Treatment of recurrent HCV infection after liver transplantation

End-stage liver disease associated with hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) and accounts for 50% of these procedures in Spain and 42% of OLT performed in the United States. Recurrent infection with HCV after OLT, however, is almost universal and is associated with substantial morbidity, mortality, and graft loss. In contrast to immunocompetent individuals, HCV infection in immunosuppressed transplant recipients usually has an accelerated course. Acute hepatitis develops in approximately 75% of HCV recipients in the first six months following OLT. By the fifth postoperative year, over 80% of HCV-infected liver transplant recipients will develop histologic evidence of chronic allograft injury secondary to hepatitis C, with up to 30% developing cirrhosis. While the choice of calcineurin inhibitor has not been clearly shown to affect the histologic recurrence of hepatitis C or the frequency of rejection in HCV-infected recipients, cumulative exposure to corticosteroids is associated with increased mortality, higher levels of HCV viremia and more severe histologic recurrence. There have been no well-controlled, large, prospective, multicenter and randomized clinical trials to determine the optimal approach to the treatment of recurrent HCV infection following OLT. Most published studies were small, lacked controls, had short follow-up periods, and were devoid of histologic analysis. Furthermore, most of the published studies are largely incomparable due to differences in the definition of recurrent hepatitis C, timing of anti-HCV therapy administration relative to transplantation, the drugs and doses used and regimens employed, and the study end points assessed (i. e. biochemical, virologic and histologic end points have not all been consistently investigated). In lieu of large studies in post-transplant patients, monotherapy with conventional interferon or monotherapy with pegylated interferon should be considered in recipients with histologically confirmed recurrence of HCV infection. The role of hepatitis C immunoglobulin and new imunosuppression agents in the management of post-transplant HCV infection is still evolving.     

Early post-operative acute phase response in patients with early graft dysfunction is predictive of 6-month and 12-month mortality in liver transplant recipients

Early allograft dysfunction (EAD) after liver transplantation is mostly a reversible event caused by factors related to ischemia/reperfusion (I/R) injury. EAD represents a hepatic injury associated with pre- and early post-transplant inflammatory cytokine responses. Aim of the present study was to evaluate the prognostic and diagnostic value of CRP in liver transplant recipients with EAD.Materials and methodsForty-seven patients with EAD were compared with 115 non-EAD patients. Pre- and post-transplant parameters were analyzed. EAD was defined based on postoperative liver function tests such as INR, bilirubin and liver enzymes. Statistical analysis was performed using SPSS version 18.0.ResultsPre-transplant liver enzyme were not significantly different in the two groups. At day 3, 5 and 10 post-transplant CRP was significantly higher in patients with EAD than in non-EAD patients (p ⩽ 0.001 for all investigations) and remained consistently high in patients with EAD and low in non-EAD patients. EAD patients with high CRP at post-transplant days 3 and 5 showed lower survival at 6-month and 12-month post-transplant than patients with low CRP.ConclusionOur results indicate a prognostic and diagnostic value of CRP in patients with early graft dysfunction and predict 6-month and 12-month mortality in liver transplant recipients.     

Chemokines stimulate bidirectional migration of human mesenchymal stem cells across bone marrow endothelial cells

Mesenchymal stem cells (MSCs) can be mobilized from the bone marrow and enter the circulation. Conversely, MSCs can be recruited from the circulation and into the bone marrow. For these migratory pathways, MSCs have to traverse the bone marrow endothelium, in a basal-to-apical and apical-to-basal direction, respectively. Here we describe the migratory cues that drive MSC transendothelial migration in both directions with focus on chemokines. Live cell imaging and electron microscopy were used to examine the interaction of human MSCs with human bone marrow endothelial cells (HBMECs), and MSC transmigration analyzed. Chemokines CXCL12, CXCL13, CXCL16, CCL11, and CCL22 significantly enhanced transendothelial migration in an apical-to-basal and basal-to-apical direction, showing preferences in terms of their capacity to stimulate the direction of migration. For apical-to-basal migration CXCL16 was the most effective (6-fold stimulation), with the rank order being CXCL16>CCL11>CXCL13>CCL22>CXCL12. In the basal-to-apical direction CCL22 was the most effective (5-fold enhancement), with the remaining chemokines being roughly equal. When MSCs interacted with HBMECs they flattened, extended long microvilli (filopodia) and podosome-like protrusions that inserted into the endothelial cells. In conclusion, chemokines enhance the migration of MSCs bidirectionally across HBMECs, with directional preferences shown for different chemokines.     

