Background:The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments.Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits.Ho...Background:The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments.Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits.However,determining the optimal dosage and route of administration to minimize toxicity while maintaining efficacy remains challenging.Methods:In this study,we investigated the effect of orally administered tacrolimus in rabbits,with an aim to achieve a whole blood target trough level of 3-10 ng/m L,and looked at signs of tissue rejection after the transplantation of a human nerve conduit to repair a severed fibular nerve.An oral dosage range of 0.25-1.5 mg/kg/d was studied for up to 1 year in 63 New Zealand rabbits.Results:We demonstrated the feasibility of long-term grafting in rabbits while maintaining safe immunosuppression,with side effects mainly limited to diarrhea.Customizing the administered dose proved crucial for graft efficacy and low toxicity,which translated into 100%individual survival.We suggest an oral tacrolimus dose of 1.0-1.5 mg/kg depending on individual heterogeneity and recommend to implement a close therapeutic drug monitoring in the rabbits to maintain a whole blood tacrolimus trough level within the range of 5-12 ng/m L,as levels below 5 ng/m L showed signs of inflammation in the graft.Conclusion:The oral administration of tacrolimus enabled efficient immunosuppression of rabbits over a 1-year period without significant side effects or loss of animals.展开更多
Florfenicol(FLO)is a chemically synthesized broad-spectrum antimicrobial agent of amide alcohols for animals,which is one of the most widely used antimicrobials in livestock,poultry,and aquaculture.With the use of FLo...Florfenicol(FLO)is a chemically synthesized broad-spectrum antimicrobial agent of amide alcohols for animals,which is one of the most widely used antimicrobials in livestock,poultry,and aquaculture.With the use of FLo,more and more attention has been paid to its hematopoietic toxicity,immunotoxicity,genotoxicity,and embryotoxicity.In this study,SPF chicks.at the age of 3 d began to drink water with the FLO at a dose of 100 mg L^(-1)for 6 consecutive days,and the growth performance of chicks was monitored,the effect of FLO on immune organs was detected by pathological examination and TdT-mediated dUTP nick-end labeling(TUNEL)apoptosis staining.In order to evaluate the level of organism immunity,the level of Newcastle disease virus antibody in serum was detected by hemagglutination inhibition test,the content of cytokines(IL-1,IL-2,IL-6,TNF-α,IFN-γ)in serum was detected by enzyme linked immunosorbent assay(ELISA),and the transcription of interferon-related genes(IRF-7,2′-5′OAS,Mx1)and cytokine genes(IL-6,TNF-α,IFN-γ)in immune organs were detected by real time fluorescence quantitative PCR.The results showed that the early application of FLO could inhibit the growth and development of chicks,and the body weight and immune organ index of the treatment group were lower than those of the control group.Histopathological examination showed that there was a decrease in the number of lymphocytes in the bursa of Fabricius in the treatment group in the early stage of drug withdrawal,and the results of TUNEL apoptosis staining in the bursa of Fabricius showed that obvious lymphocyte apoptosis occurred in the FLO treatment group.Compared with the control group,the transcription levels of interferon-related genes IRF-7,2′-5′OAS,and cytokine genes IL-6,TNF-αand IFN-γin FLO treatment group decreased to a certain extent,while the transcription level of Mx1 gene had no significant difference at all time points.The level of serum Newcastle disease virus(NDV)antibody and the contents of cytokines IL-1,IL-2 and IFN-γin the FLO treatment group were significantly lower than those in the control group in the early stage of drug withdrawal,but recovered gradually in the later stage.This study showed that FLO has a certain degree of effect on the immune function of chicks,and the results of the study laid the foundation for further research on the mechanism of FLO-induced immunotoxicity.展开更多
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive thera...Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.展开更多
Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and im...Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.展开更多
Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,...Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.展开更多
Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associ...Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.展开更多
