even induces tolerance.

Role of [18F] fludeoxyglucose positron emission tomography in the selection of liver transplantation candidates in patients with hepatocellular carcinoma.

BACKGROUND: The Milan criteria are widely accepted among many centers. However, patients with hepatocellular carcinoma beyond the Milan criteria might still benefit from liver transplantation (LT) when tumor itself is not aggressive. [18F] fluorodeoxyglucose positron emission tomography/computed tomography imaging could provide useful information of tumor behaviors, which is helpful to predict the prognosis for many tumors. METHOD: In order to determine its role in candidate selection for LT, we therefore retrospectively analyzed 103 recipients with preoperative positron emission tomography (PET) findings. RESULTS: Positive PET findings (PET+) were significantly associated with tumor nodule numbers (P=0.013), tumor grade (P=0.025), macro- (P=0.002) and micro-vascular invasion (P=0.002), as well as the Milan criteria (P=0.018). PET+ patients had significantly increased risk of tumor recurrence post-LT compared to PET negative (PET-) patients (P=0.007). The 1-, 3-, and 5-year overall survival rate of PET- patients were 96.0%, 87.2% and 76.2%, compared to 74.7%, 55.4% and 49.9% in PET+ patients, respectively (P<0.05). The 1-, 3-, and 5-year recurrence-free survival rate of PET- patients were 91.8%, 81.9% and 76.0%, compared to 70.1%, 39.3% and 21.9% in PET+ patients, respectively (P<0.05). Recipients within the Milan criteria showed comparable 1-, 3-, and 5-year survival rates in comparison with those beyond the Milan criteria with a PET- findings (1-, 3-, and 5-year overall survival rates, 97.5%, 83.3%, and 83.3% vs 90.0%, 80.0%, and 66.7%, P= 0.123; 1-, 3-, and 5-year recurrence-free survival rates, 95.1%, 73.1%, and 73.1% vs 90.0%, 78.8%, and 65.6%, P=0.148). CONCLUSIONS: Certain patients with hepatocellular carcinoma and negative PET findings, who have exceeded the Milan criteria, are also eligible candidates for LT. Preoperative PET/CT imaging is an important marker, which should be incorporated in extended candidate selection criteria for LT.

Association between ADIPOQ gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation.

BACKGROUND: New-onset diabetes after transplantation (NODAT) has become one of the major factors that affect the overall survival and long-term life quality in liver transplantation (LT) recipients. Previous studies found that the serum adiponectin concentration of diabetic patients is significantly lower than that of healthy subjects. Adiponectin regulates the blood glucose level by increasing body sensitivity to insulin through various mechanisms. In this study, we aimed to investigate the impact of diabetes related gene polymorphisms on the development of NODAT in liver recipients. METHODS: A total of 256 LT patients in a single-center were selected retrospectively for the study. Genomic DNA was extracted from explanted liver tissues, and tested for twelve diabetes mellitus associated single nucleotide polymorphisms by Sequenom MassARRAY. Modified clinical models in predicting NODAT were established and evaluated. RESULTS: The GG genotype of ADIPOQ rs1501299 gene polymorphism was significantly more frequent in NODAT than non-NODAT LT patients (56% vs 39%, P=0.014). Dominant model (GG vs GT+TT, P=0.030) and recessive model (GT+GG vs TT, P=0.005) also confirmed the genotype distribution difference between NODAT and non-NODAT groups. Age (OR=1.048, P=0.004), BMI (OR=1.107, P=0.041), and blood tacrolimus level at 1-month LT (OR=1.170, P=0.003) were clinical independent risk factors of NODAT. Furthermore, rs1501299 could improve the ability of clinical model in predicting NODAT (AUROC=0.743, P<0.001). CONCLUSION: ADIPOQ rs1501299 gene polymorphism is associated with an increased risk of NODAT, which should be added to the clinical models in predicting the occurrence of NODAT in LT recipients.

Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.