Determining virological, serological and immunological parameters of EBV infection in the development of PTLD

Post-transplant lymphoproliferative disease (PTLD) in Epstein-Barr virus (EBV) seronegative solid organ transplant recipients remains a significant problem, particularly in the first year post-transplant. Immune monitoring of a cohort of high-risk patients indicated that four EBV seronegative transplant recipients developed early-onset PTLD prior to evidence of an EBV humoral response. EBV status has been classically defined serologically, however these patients demonstrated multiple parameters of EBV infection, including the generation of EBV-specific CTL, outgrowth of spontaneous lymphoblastoid cell lines, and elevated EBV DNA levels, despite the absence of a classic EBV antibody response. As EBV serology is influenced by both immunosuppression and cytomegalovirus immunoglobulin treatment, both the EBV-specific CTL response and elevated EBV levels are more reliable indicators of EBV infection post-transplant.     

Prevention of acute liver allograft rejection by IL‐10‐engineered mesenchymal stem cells

Hepatic allograft rejection remains a challenging problem, with acute rejection episode as the major barrier for long‐term survival in liver transplant recipients. To explore a strategy to prevent allograft rejection, we hypothesized that mesenchymal stem cells (MSCs) genetically engineered with interleukin‐10 (IL‐10) could produce beneficial effects on orthotopic liver transplantation (OLT) in the experimental rat model. Syngeneic MSCs transduced with IL‐10 were delivered via the right jugular vein 30 min post‐orthotopic transplantation in the rat model. To evaluate liver morphology and measure cytokine concentration, the blood and liver samples from each animal group were collected at different time‐points (3, 5 and 7 days) post‐transplantation. The mean survival time of the rats treated with MSCs–IL‐10 was shown to be much longer than those treated with saline. According to Banff scheme grading, the saline group scores increased significantly compared with those in the MSCs–IL‐10 group. Retinoid acid receptor‐related orphan receptor gamma t (RORγt) expression was more increased in the saline group compared to those in the MSCs–IL‐10 group in a time‐dependent manner; forkhead box protein 3 (FoxP3) expression also decreased significantly in the saline group compared with those in the MSCs–IL‐10 group in a time‐dependent manner. The expression of cytokines [IL‐17, IL‐23, IL‐6, interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α] in the saline groups increased significantly compared with the time‐point‐matched MSCs–IL‐10 group, whereas cytokine expression of (IL‐10, TGF‐β1) was deceased markedly compared to that in the MSCs–IL‐10 group. These results suggest a potential role for IL‐10‐engineered MSC therapy to overcome clinical liver transplantation rejection.     

Differences in the rate of donor leucocyte migration between natural and drug-assisted tolerance following rat liver transplantation

The number involved in and the rate of migration of donor leucocytes into the following recipient organs (spleen, thymus, bone marrow, lung and mesenteric lymph nodes) were measured in two rat models of orthotopic liver transplantation (OLT) using donor-specific MHC class I antibodies. The first OLT model is one that does not require immunosuppression in order to achieve tolerance and involved the transplantation of DA (MHC haplotype, RT1^a) livers into PVG (RT1^c) recipients. The second model was one that required a 7-day (10 mg/kg) treatment with cyclosporin A (CsA) to achieve tolerance and used DA donors into Lewis (RT1¹) recipients. Recipient organs were biopsied on days 3, 20 and 87 following OLT and donor leucocyte migration was quantified by immunohistochemistry and computer densitometry of immunoblots of detergent-solublized tissues in order to resolve both membrane-bound and soluble donor MHC class I antigen. In a separate experiment, spleen biopsies were taken following OLT on days 3 and 15 from the naturally tolerizing OLT model (DA into PVG), treated with and without CsA for 7 days and compared with the (DA into Lewis) model. The initial rate of leucocyte migration between days 3 and 21 following OLT was found to be the most rapid into the spleen, followed by the bone marrow and mesenteric lymph nodes in the naturally tolerant (DA into PVG) model when compared with the (DA into Lewis) model. The number of donor leucocytes in the spleen and mesenteric lymph nodes in both models was, however, approximately the same by 87 days. No real difference in the rate of leucocyte migration was seen in the thymus or the lung for both transplant models over the time course assayed. CsA was found to lower the rate of donor leucocyte migration only over the period it was administered. The rate of donor leucocyte migration into the spleen was still much lower 15 days after OLT in the (DA into Lewis) model compared with the (DA into PVG) model treated with and without CsA. Thus the differences in the rate of donor leucocyte migration into the spleen, bone marrow and mesenteric lymph nodes immediately following OLT may offer an explanation as to why the (DA into PVG) combination is able to accept a transplanted liver without immunosuppressive therapy.     

