Objective: To use bioinformatics technology to analyse differentially expressed genes in chronic rejection after renal transplantation, we can screen out potential pathogenic targets associated with the development of...Objective: To use bioinformatics technology to analyse differentially expressed genes in chronic rejection after renal transplantation, we can screen out potential pathogenic targets associated with the development of this disease, providing a theoretical basis for finding new therapeutic targets. Methods: Gene microarray data were downloaded from the Gene Expression Profiling Integrated Database (GEO) and cross-calculated to identify differentially expressed genes (DEGs). Analysis of differentially expressed genes (DEGs) with gene ontology (GO) is a method used to study the differences in gene expression under different conditions as well as their functions and interrelationships, while Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis is a tool used to explore the functions and pathways of genes in specific biological processes. By calculating the distribution of immune cell infiltration, the result of immune infiltration in the rejection group can be analysed as a trait in Weighted Gene Co-Expression Network Analysis (WGCNA) for genes associated with rejection. Then, protein-protein interaction networks (PPI) were constructed using the STRING database and Cytoscape software to identify hub gene markers. Results: A total of 60 integrated DEGs were obtained from 3 datasets (GSE7392, GSE181757, GSE222889). By GO and KEGG analysis, the GEDs were mainly concentrated in the regulation of immune response, defence response, regulation of immune system processes, and stimulation response. The pathways were mainly enriched in antigen processing and presentation, EBV infection, graft-versus-host, allograft rejection, and natural killer cell-mediated cytotoxicity. After further screening using WGCNA and PPI networks, HLA-A, HLA-B, HLA-F, and TYROBP were identified as hub genes (Hub genes). The data GSE21374 with clinical information was selected to construct the diagnostic efficacy and risk prediction model plots of the four hub genes, and the results concluded that all four Hub genes had good diagnostic value (area under the curve in the range of 0.794-0.819). From the inference, it can be concluded that the four genes, HLA-A, HLA-B, HLA-F and TYROBP, may have an important role in the development and progression of chronic rejection after renal transplantation. Conclusion: DEGs play an important role in the study of the pathogenesis of chronic rejection after renal transplantation, and can provide theoretical support for further research on the pathogenesis of chronic rejection after renal transplantation and the discovery of new therapeutic targets through enrichment analysis and pivotal gene screening, as well as inferential analyses of related diagnostic efficacy and disease risk prediction.展开更多
Chronic rejection(CR)of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation.Although its prevalence has declined steadily with the introducti...Chronic rejection(CR)of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation.Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy,CR still represents an important cause of graft injury,which might be irreversible,leading to graft loss requiring re-transplantation.To date,we still do not fully appreciate the mechanisms underlying this process.In addition to T cell-mediated CR,which was initially the only recognized type of CR,recently a new form of liver allograft CR,antibody-mediated CR,has been identified.This has indeed opened an era of thriving research and renewed interest in the field.Liver biopsy is needed for a definitive diagnosis of CR,but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation.Moreover,the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury,which should not be disregarded.Therapies for CR may only be effective in the“early”phases,and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage.Herein,we provide an overview of the current knowledge and research on CR,focusing on early detection,identification of non-invasive biomarkers,immunosuppressive management,re-transplantation and future perspectives of CR.展开更多
Objective: To study the cause and mechanism of transplantation vasculopathy which characterized by accelerated graft arteriosclerosis (AGA), we established a mouse aorta graft model. Methods: A segment of thoracic aor...Objective: To study the cause and mechanism of transplantation vasculopathy which characterized by accelerated graft arteriosclerosis (AGA), we established a mouse aorta graft model. Methods: A segment of thoracic aortas of B10.A (2R) mice were transplanted to C57BL/10 mice abdominal aorta by end to side anastomoses. The different time point collected grafts were analyzed by morphological, histochemical and electro microscopic methods. Results: Rejection was manifested as a concentric progressive destruction of the smooth muscle cells. In contrast, the endothelial inflammation and subsequent neointimal proliferation characteristic of AGA was localized to the regions of turbulent flow, i.e. the junction of the graft with the recipient aorta. Conclusion: This model separates the processes of rejection and neointimal formation which usually manifested together in the lesion of AGA, elucidate that different mechanisms control vascular rejection and neointimal formation in chronic rejection.展开更多