Objective To observe modulatory effects of electroacupuncture （EA） on hypothalamus-pituitary adrenal （HPA） axis, thymus-exponent （TE）, γ-IFN and interleukin-2 （IL-2） in rats with exercise-induced immunosuppre...Objective To observe modulatory effects of electroacupuncture （EA） on hypothalamus-pituitary adrenal （HPA） axis, thymus-exponent （TE）, γ-IFN and interleukin-2 （IL-2） in rats with exercise-induced immunosuppression. Methods Forty-three SD rats were randomly, by using digits, divided into three groups： group A, B and C. Group A （n=10） was taken as a control group. Rats in group B （n=17） accepted intense swimming exercise for 150 min each time, 6 times each week for 8 weeks. Rats in group C （n=16） accepted EA intervention following each swimming since the second week of swimming exercise with the same duration and times as those in group B. The indices reflecting functional states of the HPA axis such as hypothalamic corticotropin releasing hormone （CRH）, plasma adrenocorticotropic hormone （ACTH）, corticosterone （CORT） etc. and changes in TE, serum γ-IFN, and IL-2 were determined. Results （1） Compared with group A, the values of ACTH and CORT in group B significantly increased （P〈0.01, P〈0.05）, but no significant differences were found in group C （both P〉0.05） though they were somewhat elevated. Compared with group A, CRH values increased by 85.14% in group B and decreased by 64.09% in group C, respectively, but both differences were without statistical significance （both P〉0.05）. Serum IL-2, γ-IFN and TE values in group B were significantly lower than those in group A（P〈0.05, P〈0.01 ）, among which γ-IFN decreased by 32.19%. The values of IL-2, γ-IFN and TE in group C tended to reduce but without significance, compared with group A. （2） Compared with group B, ACTH value in group C was very significantly lowered than that in group B （P〈0.01）, and CRH value was lower while CORT value was higher than those in group B but without significance （both P〉0.05）. The values of TE and γ-IFN in group C were significantly higher than those in group B （P〈0.01, P〈0.05）. Conclusion （1） Long-term of intense exercise induces accentuation of functions of the HPA axis and sustained high level of CORT, resulting in neuroendocrine disturbance and inhibition of immune functions. （2） EA provides favorable modulation on long-term of intense exercise-induced lowering of immune function and on the HPA axis.展开更多
AIM: To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients.
The optimal level of immunosuppression in solid organ transplantation,in particular for the liver,is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. Th...The optimal level of immunosuppression in solid organ transplantation,in particular for the liver,is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time asnew agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor,the main class of immunosuppressive agents used in liver transplantation(LT),has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C,hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations.展开更多
Acute pancreatitis(AP) is a common disease,which usually exists in its mild form.However,in a fifth of cases,the disease is severe,with local pancreatic complications or systemic organ dysfunction or both.Because the ...Acute pancreatitis(AP) is a common disease,which usually exists in its mild form.However,in a fifth of cases,the disease is severe,with local pancreatic complications or systemic organ dysfunction or both.Because the development of organ failure is the major cause of death in AP,early identification of patients likely to develop organ failure is important.AP is initiated by intracellular activation of pancreatic proenzymes and autodigestion of the pancreas.Destruction of the pancreatic parenchyma first induces an inflammatory reaction locally,but may lead to overwhelming systemic production of inflammatory mediators and early organ failure.Concomitantly,anti-inflammatory cytokines and specific cytokine inhibitors are produced.This anti-inflammatory reaction may overcompensate and inhibit the immune response,rendering the host at risk of systemic infection.At present,there is no specific treatment for AP.Increased understanding of the pathogenesis of systemic inflammation and development of organ dysfunction may provide us with drugs to ameliorate physiological disturbances.展开更多
Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immuno...Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.展开更多