Psychiatric disorders before and after living-related transplantation

The authors examined psychiatric disorders among two samples of patients who underwent living-related transplant (LRT) for kidney and liver failure. The postoperative prevalence of psychiatric disorders for adult transplant recipients was highest the first 3 months posttransplant. The incidence of psychiatric disorders in the adult recipients with living-related liver transplant (LRLT) was higher (54%, 22 of 41) than that of adult recipients with living-related kidney transplant (LRKT) (28%, 65 of 234). Twelve (80%) of the 15 adult LRLT recipients with adult child-to-parent donors exhibited paradoxical psychiatric syndrome (PPS). Among the 12 affected recipients, guilt-based psychiatric disorders of various types occurred despite successful operative outcome for both donor and recipient. The higher rate of psychiatric disorders among adult LRLT recipients was associated with the occurrence of PPS among recipients of an adult-child allograft. These results signal a new challenge for consultation psychiatrists working with transplant patients.     

Serial immunologic studies in recipients of hepatic allografts

Thirty recipients of hepatic allografts had serial immunologic evaluations. Prior to transplant, patients had marked depression of lymphocyte subsets and impaired in vitro immunoglobulin synthesis, while phytohemagglutinin responsiveness was similar to that of controls. Following transplantation and introduction of cyclosporine and low-dose steroid therapy, there was a significant decline in both T cell subsets, but only the T4 population remained significantly depressed throughout the entire study period. The T4:T8 ratio in 5 patients who experienced acute rejection episodes was 1.4 +/- 0.6 prior to transplant. It increased to a mean of 2.0 +/- 0.6 by the time the diagnosis of rejection was made. By contrast, 12 subjects transplanted during a similar time period who did not demonstrate rejection had a T4:T8 ratio of 4.0 +/- 3.9 prior to transplant which fell to 1.5 +/- 0.6 (P less than 0.01) by 1 week post-transplant. In all 12 of these, the T4:T8 ratio fell in the 7 days post-transplant. The results indicate that monitoring the T4:T8 ratio in hepatic allograft recipients may be a useful marker for determining patients at risk for a rejection episode.     

Risk factors of tuberculosis after liver transplant in a tertiary care hospital

BackgroundTuberculosis (TB) is a serious opportunistic infection in liver transplant (LT) recipients with a high rate of morbidity and mortality. This study aims to clarify the frequency and risk factors for tuberculosis in LT recipients.MethodsA total of 884 LT recipients were investigated retrospectively at China Medical University Hospital, Taichung, Taiwan. We performed a case–control study (1:2) to investigate the potential risk factors and disease onset of TB after LT.ResultsAmong the 884 LT recipients, 25 of TB cases (2.8%) were reported from 2009 to 2016. The overall incidence of TB was 744 cases per 100,000 patient-year, which was 18-fold higher than the general population in Taiwan. The median time to develop TB after liver transplant was 20 months. Of the TB cases, 15 were pulmonary TB and 10 were extra-pulmonary TB. Five cases of those extra-pulmonary TB occurred in the first post-transplant year. Overall five-year survival rate was 63.3%. Multivariate analyses identified apical fibrotic change in pre-transplant computed tomographic (CT) finding and the exposure to mammalian target of rapamycin (mTOR) inhibitors before TB event as independent risk factors for TB development (Odd ratio (OR) 10.79, 95% confidence interval (CI), 1.73–67.49, p = 0.01; OR 3.847, 95% CI 0.80–18.51, P = 0.09, respectively).ConclusionTB incidence in LT recipients is high in this study. Among those post-transplant recipients with long-term immunosuppression, abnormal CT finding and exposure to mTOR inhibitors before liver transplant might be the risk factors for TB.     

