Congestive heart failure is a major cause of morbidity and mortality as well as a major health care cost in the developed world. Despite the introduction of highly effective heart failure medical therapies and simple devices such as cardiac resynchronization therapy that reduce mortality, improve cardiac function and quality of life, there remains a large number of patients who do not respond to these therapies or whose heart failure progresses despite optimal therapy. For these patients, cardiac transplantation is an option but is limited by donor availability as well as co-morbidities which may limit survival post-transplant. For these patients, left ventricular assist devices (LVADs) offer an alternative that can improve survival as well as exercise tolerance and quality of life. These devices have continued to improve as technology has improved with substantially improved durability of the devices and fewer post-implant complications. Pump thrombosis, stroke, gastrointestinal bleeding and arrhythmias post-implant have become less common with the newest devices, making destination therapy where ventricular assist device are implanted permanently in patients with advanced heart failure, a reality and an appropriate option for many patients. This may offer an opportunity for long term survival in many patients. As the first of the totally implantable devices are introduced and go to clinical trials, LVADs may be introduced that may truly be alternatives to cardiac transplantation in selected patients. Post-implant right ventricular failure remains a significant complication and better ways to identify patients at risk as well as to manage this complication must be developed.
Arrhythmias, Cardiac ; Cardiac Resynchronization Therapy ; Exercise Tolerance ; Health Care Costs ; Heart Failure ; Heart Transplantation ; Heart-Assist Devices ; Hemorrhage ; Humans ; Mortality ; Quality of Life ; Stroke ; Thrombosis ; Tissue Donors

Preterm infants are a special group, and related severe neurological, respiratory, and digestive disorders have high disability/fatality rates. Allogeneic cell transplantation may be an effective method for the prevention and treatment of these diseases. At present, animal studies have been conducted for allogeneic cell transplantation in the treatment of hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, and necrotizing enterocolitis. The main difficulty of this technique is graft-versus-host reaction (GVHR), and successful induction of immune tolerance needs to be achieved in order to solve this problem. This article reviews the research advances in immune tolerance of allogeneic cell transplantation in preterm infants.
Apoptosis ; Cell Transplantation ; adverse effects ; Cytokines ; physiology ; Graft vs Host Reaction ; Humans ; Immune Tolerance ; Infant, Newborn ; Infant, Premature ; immunology ; Transplantation, Homologous

The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBTand the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host-microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.
Biomarkers ; Gastrointestinal Microbiome ; Graft Rejection ; immunology ; Humans ; Immunity, Mucosal ; Intestine, Small ; microbiology ; transplantation ; Metagenomics ; Transplantation Tolerance ; immunology

BACKGROUND: Forkhead box P3 (Foxp3) is the most reliable marker for regulatory T cells, which play an important role in maintaining renal allograft tolerance. Recently, Foxp3 polymorphisms have been reported to be associated with graft outcome in kidney transplantation. We analyzed the association of Foxp3 polymorphisms with renal allograft outcome. METHODS: Foxp3 polymorphisms (rs3761548 A/C, rs2280883 C/T, rs5902434 del/ATT, and rs2232365 A/G) were tested by PCR with sequence-specific primers (PCR-SSP) in 231 adult kidney transplantation recipients from 1996-2004 at Seoul National University Hospital. RESULTS: Patients with the rs3761548 CC genotype showed better graft survival than those with the AC or AA genotype (log rank test, P=0.03). Patients with the rs3761548 CC genotype also showed a lower rate of recurrence of the original glomerular disease than those with the AC or AA genotype (P=0.01). The frequency of acute rejection (AR) in patients with the rs2280883 TT genotype was lower than that in patients with the rs2280883 CT or CC genotype (26.9% vs 53.3%, P=0.038). Patients with the rs2280883 TT genotype also showed better graft survival than those with the CT or CC genotype (P=0.03). CONCLUSIONS: Foxp3 rs3761548 CC and rs2280883 TT genotypes were associated with superior graft outcome of kidney transplantation. Further studies involving a larger number of patients are needed.
Adult ; Allografts* ; Genotype ; Graft Survival ; Humans ; Kidney Transplantation* ; Kidney* ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Recurrence ; Seoul ; T-Lymphocytes, Regulatory ; Transplantation Tolerance ; Transplants