BACKGROUND & AIMS: Liver grafts from hepatitis B surface antigen (HBsAg) positive donors could have potential to increase the donor pool. However, knowledge is extremely limited in this setting because currently available data are mostly from case reports. We aimed to assess the outcomes and experiences of liver transplantation from HBsAg positive donors in a single centre study. METHODS: From January 2010 to February 2013, 42 adult patients underwent liver transplantation from HBsAg positive donors and 327 patients from HBsAg negative ones. The outcomes including complications and survival of two groups were compared and antiviral therapy retrospectively reviewed. RESULTS: HBsAg positive liver grafts were more likely to be allocated to patients with hepatitis B (HBV)-related diseases. Post-transplant evaluation showed similar graft function regaining pace and no differences in complications such as primary non-function, acute rejection and biliary complications. Patient and graft survivals were comparable to that of HBsAg negative grafts. Furthermore, HBsAg persisted after transplant in all patients that received positive grafts. The donor HBV serum status determined the one of the recipient after transplantation. No HBV flare-ups were observed under antiviral therapy of oral nucleotide analogues, regardless of using hepatitis B immunoglobulin combination. CONCLUSIONS: Utilization of HBsAg positive liver grafts seems not to increase postoperative morbidity and mortality. Therefore it is a safe way to expand the donor pool when no suitable donor is available. Our experience also suggests that hepatitis B immunoglobulin should be abandoned in recipients of HBsAg positive liver grafts, in whom HBV prophylaxis could be the only oral antiviral therapy.

Neonatal lymph node stromal cells drive myelodendritic lineage cells into a distinct population of CX3CR1+CD11b+F4/80+ regulatory macrophages in mice.

Beyond providing a scaffold for immune cells, recent studies indicate that lymph node stromal cells provide potent regulatory capacities that affect the quality of adaptive immune responses. In this study, we provide evidence that neonatal lymph node stromal cells (nnLNSCs) consistently promote the differentiation of macrophage dendritic cell progenitors as well as mature and immature dendritic cells into a distinct population of CX3CR1(+) CD11b(+)F4/80(+) regulatory macrophages (regMΦ). These cells possess remarkably low levels of T cell costimulatory molecules as well as MHC class II molecules. regMΦ do not interfere with early T-cell activation but, via nitric oxide secretion, efficiently suppress T-cell proliferation. Furthermore, CD4(+) T cells proliferating in the presence of regMΦ gain immunosuppressive capacity and MΦ isolated from day 3 nnLNs are T-cell immunosuppressive. Adoptive transfer of antigen-loaded regMΦ induce a profound antigen-specific immune suppression in vivo. Together our data show that nnLNSCs skew the differentiation of dendritic cells and their progenitors toward regMΦ, thus revealing a novel mechanism for local immune regulation.

Orthotopic liver transplantation in situs inversus adult from an ABO-incompatible donor with situs inversus.

BACKGROUND: Situs inversus is a rare congenital anomaly characterized by the complete inversion of thoracic and abdominal organs. Liver transplantation in such patients or from donors in situs inversus is technically challenging because of the reversed anatomic structures. A small number of successful liver transplantation cases concerning situs inverus in either recipients or donors have been recently reported with different graft position and orientation. Here we reported an extremely rare case of liver retransplantation from an ABO incompatible situs inversus donor to an adult situs inversus recipient. CASE PRESENTATION: A 53-year-old complete situs inversus man developed graft failure due to severe biliary complication after his first liver transplantation from a situs solitus donor. Re-transplantation was performed using a graft liver from a likewise situs inversus donor. Although the blood type between donor and recipient was incompatible, the post-operative outcome was excellent under proper prophylaxis to the antibody-mediated rejection. CONCLUSION: To the best of our knowledge, this is the first report of liver transplantation from situs inversus to situs inversus in adult recipient. Liver transplantation using situs matching donor makes the procedure much easier at the surgical point of view, which has a benefit of less potential surgical complications. Furthermore, ABO-incompatibility is acceptable for donor allocation in cases that both donor and recipient are situs inversus.

[Risk factors of biliary complications after liver transplantation from donation after cardiac death].

OBJECTIVE: To analyze the risk factors for biliary complications of liver transplantation from donation after cardiac death (DCD). METHODS: Clinical data of 109 patients undergoing liver transplantation from DCD in First Affiliated Hospital of Zhejiang University School of Medicine from October 2010 to October 2013 were studied retrospectively. The risk factors of biliary complications following DCD liver transplantation were analyzed. RESULTS: Twenty-four (22%) patients developed biliary complications after DCD liver transplantation. Univariate analysis showed that biliary complications were associated with warm ischemia time (P<0.001) and length of ICU stay (P=0.013), but not associated with ABO blood types match (P>0.05). Administration of inotropic agents and fatty liver increased the trend of biliary complications. Multivariate analysis demonstrated that warm ischemia time and length of ICU stay were independent risk factors for predicting biliary complications. CONCLUSION: Warm ischemia time and days of ICU stay are independent risk factors for predicting biliary complications after DCD liver transplantation.