Murine mesenchymal stem cells transplanted to the central nervous system of neonatal versus adult mice exhibit distinct engraftment kinetics and express receptors that guide neuronal cell migration

Mesenchymal stem cells (MSCs) have demonstrated efficacy as cellular vectors for treating a variety of nervous system disorders. Nevertheless, few studies have quantified MSC engraftment levels or explored the mechanisms that promote their survival and migration in nervous tissue. In this study, we compared the engraftment kinetics and anatomical distribution of murine, male MSCs injected intracranially into neonatal versus adult female mice using a real-time PCR assay that targets the mouse SRY gene. These analyses revealed that MSCs exhibited low but equivalent engraftment levels in the central nervous system (CNS) of neonatal and adult transplant recipients at 12 days post-injection. However, MSC engraftment levels were significantly greater at 60 and 150 days post-transplantation in neonates as compared to adults. Despite these differences, engrafted MSCs were widely distributed along the neuraxis of the CNS in both transplant groups. Collectively, these data indicate that proliferation, but not engraftment and migration, of MSCs in brain are regulated by the host microenvironment. Using a genomics approach, we also identified MSC subpopulations that express neural adhesion proteins and receptors that regulate neuronal cell migration in brain, including cadherin 2, neurexin 1, ninjurin 1, neogenin 1, neuropilin 2, and roundabout homolog 1 and 4. Functional studies indicate these proteins confer cell adhesion and migration of MSCs in response to the appropriate chemoattractant. On the basis of these findings, we conclude that the unique molecular composition of MSC subpopulations imparts to them an inherent capacity to engraft and migrate in brain. These subpopulations may represent more potent cellular vectors for treating CNS disorders.     

Mechanisms in passive enhancement of cardiac and renal allografts by serum from liver-grafted rats.

The ability of serum from PVG (haplotype RT1c) rats carrying long-term surviving orthotopic DA (RT1a) liver grafts (OLT serum) to enhance cardiac allografts has been confirmed and extended to renal allografts. One millilitre of OLT serum given at the time of allografting was sufficient to cause permanent acceptance of PVG.RT1a heart or kidney grafts in PVG recipients ('enhanced recipients'); the PVG.RT1a being congenic with respect to PVG, and sharing the RT1a haplotype with DA. Adoptive transfer of thoracic duct lymphocytes (TDL) from rats carrying enhanced liver grafts into irradiated recipients indicated that specific alloreactive clones had been functionally inactivated or deleted; this was accompanied by active suppression in which specific alloreactivity of normal TDL was partially inhibited. In vitro, splenic T cells from rats with enhanced grafts mediated allospecific suppression in mixed lymphocyte reaction (MLR). The serum of rats carrying enhanced grafts was able to specifically suppress MLR of the same donor/recipient combination. Thus enhancement by orthotopic liver transplantation (OLT) serum leads to cellular and serological changes in the recipient associated with maintenance of unresponsiveness. Such changes are similar to those seen in liver graft recipients themselves.     

Efficacy of influenza vaccination in adult liver transplant recipients

To assess the efficacy of influenza vaccination in immunocompromised adult liver transplant (LTx) recipients, the serum antibody responses of 61 of these patients and 35 liver cirrhosis patients with those of 45 of their healthy spouses were compared, after one and two vaccinations with a commercial trivalent subunit influenza vaccine. In addition, virus-specific proliferative T-cell responses were measured in LTx recipients and their healthy spouses. In all three study groups, significant rises in geometric mean antibody titers were observed for all three antigens after one vaccination. These titers did not continue to increase significantly after the second vaccination in patients with cirrhosis and control subjects but did rise for LTx recipients. The overall antibody response to all three influenza virus strains proved to be significantly lower in the LTx recipients than in the group of healthy subjects after both one and two vaccinations. More than 68% of the LTx recipients developed hemagglutination-inhibiting serum antibody titers >/=40 against all three vaccine strains after the first vaccination and more than 80% after the second vaccination. These findings correlated with the T-cell responses determined for the group of LTx recipients and healthy control individuals. Testing of the respective serum samples against influenza virus A/Sydney/5/97, which circulated in the 1997-1998 influenza season and showed a considerable mismatch with the vaccine strain A/Nanchang/933/95, indicated that such a mismatch may have significant consequences for vaccine efficacy, especially for LTx recipients. Collectively the data show that LTx recipients can be vaccinated effectively against influenza despite immunosuppressive therapy. A two-dose vaccination regimen improved vaccination efficacy in LTx recipients. Whether transplant patients generally benefit from a two-dose vaccination regimen should be evaluated further.     