In patients with inflammatory bowel disease(IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporad...In patients with inflammatory bowel disease(IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.展开更多
Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease.Beginning with th...Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease.Beginning with the revolutionary discovery of cyclosporine in the 1970s,immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors,anti-metabolites,mTOR inhibitors,steroids and antibody-based therapies.These agents target different sites in the T cell activation cascade,usually by inhibiting T cell activation or via T cell depletion.They are used as induction therapy in the immediate periand post-operative period,as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.展开更多
Due to the inherent relationship between the immune system and the hepatitis B virus(HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignanci...Due to the inherent relationship between the immune system and the hepatitis B virus(HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignancies and inflammatory disorders has been linked to HBV reactivation(HBVr). Reactivation of HBV infection in the setting of chemotherapy and immunosuppression may lead to fulminant liver failure and death, but there is a cumulative body of evidence that these are potentially preventable adverse outcomes. As chronic hepatitis B is largely asymptomatic but also endemic worldwide, clinicians caring for patients requiring chemotherapy or immunosuppression need to be vigilant of the potential for HBVr in susceptible individuals. Serological screening and prophylactic and pre-emptive antiviral treatment with a nucleos(t)ide analogue should be considered in appropriate settings. Hepatitis B prevalence is examined in this review article, as are the risks of HBVr in patients receiving chemo- and immunosuppressive therapy. Recommendations regarding screening, monitoring and the role of antiviral prophylaxis are outlined with reference to current international associations' guidelines and the best available evidence to date.展开更多
Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population compris...Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus(HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin(IL)-10and transforming growth factor(TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC Ⅰ, NIC Ⅱ and NIC Ⅲ and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.展开更多
BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with cr...BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.展开更多
AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free ...AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free survival after liver transplantation （LT）.METHODS： Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS： Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were： presence of cirrhosis （P = 0.001）, etiology of liver disease （P = 0.03）, α fetoprotein level （〈 200, 200 to 2000, or 〉 2000; P 〈 0.0001）, y-GT activity （N, N to 2N or 〉 2N; P = 0.02）, the number of nodules （1, 2-3 or ≥ 4; P = 0.02）, maximal diameter of the largest nodule （〈 3 cm, 3 to 5 cm or 〉 5 cm; P 〈 0.0001）, the sum of the diameter of the nodules （〈 3 cm, 3 to 5 cm, 5 to 10 cm or 〉10 cm; P 〈 0.0001）, bilobar location （P = 0.01）, preoperative portal thrombosis （P 〈 0.0001）, peri-operative treatment of the tumor （P = 0.002） and chemoembolization （P = 0.03）, tumor differentiation （P = 0.01）, initial type of calcineurin inhibitor （P = 0.003）, the use of antilymphocyte antibodies （P = 0.02）, rejection episodes （P = 0.003） and period of LT （P 〈 0.0001）. By multivariate analysis, 6 variables were independently associated with HCC recurrence： maximal diameter of the largest nodule （P 〈 0.0001）, time of LT （P 〈 0.0001）, tumor differentiation （P 〈 0.0001）, use of anti-lymphocyte antibody （ATG） or anti-CD3 antibody （OKT3） （P = 0.005）, preoperative portal thrombosis （P = 0.06） and the number of nodules （P = 0.06）. CONCLUSION： This study identifies immunosuppression, through the use of ATG or OKT3, as a predictive factor of tumor recurrence, and confirms the prognostic value of tumor differentiation.展开更多