Biocompatible hydrophobic cross-linked cyclodextrin-based metal-organic framework as quercetin nanocarrier for enhancing stability and controlled release.

Cyclodextrin-based metal-organic framework (CD-MOF) has been widely used in various delivery systems due to its excellent edibility and high drug loading capacity. However, its typically bulky size and high brittleness in aqueous solutions pose significant challenges for practical applications. Here, we proposed an ultrasonic-assisted method for rapid synthesis of uniformly-sized nanoscale CD-MOF, followed by its hydrophobic modification through ester bond cross-linking (Nano-CMOF). Proper ultrasound treatment effectively reduced particle size to nanoscale (393.14 nm). Notably, carbonate ester cross-linking method significantly improved water stability without altering its cubic shape and high porosity (1.3 cm3/g), resulting in a retention rate exceeding 90% in various media. Furthermore, the loading of quercetin did not disrupt cubic structure and showcased remarkable storage stability. Nano-CMOF achieved controlled release of quercetin in both aqueous environments and digestion. Additionally, Nano-CMOF demonstrated exceptional antioxidant (free radical scavenging 82.27%) and biocompatibility, indicating its significant potential as novel nutritional delivery systems in food and biomedical fields.

A case report of de novo hepatocellular carcinoma after living donor liver transplantation.

Post-transplant malignancy is the major cause of later death of recipients after liver transplantation. Tumor recurrence after liver transplantation for patients with hepatocellular carcinoma in the end stage of cirrhosis has been frequently encountered. However, de novo hepatocellular carcinoma originating from the liver allograft has only rarely been reported. Here we reported a case of de novo hepatocellular carcinoma developed 2 years after living donor liver transplantation for hepatitis B-related liver cirrhosis with viral YMDD mutation. To the best of our knowledge, this is the first report of de novo hepatocellular carcinoma in a liver graft with recurrent hepatitis B virus infection after liver transplantation for hepatitis B-related liver cirrhosis with YMDD mutation. Moreover, the de novo cancer first presented as a lung mass with minimal liver involvement and was obscured by a pulmonary fungal infection.

Risk factors of choledocholithiasis formation after liver transplantation.

Systematic study of risk factors for biliary stone post-liver transplantation is rarely performed. To investigate the risk factor of choledocholithiasis formation after liver transplantation, we conducted a case-control study. Fourteen patients were selected into a study group. The stones of the bile duct of the patients were confirmed and treated successfully by endoscopic retrograde cholangiopancreatography. For univariate analysis, we selected carefully some potential risk factors such as cold ischemia time, warm ischemia time, and biliary stricture. The results revealed that cold ischemia time and biliary stenosis were significant predictors. But multivariate analysis revealed that only biliary stenosis was a significant risk factor. In conclusion, biliary stenosis is a risk factor of bile duct stones formation after liver transplantation. Endoscopic retrograde cholangiopancreatography is effective and safe in the diagnosis or treatment of bile duct stones after liver transplantation.

Casein Hydrolysate Alleviates Adipose Chronic Inflammation in High Fat-Diet Induced Obese C57BL/6J Mice through MAPK Pathway.

Obesity-induced adipose chronic inflammation is closely related to the development of insulin resistance and T2DM. Tripeptides l-valyl-l-prolyl-l-proline (VPP) and l-isoleucyl-l-prolyl-L-proline (IPP) derived from bovine casein have been reported to prevent inflammatory changes and mitigate insulin resistance in adipocytes. In this study, we aimed to investigate the influence of casein hydrolysates (CH) containing VPP and IPP on a high fat diet (HFD)-induced obese mice and cytokine TNF-α-induced adipocytes. Our data showed that CH alleviated chronic inflammation both in vivo and in vitro. 4% CH suppressed HFD-induced systemic inflammatory factors, hypertrophic white adipocytes, and macrophage infiltration. More importantly, CH was able to improve adipocyte dysfunction induced by TNF-α by increasing the expression of CCAAT/enhancer binding protein α (C/EBP-α) rather than peroxisome proliferator-activated receptor γ (PPAR-γ). Furthermore, CH also dose-dependently suppressed mitogen-activated protein kinase (MAPK)-c-Jun N-terminal kinase (JNK) phosphorylation and enhanced the phosphorylation of Erk 1/2, but not nuclear factor-kappa B (NF-κB) p65 phosphorylation, in TNF-α-induced 3T3-L1 cells. These results indicated that CH could ameliorate adipose chronic inflammation through the MAPK pathway. Altogether, our findings suggested that 4% CH supplementation for 6 weeks exerted a protective role in preventing obesity-related inflammation and adipose dysfunction.