Objective To investigate the depressant effect and mechanism of atorvastatin on the chronic rejection of aortic allograft in rats. Methods： The models of abdominal aorta transplantation were made with micro-surgery i...Objective To investigate the depressant effect and mechanism of atorvastatin on the chronic rejection of aortic allograft in rats. Methods： The models of abdominal aorta transplantation were made with micro-surgery in rats. The recipients were divided into three groups： allograft control group, atorvastatin-treated group and isograft control group. Vascular intimal thickness in all of the groups were observed by histological examination. The expression of PCNA and α-SMA were determined by immunohistochemistry. The content of nitric oxide was determined by nitrate reductase chromatometry. Results： The vascular intimal thickness in rats of atorvastatin-treated group （11.60% ± 2.40% ） were lower than those in allograft control group （34.60 % ± 6.40 % ; P 〈 0.05） and higher than those in isograft control group （1.15 % ± 0.65 %; P〈 0.05 ）. The expression level of PCNA was decreased in atorvastatin-treated group （4.80% ± 0.80% ） than allograft control group （18.40% ± 1.80% ; P〈0.05） and higher than isograft group （1.20% ± 0.40% ; P〈0.05）. Conclusion： The expression of PCNA in the transplant aorta could be suppressed by atorvastatin, which resalted in relief of chronic rejection of aortic allograft.展开更多
Objective To study clinically the feasibility of early diagnosis of cardiac allograft vascularopathy(CAV) and chronic rejection. Methods A 13-year-old female patient with dilated cardiomy-opathy received orthotopic he...Objective To study clinically the feasibility of early diagnosis of cardiac allograft vascularopathy(CAV) and chronic rejection. Methods A 13-year-old female patient with dilated cardiomy-opathy received orthotopic heart transplantation for advanced heart failure, and subsequent immunosuppressive therapy including cyclosporine, prednisone and mofetil, and a mondily close follow-up. Coronary angiography and left ventricular endomyocardial biopsy (EMB) was perormed 9 months after the operation. Results The clinical and follow-up data of the case showed that cardiac or systemic nonspecific symptoms such as exertional chest discomfort, palpitation, fatigue or fever of unknown reasons were the first and ignorable clinical symptoms, and found disappeared after dosage addition of cyclinsporine, which indicated a early clinical manifestations of rejection or vasculopathy. While persistent sinus tachycardia on electrocadiogram, decreased left ventricular ejection fraction(from 64% -68% down to 47% - 50% ),展开更多
In this study antigen independent factor in the pathogenesis of chronic rejection of organ transplants was examined. Kidney isografts and allografts were transplanted orthotopically into bilaterally nephroectomized r...In this study antigen independent factor in the pathogenesis of chronic rejection of organ transplants was examined. Kidney isografts and allografts were transplanted orthotopically into bilaterally nephroectomized rat recipients and studied functionally, morphologically and immunohistologically, at serial intervals up to 52 weeks after transplantation. Allograft recipients developed progressive proteinuria after 12 weeks, with gradual renal failure ultimately leading to death. At the same time, morphological changes, including progressive arteriosclerosis and glomerulosclerosis, tubular atrophy and interstitial fibrosis, developed. Immunohistologically, macrophages infiltrated glomeruli during this period and cytokines became unregulated. Our results showed that antigen independent functional and morphological changes occurred in long term kidney isografts and mimicked those appearing much earlier in allografts that reject chronically. Initial injury and extent of functioning renal mass is suggested to be important factor for such late changes.展开更多
Liver transplantation(LT)is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease.With improvements in organ preservation techniques,perioperative care,and im...Liver transplantation(LT)is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease.With improvements in organ preservation techniques,perioperative care,and immunosuppression,there is better patient and graft survival following LT,and assessment of the liver allograft in long-term survivors is becoming increasingly important.Recurrent or de novo viral or autoimmune injury remains the most common causes of chronic hepatitis and fibrosis following liver transplantation in adults.However,no obvious cause can be identified in many adults with controlled recurrent disease and the majority of pediatric LT recipients,as they have been transplanted for non-recurrent liver diseases.Serial surveillance liver biopsies post LT have been evaluated in several adult and pediatric centers to identify long-term pathological changes.Pathological findings are frequently present in liver biopsies obtained after a year post LT.The significance of these findings is uncertain as many of these are seen in protocol liver biopsies from patients with clinically good allograft function and normal liver chemistry parameters.This narrative review summaries the factors predisposing to long-term liver allograft fibrosis,highlighting the putative role of idiopathic post-LT hepatitis and chronic antibody mediated rejection in its pathogenesis.展开更多
Postoperative biliary complications remain a substantial challenge after living donor liver transplantation,especially due to its heterogeneous clinical presentation.