Impact of HLA-C and Bw epitopes disparity on liver transplantation outcome

The occurrence of graft rejection episodes after orthotopic liver transplantation (OLT) despite the use of immunosuppressive drugs designed to suppress T lymphocyte functions, indicates the involvement of other types of cells in this process. The activity of natural killer cells and their killer immunoglobulin-like receptors (KIR) is regulated by human leukocyte antigen (HLA) class I determinants; C and Bw epitopes. Because recipient/donor pairs are usually HLA mismatched, recipient natural killer alloreactivity may be the mediating factor in rejection. In this retrospective study, we have analyzed rejection occurrence and outcome in 66 OLT recipients, 42 with and 24 without C or Bw epitope disparity in the rejection direction. Recipients transplanted from donors with no C epitope disparity had significantly fewer rejection episodes in the first year after transplantation compared with recipients transplanted across C epitope disparity (p = 0.0002). Moreover, this effect was more pronounced when the outcome was analyzed in OLT recipients across negative crossmatching for the anti-HLA class I and II antibodies. In contrast, Bw epitope disparity did not affect the outcome. In conclusion, C epitopes disparity between recipients and donors in the rejection direction appears to influence posttransplant liver outcome. This finding may be helpful in the choice of appropriate liver donor and planning immune suppression.     

Early use of PCSK9 inhibitor therapy after heart transplantation from a hepatitis C virus positive donor

Although statin therapy is a primary treatment to prevent cardiac allograft vasculopathy (CAV), its use may be delayed due to pharmacologic interactions in the early post-transplant period among heart transplant (HT) recipients with hepatitis C virus positive (HCV+) donors. Further examination of the possible benefits of early, nonstatin lipid-lowering therapies (LLT), such as PCSK9 inhibitors (PCSK9i), among this specific subset of transplant recipients is therefore becoming increasingly important. We report a 60-year-old man who received a HT from a HCV+ donor for end-stage ischemic cardiomyopathy. In the early post-transplant period, there was concern for drug-drug interactions between statin, immunosuppressant, and direct acting antiviral (DAA) therapy. In addition, prior to transplant, he reported statin-associated muscle symptoms in response to multiple statins, which persisted despite attempts to re-challenge and use an every-other-day dosing strategy. Therefore, the patient was started on PCSK9i therapy after transplantation and while receiving curative DAA therapy for HCV. As the number of HT recipients of HCV+ donors continue to rise, investigation into the safety and benefits of early use of PCSK9i for the reduction of CAV and improved cardiovascular and mortality outcomes should be pursued.     

p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients.

Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for post-transplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in >10% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53+ (P=0.0007) and Ki-67+ cases (P=0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level >or=100 ng/ml at time of diagnosis, compared to those with an AFP level <100 ng/ml (P=0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level >or=100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.     

Novel immunoassay for the detection of hepatitis B surface 'escape' mutants and its application in liver transplant recipients