AIM: To present the characteristics and the course of a series of anti- hepatitis B virus core antibody (HBc) antibody positive patients, who experienced hepatitis B virus (HBV) reactivation after immunosuppression. M...AIM: To present the characteristics and the course of a series of anti- hepatitis B virus core antibody (HBc) antibody positive patients, who experienced hepatitis B virus (HBV) reactivation after immunosuppression. METHODS: We retrospectively evaluated in our tertiary centers the medical records of hepatitis B virus surface antigen (HBsAg) negative patients who suffered from HBV reactivation after chemotherapy or immunosuppression during a 3-year period (2009-2011). Accordingly, the clinical, laboratory and virological characteristics of 10 anti-HBc (+) anti-HBs (-)/HBsAg (-) and 4 anti-HBc (+)/antiHBs (+)/HBsAg (-) patients, who developed HBV reactivation after the initiation of chemotherapy or immunosuppressive treatment were analyzed. Quantitative determination of HBV DNA during reactivation was performed in all cases by a quantitative real time polymerase chain reaction kit (COBAS Taqman HBV Test; cut-off of detection: 6 IU/mL). RESULTS: Twelve out of 14 patients were males; median age 74.5 years. In 71.4% of them the primary diagnosis was hematologic malignancy; 78.6% had received rituximab (R) as part of the immunosuppressive regimen. The median time from last chemotherapy schedule till HBV reactivation for 10 out of 11 patients who received R was 3 (range 2-17) mo. Three patients (21.4%) deteriorated, manifesting ascites and hepatic encephalopathy and 2 (14.3%) of them died due to liver failure. CONCLUSION: HBsAg-negative anti-HBc antibody positive patients can develop HBV reactivation even 2 years after stopping immunosuppression, whereas prompt antiviral treatment on diagnosis of reactivation can be lifesaving.展开更多
Liver transplantation has been the treatment of choice for end-stage liver disease since 1983.Cancer has emerged as a major long-term cause of death for liver transplant recipients.Many retrospective studies that have...Liver transplantation has been the treatment of choice for end-stage liver disease since 1983.Cancer has emerged as a major long-term cause of death for liver transplant recipients.Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers postliver transplantation;some have also studied risk factors.Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers.Risk of head and neck,lung,esophageal,cervical cancers and Kaposi’s sarcoma is high,but risk of colorectal cancer is not clearly demonstrated.There appears to be no excess risk of developing breast or prostate cancer.Environmental risk factors such as viral infection and tobacco consumption,and personal risk factors such as obesity play a key role,but recent data also implicate the role of calcineurin inhibitors,whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis.In this paper,we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and,ultimately,discuss how to prevent these cancers.Immunosuppressive protocol changes,including a calcineurin inhibitor-free regimen,combined with dietary guidelines and smoking cessation,are theoretically the best preventive measures.展开更多
Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced...Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.展开更多
基金the Canadian Institutes of Health Research(CIHR),Grant/Award Number:PJT-175016the Fonds de recherche du Québec(FRQ)through the research centre grant for the CHU de Québec-UniversitéLaval Research Center,Grant/Award Number:30641+2 种基金the Quebec Cell,Tissue and Gene Therapy Network—ThéCellthe FRQS,the Fondation du CHU de Québec-UniversitéLavalNeuro Québec。
文摘Background:The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments.Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits.However,determining the optimal dosage and route of administration to minimize toxicity while maintaining efficacy remains challenging.Methods:In this study,we investigated the effect of orally administered tacrolimus in rabbits,with an aim to achieve a whole blood target trough level of 3-10 ng/m L,and looked at signs of tissue rejection after the transplantation of a human nerve conduit to repair a severed fibular nerve.An oral dosage range of 0.25-1.5 mg/kg/d was studied for up to 1 year in 63 New Zealand rabbits.Results:We demonstrated the feasibility of long-term grafting in rabbits while maintaining safe immunosuppression,with side effects mainly limited to diarrhea.Customizing the administered dose proved crucial for graft efficacy and low toxicity,which translated into 100%individual survival.We suggest an oral tacrolimus dose of 1.0-1.5 mg/kg depending on individual heterogeneity and recommend to implement a close therapeutic drug monitoring in the rabbits to maintain a whole blood tacrolimus trough level within the range of 5-12 ng/m L,as levels below 5 ng/m L showed signs of inflammation in the graft.Conclusion:The oral administration of tacrolimus enabled efficient immunosuppression of rabbits over a 1-year period without significant side effects or loss of animals.