BACKGROUND Gastroesophageal reflux disease has been shown to contribute to allograft injury and rejection outcomes in lung transplantation through a proposed mechanism of aspiration,inflammation,and allograft injury.T...BACKGROUND Gastroesophageal reflux disease has been shown to contribute to allograft injury and rejection outcomes in lung transplantation through a proposed mechanism of aspiration,inflammation,and allograft injury.The value of pre-transplant reflux testing in predicting reduction in pulmonary function after lung transplantation is unclear.We hypothesized that increased reflux burden on pre-transplant reflux testing is associated with pulmonary function decline following lung transplant.AIM To assess the relationship between pre-transplant measures of reflux and pulmonary function decline in lung transplant recipients.METHODS This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant reflux testing with 24-hour pH-impedance off acid suppression at a tertiary center in 2007-2016.Patients with pre-transplant fundoplication were excluded.Time-to-event analysis was performed using Cox proportional hazards models to assess associations between reflux measures and reduction in forced expiratory volume in 1 second(FEV1)of≥20%post-transplant.Patients not meeting endpoint were censored at time of post-transplant fundoplication,last clinic visit,or death,whichever was earliest.RESULTS Seventy subjects(58%men,mean age:56 years)met the inclusion criteria.Interstitial lung disease represented the predominant pulmonary diagnosis(40%).Baseline demographics were similar between groups and were not associated with pulmonary decline.The clinical endpoint(≥20%FEV1 decline)was reached in 18 subjects(26%).In time-to-event univariate analysis,FEV1 decline was associated with increased acid exposure time(AET)[hazard ratio(HR)=3.49,P=0.03]and increased proximal acid reflux(HR=3.34,P=0.04)with confirmation on Kaplan-Meier analysis.Multivariate analysis showed persistent association between pulmonary decline and increased AET(HR=3.37,P=0.04)when controlling for potential confounders including age,body mass index,and sex.Subgroup analysis including only patients with FEV1 decline showed that all subjects with abnormal AET progressed to bronchiolitis obliterans syndrome.CONCLUSION Increased reflux burden on pre-transplant testing was associated with significant pulmonary function decline posttransplant.Pre-transplant reflux assessment may provide clinically relevant information in the prognostication and management of transplant recipients.展开更多
Rejection is one of the key factors that determine the long-term allograft function and survival in renal transplant patients.Reliable and timely diagnosis is important to treat rejection as early as possible.Allograf...Rejection is one of the key factors that determine the long-term allograft function and survival in renal transplant patients.Reliable and timely diagnosis is important to treat rejection as early as possible.Allograft biopsies are not suitable for continuous monitoring of rejection.Thus,there is an unmet need for non-invasive methods to diagnose acute and chronic rejection.Proteomics in urine and blood samples has been explored for this purpose in 29 studies conducted since 2003.This review describes the different proteomic approaches and summarizes the results from the studies that examined proteomics for the rejection diagnoses.The potential limitations and open questions in establishing proteomic markers for rejection are discussed,including ongoing trials and future challenges to this topic.展开更多
The state-of-the-art immunosuppression drugs do not ensure indefi nite transplant survival,and most transplants are continuously lost to chronic rejection even years posttransplantation.This form of rejection is respo...The state-of-the-art immunosuppression drugs do not ensure indefi nite transplant survival,and most transplants are continuously lost to chronic rejection even years posttransplantation.This form of rejection is responsible for long-term failure of transplanted organs.The mechanisms involved in development of chronic rejection are not well-understood.One of the main features of chronic rejection is progressive luminal narrowing of graft vessels,which results in compromised blood flow,ischemia,cell death,and finally graft failure.All the existing immunosuppressive regimens are targeting acute rejection,and at present there is no available therapy for prevention of chronic rejection.Chronic rejection involves two major,but interrelated responses:The first is the host immune response against the transplant mediated primarily by alloreactive T and B cells,and the second is injury and repair of the graft(vasculopathy of graft vessels).Here we focus on recent advances in understanding the cellular and molecular aspects of chronic transplant vasculopathy and function of macrophages,topics pivotal for development of novel antichronic rejection therapies.展开更多
Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells ...Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells in the complex milieu of the liver.In this section,we will comment on the importance of donorspecific anti-human leukocyte antigen(HLA)antibodies(DSA)as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor(KIR)genotypes in the evolution of liver transplantation.Thus,HLA compatibility,viral infections,and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival.There have been reports of increased risk of acute and chronic rejection with ductopenia,faster graft fibrosis,biliary problems,poorer survival,and even de novo autoimmune hepatitis when DSAs are present in the recipient.Higher mean fluorescence intensity(MFI)values of the DSAs and smaller graft size were associated with poorer patient outcomes,implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods,according to the investigators.Similarly,in a combined kidney-liver transplant,a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment.The renal graft was lost owing to antibody-mediated rejection(AMR).The HLA antigens expressed by the transplanted liver graft influenced antibody elimination.Pathologists are increasingly diagnosing AMR in liver transplants,and desensitization therapy has even been employed in situations of AMR,particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex.In conclusion,after revealing the negative impacts of DSAs with high MFI,pretransplant virtual crossmatch techniques may be appropriate to improve evolution;however,they may extend cold ischemia periods by requiring the donor to be typed.展开更多