Using biomarkers as prediction tools or therapeutic targets can be a valuable strategy in transplantation. Recent studies identified biomarkers of acute rejection (AR) and operational tolerance (TOL) through the application of meta-analysis. In this study, we comparatively analyzed the signature genes in acute rejection and operational tolerance seen in human allogeneic transplantations using massive bioinformatical meta-analysis. To identify the signature genes in opposite immunological conditions, AR and TOL, we first collected the 1,252 gene expression data specifically intended for those circumstances. Then we excluded based on biological cut-values, Principal Component Analysis (PCA) as well as Multi-Dimensional Scaling (MDS). Using differentially expressed genes (DEGs) from meta-analysis, we then applied a ranked scoring system to identify the signature genes of AR and TOL. We identified 53 up-regulated and 32 down-regulated signature genes in acute rejection condition. Among them, ISG20, CXCL9, CXCL10, CCL19, FCER1G, PMSE1, UBD are highly expressed in AR condition. In operational tolerance, we identified 110 up-regulated and 48 down-regulated signature genes. TCL1A, BLNK, MS4A1, EBF1, IGHM are up-regulated in TOL condition. These genes are highly representative of AR or TOL across the different organs such as liver, kidney and heart. Since immune response is the sum of complex biological and molecular dynamics, these signature genes as well as pathway analysis using a systems biology approach could be used to catch the insights of the certain pathways that would be overlooked with the conventional gene-level comparative analysis.
Biomarkers ; Gene Expression ; Graft Rejection ; Heart ; Humans ; Kidney ; Liver ; Molecular Dynamics Simulation ; Principal Component Analysis ; Systems Biology ; Transplantation Tolerance

Intraportal transplantation of islets is no longer considered to be an ideal procedure and finding the extrahepatic alternative site is becoming a subject of high priority. Herein, in this study, we would introduce our initial outcomes of using gastric submucosa (GS) and liver as sites of islet autotransplantation in pancreatectomized diabetic Beagles. Total pancreatectomy was performed in Beagles and then their own islets extracted from the excised pancreas were transplanted into GS (GS group, n=8) or intrahepatic via portal vein (PV group, n=5). Forty-eight hours post transplantation, graft containing tissue harvested from the recipients revealed the presence of insulin-positive cells. All recipients in GS group achieved euglycemia within 1 day, but returned to a diabetic state at 6 to 8 days post-transplantation (mean survival time, 7.16±0.69 days). However, all of the animals kept normoglycemic until 85 to 155 days post-transplantation in PV group (mean survival time, 120±28.58 days; P<0.01 vs. GS group). The results of intravenous glucose tolerance test (IVGTT) confirmed that the marked improvement in glycometabolism was obtained in intrahepatic islet autotransplantation. Thus, our findings indicate that the liver is still superior to the GS as the site of islet transplantation, at least in our islet autotransplant model in pancreatectomized diabetic Beagles.
Animals ; Diabetes Mellitus, Experimental ; metabolism ; pathology ; therapy ; Dogs ; Gastric Mucosa ; metabolism ; transplantation ; Glucose ; metabolism ; Glucose Tolerance Test ; Graft Survival ; Humans ; Insulin ; metabolism ; Islets of Langerhans Transplantation ; Liver ; pathology ; Liver Transplantation ; Transplantation, Autologous

No abstract available.
Adult ; Female ; Graft Rejection/immunology/*prevention & control ; Graft Survival ; *Hematopoietic Stem Cell Transplantation ; Humans ; *Immune Tolerance ; Immunosuppressive Agents/therapeutic use ; Kidney Failure, Chronic/diagnosis/*surgery ; *Kidney Transplantation ; Living Donors ; Siblings ; Time Factors ; *Transplantation Chimera ; Treatment Outcome