文摘Florfenicol(FLO)is a chemically synthesized broad-spectrum antimicrobial agent of amide alcohols for animals,which is one of the most widely used antimicrobials in livestock,poultry,and aquaculture.With the use of FLo,more and more attention has been paid to its hematopoietic toxicity,immunotoxicity,genotoxicity,and embryotoxicity.In this study,SPF chicks.at the age of 3 d began to drink water with the FLO at a dose of 100 mg L^(-1)for 6 consecutive days,and the growth performance of chicks was monitored,the effect of FLO on immune organs was detected by pathological examination and TdT-mediated dUTP nick-end labeling(TUNEL)apoptosis staining.In order to evaluate the level of organism immunity,the level of Newcastle disease virus antibody in serum was detected by hemagglutination inhibition test,the content of cytokines(IL-1,IL-2,IL-6,TNF-α,IFN-γ)in serum was detected by enzyme linked immunosorbent assay(ELISA),and the transcription of interferon-related genes(IRF-7,2′-5′OAS,Mx1)and cytokine genes(IL-6,TNF-α,IFN-γ)in immune organs were detected by real time fluorescence quantitative PCR.The results showed that the early application of FLO could inhibit the growth and development of chicks,and the body weight and immune organ index of the treatment group were lower than those of the control group.Histopathological examination showed that there was a decrease in the number of lymphocytes in the bursa of Fabricius in the treatment group in the early stage of drug withdrawal,and the results of TUNEL apoptosis staining in the bursa of Fabricius showed that obvious lymphocyte apoptosis occurred in the FLO treatment group.Compared with the control group,the transcription levels of interferon-related genes IRF-7,2′-5′OAS,and cytokine genes IL-6,TNF-αand IFN-γin FLO treatment group decreased to a certain extent,while the transcription level of Mx1 gene had no significant difference at all time points.The level of serum Newcastle disease virus(NDV)antibody and the contents of cytokines IL-1,IL-2 and IFN-γin the FLO treatment group were significantly lower than those in the control group in the early stage of drug withdrawal,but recovered gradually in the later stage.This study showed that FLO has a certain degree of effect on the immune function of chicks,and the results of the study laid the foundation for further research on the mechanism of FLO-induced immunotoxicity.
文摘Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
基金Supported by National Natural Science Foundation of China,No.82320108022,No.82322076 and No.82104466.
文摘Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.
基金the Fundamental Research Funds for the Central Universities,China(Grant No.:3332022147)the CAMS Innovation Fund for Medical Sciences,China(Grant Nos.:2021-I2M-1-071 and 2021-I2M-1-031)the National Natural Science Foundation of China(Grant No.:81872999).
文摘Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.
基金Supported by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica(PAPIIT)de la Dirección General de Asuntos de Personal Académico,No.IN212722 and No.IA208424Consejo Mexiquense de Ciencia y Tecnología,No.CS000132Consejo Nacional de Humanidades,Ciencia y Tecnología,No.CF-2023-I-563.
文摘Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.
基金Supported by Guangdong Natural Science Foundation Project: 050042740
文摘Objective To observe modulatory effects of electroacupuncture （EA） on hypothalamus-pituitary adrenal （HPA） axis, thymus-exponent （TE）, γ-IFN and interleukin-2 （IL-2） in rats with exercise-induced immunosuppression. Methods Forty-three SD rats were randomly, by using digits, divided into three groups： group A, B and C. Group A （n=10） was taken as a control group. Rats in group B （n=17） accepted intense swimming exercise for 150 min each time, 6 times each week for 8 weeks. Rats in group C （n=16） accepted EA intervention following each swimming since the second week of swimming exercise with the same duration and times as those in group B. The indices reflecting functional states of the HPA axis such as hypothalamic corticotropin releasing hormone （CRH）, plasma adrenocorticotropic hormone （ACTH）, corticosterone （CORT） etc. and changes in TE, serum γ-IFN, and IL-2 were determined. Results （1） Compared with group A, the values of ACTH and CORT in group B significantly increased （P〈0.01, P〈0.05）, but no significant differences were found in group C （both P〉0.05） though they were somewhat elevated. Compared with group A, CRH values increased by 85.14% in group B and decreased by 64.09% in group C, respectively, but both differences were without statistical significance （both P〉0.05）. Serum IL-2, γ-IFN and TE values in group B were significantly lower than those in group A（P〈0.05, P〈0.01 ）, among which γ-IFN decreased by 32.19%. The values of IL-2, γ-IFN and TE in group C tended to reduce but without significance, compared with group A. （2） Compared with group B, ACTH value in group C was very significantly lowered than that in group B （P〈0.01）, and CRH value was lower while CORT value was higher than those in group B but without significance （both P〉0.05）. The values of TE and γ-IFN in group C were significantly higher than those in group B （P〈0.01, P〈0.05）. Conclusion （1） Long-term of intense exercise induces accentuation of functions of the HPA axis and sustained high level of CORT, resulting in neuroendocrine disturbance and inhibition of immune functions. （2） EA provides favorable modulation on long-term of intense exercise-induced lowering of immune function and on the HPA axis.