In order to investigate the origin of neointimal smooth muscle cells in transplant arterio- sclerosis in rat aortic allograft, sex-mismatched bone marrow transplantation was performed from male Wistar rats to female W...In order to investigate the origin of neointimal smooth muscle cells in transplant arterio- sclerosis in rat aortic allograft, sex-mismatched bone marrow transplantation was performed from male Wistar rats to female Wistar rats. Four weeks after transplantation, the aortic transplant model was established by means of micro-surgery in rats. The recipients were divided into 4 groups: female Wistar-female Wistar aortic isografts, female SD-female Wistar aortic allografts, male SD-male Wis- tar aortic allografts, female SD-chimera Wistar aortic allografts. Eight weeks after transplantation, aortic grafts were removed at autopsy and processed for histological evaluation and immunohisto- chemistry. The results indicated that excessive accumulation of α-SMA-positive smooth muscle cells resulted in significant neointima formation and vascular lumen stricture in rat aortic allografts. Neointima assay revealed that the neointimal area and NIA/MA ratio of transplanted artery were sig- nificantly increased in all of aortic allograft groups as compared with those in aortic isograft group (P<0.01). Neointimal smooth muscle cells were harvested from cryostat sections of aortic allograft by microdissection method. The Sry gene-specific PCR was performed, and the result showed that a dis- tinct DNA band of 225 bp emerged in the male-male aortic allograft group and chimera aortic al- lograft group respectively, but not in the female-female aortic allograft group. It was suggested that recipient bone-marrow cells, as the origin of neointimal smooth muscle cells, contributed to the pathological neointimal hyperplasia of aortic allograft and transplant arteriosclerosis.展开更多
To establish a murine carotid artery transplantation model for the study of the chronic rejection, 80 rats were divided into two groups, an allotransplant （ACI-Lewis） group and an isotransplant （Lewis-Lewis） group...To establish a murine carotid artery transplantation model for the study of the chronic rejection, 80 rats were divided into two groups, an allotransplant （ACI-Lewis） group and an isotransplant （Lewis-Lewis） group （control group）. The donor carotid artery and the recipient carotid artery were anastomosed by using a polyethylene cuff （internal diameter： 0.7 mm, length： 3 mm）.The pathological changes of carotid artery transplant were observed 14, 28 and 56 days after the transplantation. The results showed that the model was successfully established in 95% of the animals. The chronic rejection-associated arteriosclerosis was induced 28 days after the transplantation. The new chronic rejection model of carotid artery by using cuff technique caused fewer traumas and was easy to make. The pathological changes of the transplant mimicked the chronic rejection-associated arteriosclerosis found in human transplant.展开更多
hronic rejection is the main factor to result in the loss of renal allograft In order to look for a potential therapy chronic rejection, we investigated the efficacy of estradiol on preventing renal chronic rejectio...hronic rejection is the main factor to result in the loss of renal allograft In order to look for a potential therapy chronic rejection, we investigated the efficacy of estradiol on preventing renal chronic rejection The kidneys of female F344 rats were orthotopically transplanted into ovatiectomized female Lewis rats and treated for 16 weeks with either estradiol or vehicle Compared with controls treated with vehicle, estradiol treatment reduced urinary protein excretion, glomerular sclerosis, interstitial infiltration and fibrosis, vascular lesions, in parallel to a reduced ICAM 1 and TGF β mRNA expression Our results suggested that estrodiol could significantly decrease the progression of chronic rejection, at least in female recipients, and the reduced adhesion molecule and TGF β gene expression may be involved in the mechanism for estradiol to prevent chronic rejection展开更多
Chronic allograft vasculopathy(CAV)remains a major obstacle for long-term survival of grafts even though therapeutic strategies have improved considerably in recent years.CAV is characterized by concentric and diffuse...Chronic allograft vasculopathy(CAV)remains a major obstacle for long-term survival of grafts even though therapeutic strategies have improved considerably in recent years.CAV is characterized by concentric and diffuse neointimal formation,medial apoptosis,infiltration of lymphocyte or inflammatory cells,and deposition of extracellular matrix both in arteries and veins.Recent studies have shown that stem cells derived from the recipient contribute to neointimal formation under the regulation of chemokines and cytokines.Arterial remodeling in allografts eventually causes ischemic graft failure.The pathogenesis is multi-factorial with both immunologic and non-immunological factors being involved.The immunological factors have been discussed extensively in other articles.This review focuses mainly on the arterial remodeling that occurs in 3 layers of vessel walls including intimal injury,accumulation of smooth muscle-like cells in the neointimal,medial smooth muscle cell apoptosis,adventitial fibrosis,and deposition of extracellular matrix.展开更多
Objective: To evaluate the relationship between chronic kidney dysfunction after transplantation and chronic vascular rejection (CVR), and to evaluate the efficacy and safety of Tanshinone (Tan) and Herba Lysimachiae ...Objective: To evaluate the relationship between chronic kidney dysfunction after transplantation and chronic vascular rejection (CVR), and to evaluate the efficacy and safety of Tanshinone (Tan) and Herba Lysimachiae (Lys) combined with Mycophenolate Mofetil (MMF) to fight against CVR, and to reduce the incidence of chronic dysfunction in rat renal transplantation model. Methods: Sixty-five male SD rats as donors and sixty-five male Wistar rats as recipients were used. The recipients were divided into five Groups, including Group A: Lys+Cyclosporine A (CsA), Group B: Tan+CsA, Group C: MMF+CsA, Group D: CsA, and Group E: normal saline. Kidney function and morphological changes were assessed at 2, 4, and 6 weeks after transplantation. All sections of renal grafts were stained with monoclonal antibodies (McAB), including major histocompability complex class II (OX-6), lymphocyte function antigen-1 (CD11b/CD18), intercellular adhesive molecular-1 (IA29), CD+8 (OX-8), and proliferation cell nuclear antigen (PCNA) (5A10, IgG1k) were used. Results:The two control groups developed typical chronic