Hepatitis B virus (HBV) strains with mutations in the surface gene are responsible for the failure of prophylaxis with hepatitis B immunoglobulin (HBIG) in a proportion of patients transplanted for HBsAg positive cirrhosis. So far, the emergence and evolution of these 'surface antibody escape' mutants have been studied by DNA sequencing. In this study the use of an immunoassay is described for diagnosis and characterisation of HBV recurrence after liver transplantation (OLT), based on a monoclonal antibody able to recognise both wild-type and mutant HBsAg. Pre- and post-transplant samples from 22 patients transplanted for HBsAg positive cirrhosis were studied: Group A: 12 patients who reinfected the graft despite receiving HBIG; Group B: 6 patients with no HBV recurrence with continuous HBIG; Group C: 4 patients with HBV recurrence without prophylaxis. By running the new assay in parallel with an immunoassay that is susceptible to HBsAg mutants, 4 of 12 cases were identified in Group A with HBV recurrence due to surface antibody escape mutants, whereas in 8 patients this was due to the wild-type HBV. The results from the immunoassays were confirmed in all cases by HBV DNA sequencing. The surface gene mutations in the 4 patients affected codons 144 and 145 and in one of these 4 patients HBV strains with mutations in both codons were detected before and after transplantation. The epitope recognised by the new monoclonal antibody that reacts with both wild-type and mutant HBsAg seems to remain stable in the HBIG-induced HBV mutants. This serological approach allows rapid and cost-effective screening for HBsAg escape mutants in the liver transplant setting and may be helpful in the selection of appropriate prophylaxis.     

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

The initial step in Langerhans cell (LC) migration from the epidermis to the lymph node involves migration of maturing LC into the dermis. Here, we investigated the migration of LC out of the epidermis after exposure of the skin to contact allergens. Ex vivo intact human skin, epidermal sheets, and LC derived from the MUTZ-3 cell line (MUTZ-LC) were used to determine whether dermal fibroblasts play a role in mediating LC migration towards the dermis. Exposure of epidermal sheets or MUTZ-LC to allergens (nickel sulphate, 2,4-dinitrochlorobenzene, and cinnamaldehyde) or a cytokine maturation cocktail resulted in LC migration towards dermal fibroblasts. This was due to upregulation of CXCR4 on maturing LC and secretion of CXCL12/stromal derived factor-1 chemokine by fibroblasts. Neutralizing antibodies to either CXCL12 or CXCR4 completely blocked migration. Injection of CXCL12 neutralizing antibodies into intact human skin totally inhibited LC migration into the dermis. In contrast, neutralizing antibodies to CCL19/CCL21 did not inhibit migration into the dermis. We describe a novel and essential role of dermis-derived CXCL12 in initiating migration of maturing human LC to the dermis thus permitting their further journey to the draining lymph nodes.     

HBV感染者肝移植后淋巴细胞亚群变化分析

目的:探讨HBV感染患者肝移植后短期淋巴细胞亚群和细胞因子的变化规律,为肝移植后免疫状态的监测提供依据。方法:用流式细胞术(FCM)和酶联免疫吸附试验(ELISA)检测20例HBV感染相关的终末期肝病和肝癌患者肝移植前和移植后12 h、3 d、10 d、30 d、60 d的外周血淋巴细胞亚群和细胞因子水平,与22例健康人比较。结果:HBV感染患者肝移植前淋巴细胞各亚群绝对值显著低于健康对照,移植后12 h淋巴细胞各亚群绝对值大大降低,3 d后回升,移植后10 d起CD3、CD4、CD8及NK细胞百分比和绝对值达到稳定,60 d时其绝对值比移植前大大升高,但仍显著低于健康对照;移植后12 h时IFN-γ和IL-10水平升高数倍,3 d后显著下降,60 d时IL-10水平仍高于健康对照。结论:肝移植后10 d患者淋巴细胞亚群绝对数量升高至稳定水平,但仍低于正常;肝移植后免疫倾向于Th2极化。     

Prospective Follow-up of Epstein-Barr Virus Load in Adult Kidney Transplant Recipients by Semiquantitative Polymerase Chain Reaction in Blood and Saliva Samples

The aim of the study presented here was to set up and standardize a semiquantitative polymerase chain reaction method for monitoring Epstein-Barr virus (EBV) DNA levels in blood and saliva samples from transplant recipients and to determine the value of these levels as an early marker for the development of post-transplant lymphoproliferative disorders. EBV DNA load was prospectively measured in 53 adult kidney transplant recipients. Results were correlated with clinical features and degree of immunosuppression. Healthy blood donors and patients with infectious mononucleosis were used as controls. Levels higher than 500 EBV DNA copies/75,000 peripheral blood mononuclear cells were found in all patients with infectious mononucleosis and in all patients with post-transplant lymphoproliferative disorder but in only 7.5% of transplant recipients without that complication. Electronic Publication     

Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV- and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-blood-vessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.