Non-iatrogenic implantation of cutaneous metastasis from hepatocellular carcinoma.

PURPOSE: Cutaneous metastases as an extrahepatic metastasis from hepatomas (HCC) is extremely rare and always carry a poor prognosis and less survival time. Previously, there has been a limited number of literature that reported skin metastasis in a large number of cases, which has rarely been discussed in the empirical treatment and therapy of cutaneous metastasis, especially for non-iatrogenic implantation. It is necessary to discuss this kind of metastasis. PATIENTS AND METHODS: We summarize cases from our medical center from 2013 to 2021, there are 12 patients diagnosed with non-iatrogenic implantation of cutaneous metastasis after HCC. We conducted the investigation of the clinical prognosis, pathological characteristics, and treatment of those patients. RESULTS: All patients were male, the age ranged from 21 to 71 years old, the average size of primary HCC was over 5 cm, there was four patient's cutaneous metastasis from the skin of head (including scalp and occipital region), followed by right abdominal (2 patients), right chest wall (2 patients), back (2 patients), umbilical (1 patient), gluteal region (1 patient). The cutaneous metastases presented as solitary or multiple nodules, papules, and erythema without ulcers with sizes between 0.5 cm and 5 cm. 7 patients died after being diagnosed with cutaneous metastasis within 2-19 months. CONCLUSIONS: The rate of non-iatrogenic implantation cutaneous metastasis is low, but the prognosis is poor, combining with histopathological analysis and history of diseases can be helpful in diagnosis. For large HCC (> 5 cm), systematic treatment is recommended to prevent the occurrence of cutaneous metastasis and improve the prognosis after hepatectomy.

Splenectomy for treating hepatosplenic candidiasis: Two cases and literature review suggesting its feasibility.

Background: Hepatosplenic candidiasis is a rare but severe complication in immunocompromised patients undergoing chemotherapy. Antifungal agents are widely accepted as the first choices for therapy. However, resistance to or side-effect of antifungal agents may comxpromise its efficiency. Splenectomy has also been rarely performed as treatment for this disease. Methods: We present two cases of splenectomy for treating hepatosplenic candidiasis after failure of the initial drug therapy. Literatures on splenectomy as treatment for hepatosplenic candidiasis were searched in Pubmed and summarized. Results: Two leukemia patients developed hepatosplenic candidiasis after received chemotherapy for their primary diseases. Various antifungal agents including amphotericin B were all demonstrated failure to cure fever and the Candida abscesses due to resistance or intractable side-effect. Laparoscopic splenectomy were finally performed and resolved the candidiasis successfully. A total of 12 splenectomy cases for treating hepatosplenic candidiasis had been previously reported in literature. All the cases showed either resistance or unimproved to initial antifungal therapies. Splenectomy provided salvage therapeutic value in all cases. Conclusion: Splenectomy has therapeutic effect and may change the traditional concept in most surgeons. The present study may expand an alternative strategy in clinical practice guideline for the management of hepatosplenic candidiasis.

Douchi Peptides VY and SFLLR Improve Glucose Homeostasis and Gut Dysbacteriosis in High-Fat Diet-Induced Insulin Resistant Mice.

SCOPE: Two peptides VY (Val-Tyr) and SFLLR (Ser-Phe-Leu-Leu-Arg) are recently identified from soy-fermented douchi with hypoglycemic activity in cells. The study aims to understand their potential effects on glucose metabolism and insulin sensitivity as well as their mechanisms of action in a high-fat diet (HFD) induced insulin resistant model. METHODS AND RESULTS: C57BL/6 mice are fed HFD for 8 weeks, followed by peptide supplementation (doses: 10 and 50 mg kg-1 body weight) for 8 weeks. Peptides supplementation, especially SFLLR, reduces body weight gain, insulin resistance, hyperglycemia, inflammation, liver injury, and lipid accumulation. In both muscle and liver, both peptides activate glycogen synthase (GS), the key enzyme for glycogen synthesis, and also inhibit phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6PC), two rate-limiting enzymes for gluconeogenesis, via insulin and AMPK (5'-adenosine monophosphate-activated protein kinase) signaling pathways. Furthermore, VY and SFLLR supplementation reverse HFD-induced gut dysbacteriosis by decreasing the abundance of Enterococcus, Oscillibacter, and Deferribacter, and also increase the abundances of Alistipes, Lactobacillus, Faecalibaculum, Akkermansia, and Bifidobacterium (usually beneficial in the intestine). CONCLUSION: The study reveals the potential applications of peptides VY and SFLLR as a diet-based strategy for the prevention of type 2 diabetes.