rejection episodes, and the histologic feature indication of kidney chronic rejection includes loss of renal units and presence of an obliteration arteriopathy involving large renal arteries. These were associated with serum levels of BUN and SCr increased and different degrees of glomerulosclerosis. Their mean survival time was lower than that of other groups. By contrast, serum levels of cytokine in control groups was significantly increased when compared with group B and C (P<0.05). Both group B and C had minimum changes in glomeruli and arteries, and expression levels of PCNA on the glomeruli and tubular cells were higher than those of other groups (P<0.05). However, there was no significant difference (P>0.05) between group B and C. Conclusions: CVR may activate the risk of the factor responsible for the development of graft chronic dysfunction that causes slow, progressive destruction of the transplanted kidney. Tanshinone was extracted from Salvia miltiorrhiza and purified for use in medicine. Especially when Tanshinone combined with a low-dose of CsA, it may fight against the CVR by inhibiting cell infiltration, and improving microcirculation of the graft, and thus the incidence of CVR is reduced. It is suggested that Tanshinone can be applied to treat patients with chronic renal dysfunction when used in combination with a low-dose Cyclosporine.展开更多
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 metabofism. The influence of th...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 metabofism. 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 SBT and 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 allografl 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.展开更多
基金National Natural Science Foundation of China(No.82260154)。
文摘Objective: To use bioinformatics technology to analyse differentially expressed genes in chronic rejection after renal transplantation, we can screen out potential pathogenic targets associated with the development of this disease, providing a theoretical basis for finding new therapeutic targets. Methods: Gene microarray data were downloaded from the Gene Expression Profiling Integrated Database (GEO) and cross-calculated to identify differentially expressed genes (DEGs). Analysis of differentially expressed genes (DEGs) with gene ontology (GO) is a method used to study the differences in gene expression under different conditions as well as their functions and interrelationships, while Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis is a tool used to explore the functions and pathways of genes in specific biological processes. By calculating the distribution of immune cell infiltration, the result of immune infiltration in the rejection group can be analysed as a trait in Weighted Gene Co-Expression Network Analysis (WGCNA) for genes associated with rejection. Then, protein-protein interaction networks (PPI) were constructed using the STRING database and Cytoscape software to identify hub gene markers. Results: A total of 60 integrated DEGs were obtained from 3 datasets (GSE7392, GSE181757, GSE222889). By GO and KEGG analysis, the GEDs were mainly concentrated in the regulation of immune response, defence response, regulation of immune system processes, and stimulation response. The pathways were mainly enriched in antigen processing and presentation, EBV infection, graft-versus-host, allograft rejection, and natural killer cell-mediated cytotoxicity. After further screening using WGCNA and PPI networks, HLA-A, HLA-B, HLA-F, and TYROBP were identified as hub genes (Hub genes). The data GSE21374 with clinical information was selected to construct the diagnostic efficacy and risk prediction model plots of the four hub genes, and the results concluded that all four Hub genes had good diagnostic value (area under the curve in the range of 0.794-0.819). From the inference, it can be concluded that the four genes, HLA-A, HLA-B, HLA-F and TYROBP, may have an important role in the development and progression of chronic rejection after renal transplantation. Conclusion: DEGs play an important role in the study of the pathogenesis of chronic rejection after renal transplantation, and can provide theoretical support for further research on the pathogenesis of chronic rejection after renal transplantation and the discovery of new therapeutic targets through enrichment analysis and pivotal gene screening, as well as inferential analyses of related diagnostic efficacy and disease risk prediction.
文摘Chronic rejection(CR)of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation.Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy,CR still represents an important cause of graft injury,which might be irreversible,leading to graft loss requiring re-transplantation.To date,we still do not fully appreciate the mechanisms underlying this process.In addition to T cell-mediated CR,which was initially the only recognized type of CR,recently a new form of liver allograft CR,antibody-mediated CR,has been identified.This has indeed opened an era of thriving research and renewed interest in the field.Liver biopsy is needed for a definitive diagnosis of CR,but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation.Moreover,the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury,which should not be disregarded.Therapies for CR may only be effective in the“early”phases,and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage.Herein,we provide an overview of the current knowledge and research on CR,focusing on early detection,identification of non-invasive biomarkers,immunosuppressive management,re-transplantation and future perspectives of CR.
文摘Objective: To study the cause and mechanism of transplantation vasculopathy which characterized by accelerated graft arteriosclerosis (AGA), we established a mouse aorta graft model. Methods: A segment of thoracic aortas of B10.A (2R) mice were transplanted to C57BL/10 mice abdominal aorta by end to side anastomoses. The different time point collected grafts were analyzed by morphological, histochemical and electro microscopic methods. Results: Rejection was manifested as a concentric progressive destruction of the smooth muscle cells. In contrast, the endothelial inflammation and subsequent neointimal proliferation characteristic of AGA was localized to the regions of turbulent flow, i.e. the junction of the graft with the recipient aorta. Conclusion: This model separates the processes of rejection and neointimal formation which usually manifested together in the lesion of AGA, elucidate that different mechanisms control vascular rejection and neointimal formation in chronic rejection.