Liver transplantation is the most effective treatment for end-stage liver diseases (ESLD) with satisfactory clinical results and so is considered as the treatment of choice for ESLD and early hepatocellular carcinoma with cirrhotic liver. Unfortunately, adverse effects of life-long immunosuppression prevent the development of alternative strategies to achieve better long-term outcome. Achieving clinical operational tolerance is one of the ultimate goals in the clinical transplantation field. Around 15% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal, and the percentage may be even higher in pediatric living donor liver transplantation recipients. One of the possible explainable mechanisms is a T cell fatigue from large amount of antigen loaded. Despite continuing progress, clinical operational tolerance is still rare in liver transplantation. Reprogramming the recipient immune system by creating chimerism and utilizing regulatory cell therapies are among the newer promising means to achieve clinical liver transplantation tolerance in the future. In animal studies, administration of donor specific regulatory T cells allows a prolonged survival without immunosuppressive agents. In this review, proposed mechanisms for clinical tolerance will be offered and current experimental trial will be introduced.
Animals ; Carcinoma, Hepatocellular ; Chimerism ; End Stage Liver Disease ; Fatigue ; Humans ; Immune System ; Immune Tolerance* ; Immunosuppression ; Immunosuppressive Agents ; Liver ; Liver Diseases ; Liver Transplantation* ; Living Donors ; T-Lymphocytes, Regulatory ; Tissue Donors

The aim of this study was to investigate the effects of CD4(+)CD25(+) regulatory T cells (Treg) on allogeneic hematopoietic stem cell transplantation (HSCT) in sensitized mice so as to provide experimental evidence for clinical treatment of allogeneic HSCT rejection in sensitized recipients. The BALB/c mice were divided into 5 groups: group A - mice were sensitized with injection of splenocytes; group B - mice were sensitized with splenocytes and treated with >5×10(5) Treg on day 7 before transplantation; group C - mice were sensitized with splenocytes and treated with 5×10(5) Treg on day 13 and 7 before transplantation; group D - mice were not sensitized, but treated with equal volume of PBS as control; group E - blank control. Each group had 15 mice. On day 0 of transplantation, mice in each group were irradiated lethally with 8 Gy by linear accelerator, and the bone marrow cells of C57BL/6 labeled by fluorescence staining were intravenously injected via the tail vein. The fluorescent cells in peripheral blood and organ tissue were detected by flow cytometry on different time points for homing assessment. Survival rates and hematopoietic reconstitution were also recorded and monitored. The results showed that on 12 and 24 hours after transplantation, as compared with the sensitized group, the number of fluorescence homing cells in different tissue of the applied Treg groups increased significantly and the differences were statistically significant (P < 0.05). The mice in sensitized group and blank control group all died on the 6-13 day, whereas the median survival time of mice in applied Treg once and twice were 15 days and 16 days respectively. Comparing with sensitized group, the difference was statistically significant (P < 0.001), but there was no significant difference between these two groups applied regulatory T cell (P > 0.05). It is concluded that applying Treg can induce immune tolerance of sensitized recipient to allogeneic HSCT and inhibit immune destruction and prolong the survival time, but can not induce full immune tolerance and at last sensitized mice died of rejection of hematopoietic stem cells.
Animals ; Graft vs Host Disease ; etiology ; Hematopoietic Stem Cell Transplantation ; methods ; Immune Tolerance ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory ; immunology ; Transplantation, Homologous

This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.
Adult ; Calcineurin Inhibitors/*administration & dosage ; Drug Synergism ; Female ; Graft Rejection/*etiology/*prevention & control ; Graft Survival/drug effects ; Humans ; Immunosuppressive Agents ; Kidney Transplantation/adverse effects/*methods ; Male ; Renal Insufficiency/diagnosis/*therapy ; Republic of Korea ; Severity of Illness Index ; Sirolimus/*administration & dosage ; Transplantation Tolerance/drug effects ; Treatment Outcome