文摘AIM: To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients.
文摘The optimal level of immunosuppression in solid organ transplantation,in particular for the liver,is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time asnew agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor,the main class of immunosuppressive agents used in liver transplantation(LT),has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C,hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations.
文摘Acute pancreatitis(AP) is a common disease,which usually exists in its mild form.However,in a fifth of cases,the disease is severe,with local pancreatic complications or systemic organ dysfunction or both.Because the development of organ failure is the major cause of death in AP,early identification of patients likely to develop organ failure is important.AP is initiated by intracellular activation of pancreatic proenzymes and autodigestion of the pancreas.Destruction of the pancreatic parenchyma first induces an inflammatory reaction locally,but may lead to overwhelming systemic production of inflammatory mediators and early organ failure.Concomitantly,anti-inflammatory cytokines and specific cytokine inhibitors are produced.This anti-inflammatory reaction may overcompensate and inhibit the immune response,rendering the host at risk of systemic infection.At present,there is no specific treatment for AP.Increased understanding of the pathogenesis of systemic inflammation and development of organ dysfunction may provide us with drugs to ameliorate physiological disturbances.
文摘Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.
文摘In patients with inflammatory bowel disease(IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.
文摘Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease.Beginning with the revolutionary discovery of cyclosporine in the 1970s,immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors,anti-metabolites,mTOR inhibitors,steroids and antibody-based therapies.These agents target different sites in the T cell activation cascade,usually by inhibiting T cell activation or via T cell depletion.They are used as induction therapy in the immediate periand post-operative period,as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.
文摘Due to the inherent relationship between the immune system and the hepatitis B virus(HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignancies and inflammatory disorders has been linked to HBV reactivation(HBVr). Reactivation of HBV infection in the setting of chemotherapy and immunosuppression may lead to fulminant liver failure and death, but there is a cumulative body of evidence that these are potentially preventable adverse outcomes. As chronic hepatitis B is largely asymptomatic but also endemic worldwide, clinicians caring for patients requiring chemotherapy or immunosuppression need to be vigilant of the potential for HBVr in susceptible individuals. Serological screening and prophylactic and pre-emptive antiviral treatment with a nucleos(t)ide analogue should be considered in appropriate settings. Hepatitis B prevalence is examined in this review article, as are the risks of HBVr in patients receiving chemo- and immunosuppressive therapy. Recommendations regarding screening, monitoring and the role of antiviral prophylaxis are outlined with reference to current international associations' guidelines and the best available evidence to date.
基金Supported by The Instituto Nacional de Salud PúblicaMexicoby the grant from CONACYT-FOSISS SALUD2008-C01-494 87701,Mexico
文摘Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus(HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin(IL)-10and transforming growth factor(TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC Ⅰ, NIC Ⅱ and NIC Ⅲ and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.
文摘BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.