文摘Objective To investigate the depressant effect and mechanism of atorvastatin on the chronic rejection of aortic allograft in rats. Methods： The models of abdominal aorta transplantation were made with micro-surgery in rats. The recipients were divided into three groups： allograft control group, atorvastatin-treated group and isograft control group. Vascular intimal thickness in all of the groups were observed by histological examination. The expression of PCNA and α-SMA were determined by immunohistochemistry. The content of nitric oxide was determined by nitrate reductase chromatometry. Results： The vascular intimal thickness in rats of atorvastatin-treated group （11.60% ± 2.40% ） were lower than those in allograft control group （34.60 % ± 6.40 % ; P 〈 0.05） and higher than those in isograft control group （1.15 % ± 0.65 %; P〈 0.05 ）. The expression level of PCNA was decreased in atorvastatin-treated group （4.80% ± 0.80% ） than allograft control group （18.40% ± 1.80% ; P〈0.05） and higher than isograft group （1.20% ± 0.40% ; P〈0.05）. Conclusion： The expression of PCNA in the transplant aorta could be suppressed by atorvastatin, which resalted in relief of chronic rejection of aortic allograft.
文摘Objective To study clinically the feasibility of early diagnosis of cardiac allograft vascularopathy(CAV) and chronic rejection. Methods A 13-year-old female patient with dilated cardiomy-opathy received orthotopic heart transplantation for advanced heart failure, and subsequent immunosuppressive therapy including cyclosporine, prednisone and mofetil, and a mondily close follow-up. Coronary angiography and left ventricular endomyocardial biopsy (EMB) was perormed 9 months after the operation. Results The clinical and follow-up data of the case showed that cardiac or systemic nonspecific symptoms such as exertional chest discomfort, palpitation, fatigue or fever of unknown reasons were the first and ignorable clinical symptoms, and found disappeared after dosage addition of cyclinsporine, which indicated a early clinical manifestations of rejection or vasculopathy. While persistent sinus tachycardia on electrocadiogram, decreased left ventricular ejection fraction(from 64% -68% down to 47% - 50% ),
文摘In this study antigen independent factor in the pathogenesis of chronic rejection of organ transplants was examined. Kidney isografts and allografts were transplanted orthotopically into bilaterally nephroectomized rat recipients and studied functionally, morphologically and immunohistologically, at serial intervals up to 52 weeks after transplantation. Allograft recipients developed progressive proteinuria after 12 weeks, with gradual renal failure ultimately leading to death. At the same time, morphological changes, including progressive arteriosclerosis and glomerulosclerosis, tubular atrophy and interstitial fibrosis, developed. Immunohistologically, macrophages infiltrated glomeruli during this period and cytokines became unregulated. Our results showed that antigen independent functional and morphological changes occurred in long term kidney isografts and mimicked those appearing much earlier in allografts that reject chronically. Initial injury and extent of functioning renal mass is suggested to be important factor for such late changes.
文摘Liver transplantation(LT)is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease.With improvements in organ preservation techniques,perioperative care,and immunosuppression,there is better patient and graft survival following LT,and assessment of the liver allograft in long-term survivors is becoming increasingly important.Recurrent or de novo viral or autoimmune injury remains the most common causes of chronic hepatitis and fibrosis following liver transplantation in adults.However,no obvious cause can be identified in many adults with controlled recurrent disease and the majority of pediatric LT recipients,as they have been transplanted for non-recurrent liver diseases.Serial surveillance liver biopsies post LT have been evaluated in several adult and pediatric centers to identify long-term pathological changes.Pathological findings are frequently present in liver biopsies obtained after a year post LT.The significance of these findings is uncertain as many of these are seen in protocol liver biopsies from patients with clinically good allograft function and normal liver chemistry parameters.This narrative review summaries the factors predisposing to long-term liver allograft fibrosis,highlighting the putative role of idiopathic post-LT hepatitis and chronic antibody mediated rejection in its pathogenesis.
文摘Postoperative biliary complications remain a substantial challenge after living donor liver transplantation,especially due to its heterogeneous clinical presentation.
文摘BACKGROUND Gastroesophageal reflux disease has been shown to contribute to allograft injury and rejection outcomes in lung transplantation through a proposed mechanism of aspiration,inflammation,and allograft injury.The value of pre-transplant reflux testing in predicting reduction in pulmonary function after lung transplantation is unclear.We hypothesized that increased reflux burden on pre-transplant reflux testing is associated with pulmonary function decline following lung transplant.AIM To assess the relationship between pre-transplant measures of reflux and pulmonary function decline in lung transplant recipients.METHODS This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant reflux testing with 24-hour pH-impedance off acid suppression at a tertiary center in 2007-2016.Patients with pre-transplant fundoplication were excluded.Time-to-event analysis was performed using Cox proportional hazards models to assess associations between reflux measures and reduction in forced expiratory volume in 1 second(FEV1)of≥20%post-transplant.Patients not meeting endpoint were censored at time of post-transplant fundoplication,last clinic visit,or death,whichever was earliest.RESULTS Seventy subjects(58%men,mean age:56 years)met the inclusion criteria.Interstitial lung disease represented the predominant pulmonary diagnosis(40%).Baseline demographics were similar between groups and were not associated with pulmonary decline.The clinical endpoint(≥20%FEV1 decline)was reached in 18 subjects(26%).In time-to-event univariate analysis,FEV1 decline was associated with increased acid exposure time(AET)[hazard ratio(HR)=3.49,P=0.03]and increased proximal acid reflux(HR=3.34,P=0.04)with confirmation on Kaplan-Meier analysis.Multivariate analysis showed persistent association between pulmonary decline and increased AET(HR=3.37,P=0.04)when controlling for potential confounders including age,body mass index,and sex.Subgroup analysis including only patients with FEV1 decline showed that all subjects with abnormal AET progressed to bronchiolitis obliterans syndrome.CONCLUSION Increased reflux burden on pre-transplant testing was associated with significant pulmonary function decline posttransplant.Pre-transplant reflux assessment may provide clinically relevant information in the prognostication and management of transplant recipients.