Digestion, absorption, and transport properties of soy-fermented douchi hypoglycemic peptides VY and SFLLR under simulated gastrointestinal digestion and Caco-2 cell monolayers.

Two novel hypoglycemic peptides VY and SFLLR were identified from douchi as the major peptides responsible for the glucose uptake activity. The present work aimed to elucidate their digestion, absorption and transport properties using simulated digestion and Caco-2 cell monolayers transport models. Besides, the effects of digestion and absorption on the structure and activity were also studied. The results showed that VY was resistant to gastrointestinal tract digestion and could cross Caco-2 cell monolayers intactly via both TJs-mediated passive paracellular pathway and PepT1-mediated active route. In comparison, SFLLR was partially degraded into small fragments of SFLL, SFL, and SF by the digestive system, leading to increased glucose uptake activity. Notably, SFLLR, SFLL, and SFL were partly hydrolyzed by aminopeptidase N or dipeptidyl peptidase IV during transport, but they were transported intact. SFL was transported via both paracellular diffusion and PepT1-mediated routes, while SFLLR and SFLL were via paracellular route only.

Cyclodextrin-based metal-organic framework materials: Classifications, synthesis strategies and applications in variegated delivery systems.

Metal-organic frameworks (MOFs) are coordination compounds that possess an adjustable structure and controllable function. Despite their wide applications in various industries, the use of MOFs in the fields of food and biomedicine is limited mainly due to their potential biological toxicity. Researchers have thus focused on developing biocompatible MOFs to address this issue. Among them, cyclodextrin-based metal-organic frameworks (CD-MOFs) have emerged as a promising alternative. CD-MOFs are novel MOFs synthesized using naturally carbohydrate cyclodextrin and alkali metal cations, and possess renewable, non-toxic, and edible characteristics. Due to their high specific surface area, controllable porosity, great biocompatibility, CD-MOFs have been widely used in various delivery systems, such as encapsulation of nutraceuticals, flavors, and antibacterial agents. Although the field of CD-MOF materials is still in its early stages, they provide a promising direction for the development of MOF materials in the delivery field. This review describes classification and structural characteristics, followed by an introduction to formation mechanism and commonly used synthetic methods for CD-MOFs. Additionally, we discuss the status of the application of various delivery systems based on CD-MOFs. Finally, we address the challenges and prospects of CD-MOF materials, with the aim of providing new insights and ideas for their future development.

Tolerance induction towards cardiac allografts under costimulation blockade is impaired in CCR7-deficient animals but can be restored by adoptive transfer of syngeneic plasmacytoid dendritic cells.

Deficiency of transplant recipients for the chemokine receptor CCR7 was originally described to slightly increase the survival time of vascularized solid organ grafts, probably due to a reduced priming of alloreactive T cells. Using a model of allotolerance induction by donor-specific splenocyte transfusion (DST) in combination with anti-CD40L mAb-mediated costimulation blockade (CSB), we show here a striking failure of CCR7-deficient (CCR7(-/-) ) recipients to tolerate cardiac allografts. Furthermore, in addition to the recently described lack of Treg, CCR7(-/-) mice were found to harbor significantly reduced numbers of plasmacytoid dendritic cells (pDCs) within peripheral as well as mesenteric lymph nodes (LNs), but not the bone marrow or spleen. pDCs had previously been suggested to function as tolerogenic APC during allograft transplantation, and a single transfer of syngeneic WT pDCs, but not conventional DCs, was indeed sufficient to rescue graft survival in DST+CSB-treated CCR7(-/-) recipients in a dose-dependent manner. We therefore conclude that the nearly complete absence of pDCs within LNs of CCR7(-/-) mice prevents the successful induction of DST+CSB-mediated allotolerance, leading to the observed acute rejection of cardiac allografts under tolerizing conditions.