文摘AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free survival after liver transplantation （LT）.METHODS： Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS： Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were： presence of cirrhosis （P = 0.001）, etiology of liver disease （P = 0.03）, α fetoprotein level （〈 200, 200 to 2000, or 〉 2000; P 〈 0.0001）, y-GT activity （N, N to 2N or 〉 2N; P = 0.02）, the number of nodules （1, 2-3 or ≥ 4; P = 0.02）, maximal diameter of the largest nodule （〈 3 cm, 3 to 5 cm or 〉 5 cm; P 〈 0.0001）, the sum of the diameter of the nodules （〈 3 cm, 3 to 5 cm, 5 to 10 cm or 〉10 cm; P 〈 0.0001）, bilobar location （P = 0.01）, preoperative portal thrombosis （P 〈 0.0001）, peri-operative treatment of the tumor （P = 0.002） and chemoembolization （P = 0.03）, tumor differentiation （P = 0.01）, initial type of calcineurin inhibitor （P = 0.003）, the use of antilymphocyte antibodies （P = 0.02）, rejection episodes （P = 0.003） and period of LT （P 〈 0.0001）. By multivariate analysis, 6 variables were independently associated with HCC recurrence： maximal diameter of the largest nodule （P 〈 0.0001）, time of LT （P 〈 0.0001）, tumor differentiation （P 〈 0.0001）, use of anti-lymphocyte antibody （ATG） or anti-CD3 antibody （OKT3） （P = 0.005）, preoperative portal thrombosis （P = 0.06） and the number of nodules （P = 0.06）. CONCLUSION： This study identifies immunosuppression, through the use of ATG or OKT3, as a predictive factor of tumor recurrence, and confirms the prognostic value of tumor differentiation.
文摘AIM: To present the characteristics and the course of a series of anti- hepatitis B virus core antibody (HBc) antibody positive patients, who experienced hepatitis B virus (HBV) reactivation after immunosuppression. METHODS: We retrospectively evaluated in our tertiary centers the medical records of hepatitis B virus surface antigen (HBsAg) negative patients who suffered from HBV reactivation after chemotherapy or immunosuppression during a 3-year period (2009-2011). Accordingly, the clinical, laboratory and virological characteristics of 10 anti-HBc (+) anti-HBs (-)/HBsAg (-) and 4 anti-HBc (+)/antiHBs (+)/HBsAg (-) patients, who developed HBV reactivation after the initiation of chemotherapy or immunosuppressive treatment were analyzed. Quantitative determination of HBV DNA during reactivation was performed in all cases by a quantitative real time polymerase chain reaction kit (COBAS Taqman HBV Test; cut-off of detection: 6 IU/mL). RESULTS: Twelve out of 14 patients were males; median age 74.5 years. In 71.4% of them the primary diagnosis was hematologic malignancy; 78.6% had received rituximab (R) as part of the immunosuppressive regimen. The median time from last chemotherapy schedule till HBV reactivation for 10 out of 11 patients who received R was 3 (range 2-17) mo. Three patients (21.4%) deteriorated, manifesting ascites and hepatic encephalopathy and 2 (14.3%) of them died due to liver failure. CONCLUSION: HBsAg-negative anti-HBc antibody positive patients can develop HBV reactivation even 2 years after stopping immunosuppression, whereas prompt antiviral treatment on diagnosis of reactivation can be lifesaving.
文摘Liver transplantation has been the treatment of choice for end-stage liver disease since 1983.Cancer has emerged as a major long-term cause of death for liver transplant recipients.Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers postliver transplantation;some have also studied risk factors.Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers.Risk of head and neck,lung,esophageal,cervical cancers and Kaposi’s sarcoma is high,but risk of colorectal cancer is not clearly demonstrated.There appears to be no excess risk of developing breast or prostate cancer.Environmental risk factors such as viral infection and tobacco consumption,and personal risk factors such as obesity play a key role,but recent data also implicate the role of calcineurin inhibitors,whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis.In this paper,we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and,ultimately,discuss how to prevent these cancers.Immunosuppressive protocol changes,including a calcineurin inhibitor-free regimen,combined with dietary guidelines and smoking cessation,are theoretically the best preventive measures.
基金the National Natural Science Foundation of China,Nos.82172147(to YL),81571880(to YL),81373147(to YL),30901555(to JZ),30972870(to YL)the Natural Science Foundation of Hunan Province,Nos.2021JJ30900,2016JJ2157(both to YL)。
文摘Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.