基金Supported by The Deutsche Forschungsgemeinschaft,No.GW 4/6-1
文摘Rejection is one of the key factors that determine the long-term allograft function and survival in renal transplant patients.Reliable and timely diagnosis is important to treat rejection as early as possible.Allograft biopsies are not suitable for continuous monitoring of rejection.Thus,there is an unmet need for non-invasive methods to diagnose acute and chronic rejection.Proteomics in urine and blood samples has been explored for this purpose in 29 studies conducted since 2003.This review describes the different proteomic approaches and summarizes the results from the studies that examined proteomics for the rejection diagnoses.The potential limitations and open questions in establishing proteomic markers for rejection are discussed,including ongoing trials and future challenges to this topic.
文摘The state-of-the-art immunosuppression drugs do not ensure indefi nite transplant survival,and most transplants are continuously lost to chronic rejection even years posttransplantation.This form of rejection is responsible for long-term failure of transplanted organs.The mechanisms involved in development of chronic rejection are not well-understood.One of the main features of chronic rejection is progressive luminal narrowing of graft vessels,which results in compromised blood flow,ischemia,cell death,and finally graft failure.All the existing immunosuppressive regimens are targeting acute rejection,and at present there is no available therapy for prevention of chronic rejection.Chronic rejection involves two major,but interrelated responses:The first is the host immune response against the transplant mediated primarily by alloreactive T and B cells,and the second is injury and repair of the graft(vasculopathy of graft vessels).Here we focus on recent advances in understanding the cellular and molecular aspects of chronic transplant vasculopathy and function of macrophages,topics pivotal for development of novel antichronic rejection therapies.
基金Instituto de Salud Carlos III,Spanish Ministry of Economy and Competitiveness,No.PI15/01370 and P19/01194and the European Union with the European Fund of Regional Development with the principle of“A manner to build Europe”.
文摘Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells in the complex milieu of the liver.In this section,we will comment on the importance of donorspecific anti-human leukocyte antigen(HLA)antibodies(DSA)as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor(KIR)genotypes in the evolution of liver transplantation.Thus,HLA compatibility,viral infections,and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival.There have been reports of increased risk of acute and chronic rejection with ductopenia,faster graft fibrosis,biliary problems,poorer survival,and even de novo autoimmune hepatitis when DSAs are present in the recipient.Higher mean fluorescence intensity(MFI)values of the DSAs and smaller graft size were associated with poorer patient outcomes,implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods,according to the investigators.Similarly,in a combined kidney-liver transplant,a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment.The renal graft was lost owing to antibody-mediated rejection(AMR).The HLA antigens expressed by the transplanted liver graft influenced antibody elimination.Pathologists are increasingly diagnosing AMR in liver transplants,and desensitization therapy has even been employed in situations of AMR,particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex.In conclusion,after revealing the negative impacts of DSAs with high MFI,pretransplant virtual crossmatch techniques may be appropriate to improve evolution;however,they may extend cold ischemia periods by requiring the donor to be typed.
基金grants from the National Natural Sciences Foundation of China (No. 30271242, 30371396)
文摘In order to investigate the origin of neointimal smooth muscle cells in transplant arterio- sclerosis in rat aortic allograft, sex-mismatched bone marrow transplantation was performed from male Wistar rats to female Wistar rats. Four weeks after transplantation, the aortic transplant model was established by means of micro-surgery in rats. The recipients were divided into 4 groups: female Wistar-female Wistar aortic isografts, female SD-female Wistar aortic allografts, male SD-male Wis- tar aortic allografts, female SD-chimera Wistar aortic allografts. Eight weeks after transplantation, aortic grafts were removed at autopsy and processed for histological evaluation and immunohisto- chemistry. The results indicated that excessive accumulation of α-SMA-positive smooth muscle cells resulted in significant neointima formation and vascular lumen stricture in rat aortic allografts. Neointima assay revealed that the neointimal area and NIA/MA ratio of transplanted artery were sig- nificantly increased in all of aortic allograft groups as compared with those in aortic isograft group (P<0.01). Neointimal smooth muscle cells were harvested from cryostat sections of aortic allograft by microdissection method. The Sry gene-specific PCR was performed, and the result showed that a dis- tinct DNA band of 225 bp emerged in the male-male aortic allograft group and chimera aortic al- lograft group respectively, but not in the female-female aortic allograft group. It was suggested that recipient bone-marrow cells, as the origin of neointimal smooth muscle cells, contributed to the pathological neointimal hyperplasia of aortic allograft and transplant arteriosclerosis.
基金supported by a grant from the National Natural Sciences Foundation of China (No. 30500656).
文摘To establish a murine carotid artery transplantation model for the study of the chronic rejection, 80 rats were divided into two groups, an allotransplant （ACI-Lewis） group and an isotransplant （Lewis-Lewis） group （control group）. The donor carotid artery and the recipient carotid artery were anastomosed by using a polyethylene cuff （internal diameter： 0.7 mm, length： 3 mm）.The pathological changes of carotid artery transplant were observed 14, 28 and 56 days after the transplantation. The results showed that the model was successfully established in 95% of the animals. The chronic rejection-associated arteriosclerosis was induced 28 days after the transplantation. The new chronic rejection model of carotid artery by using cuff technique caused fewer traumas and was easy to make. The pathological changes of the transplant mimicked the chronic rejection-associated arteriosclerosis found in human transplant.
文摘hronic rejection is the main factor to result in the loss of renal allograft In order to look for a potential therapy chronic rejection, we investigated the efficacy of estradiol on preventing renal chronic rejection The kidneys of female F344 rats were orthotopically transplanted into ovatiectomized female Lewis rats and treated for 16 weeks with either estradiol or vehicle Compared with controls treated with vehicle, estradiol treatment reduced urinary protein excretion, glomerular sclerosis, interstitial infiltration and fibrosis, vascular lesions, in parallel to a reduced ICAM 1 and TGF β mRNA expression Our results suggested that estrodiol could significantly decrease the progression of chronic rejection, at least in female recipients, and the reduced adhesion molecule and TGF β gene expression may be involved in the mechanism for estradiol to prevent chronic rejection
基金supported by grants from the National Natural Science Foundation of China(No.30700798)from the Ph.D.Programs Foundation for Young Teachers of Ministry of Education of China(No.20070487158).
文摘Chronic allograft vasculopathy(CAV)remains a major obstacle for long-term survival of grafts even though therapeutic strategies have improved considerably in recent years.CAV is characterized by concentric and diffuse neointimal formation,medial apoptosis,infiltration of lymphocyte or inflammatory cells,and deposition of extracellular matrix both in arteries and veins.Recent studies have shown that stem cells derived from the recipient contribute to neointimal formation under the regulation of chemokines and cytokines.Arterial remodeling in allografts eventually causes ischemic graft failure.The pathogenesis is multi-factorial with both immunologic and non-immunological factors being involved.The immunological factors have been discussed extensively in other articles.This review focuses mainly on the arterial remodeling that occurs in 3 layers of vessel walls including intimal injury,accumulation of smooth muscle-like cells in the neointimal,medial smooth muscle cell apoptosis,adventitial fibrosis,and deposition of extracellular matrix.
文摘Objective: To evaluate the relationship between chronic kidney dysfunction after transplantation and chronic vascular rejection (CVR), and to evaluate the efficacy and safety of Tanshinone (Tan) and Herba Lysimachiae (Lys) combined with Mycophenolate Mofetil (MMF) to fight against CVR, and to reduce the incidence of chronic dysfunction in rat renal transplantation model. Methods: Sixty-five male SD rats as donors and sixty-five male Wistar rats as recipients were used. The recipients were divided into five Groups, including Group A: Lys+Cyclosporine A (CsA), Group B: Tan+CsA, Group C: MMF+CsA, Group D: CsA, and Group E: normal saline. Kidney function and morphological changes were assessed at 2, 4, and 6 weeks after transplantation. All sections of renal grafts were stained with monoclonal antibodies (McAB), including major histocompability complex class II (OX-6), lymphocyte function antigen-1 (CD11b/CD18), intercellular adhesive molecular-1 (IA29), CD+8 (OX-8), and proliferation cell nuclear antigen (PCNA) (5A10, IgG1k) were used. Results:The two control groups developed typical chronic rejection episodes, and the histologic feature indication of kidney chronic rejection includes loss of renal units and presence of an obliteration arteriopathy involving large renal arteries. These were associated with serum levels of BUN and SCr increased and different degrees of glomerulosclerosis. Their mean survival time was lower than that of other groups. By contrast, serum levels of cytokine in control groups was significantly increased when compared with group B and C (P<0.05). Both group B and C had minimum changes in glomeruli and arteries, and expression levels of PCNA on the glomeruli and tubular cells were higher than those of other groups (P<0.05). However, there was no significant difference (P>0.05) between group B and C. Conclusions: CVR may activate the risk of the factor responsible for the development of graft chronic dysfunction that causes slow, progressive destruction of the transplanted kidney. Tanshinone was extracted from Salvia miltiorrhiza and purified for use in medicine. Especially when Tanshinone combined with a low-dose of CsA, it may fight against the CVR by inhibiting cell infiltration, and improving microcirculation of the graft, and thus the incidence of CVR is reduced. It is suggested that Tanshinone can be applied to treat patients with chronic renal dysfunction when used in combination with a low-dose Cyclosporine.
文摘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 metabofism. 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 SBT and 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 allografl 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.
