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Biomedical subjects

Suzanne Norris

Publications and source records attributed to Suzanne Norris.

At least 19 recordsLinked to original sources
PubMed2006

HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C.

Patients infected with HIV-1 who are heterozygous at HLA class I loci present greater variety of antigenic peptides to CD8+ cytotoxic T lymphocytes, slowing progression to AIDS. A similar broad immune response in chronic hepatitis C (CHC) infection could result in greater hepatic injury. Although specific HLA class II alleles may influence outcome in CHC patients, the role of HLA class I heterogeneity is generally less clearly defined. Our aims were to determine whether HLA class I allelic diversity is associated with disease severity and progression of fibrosis in CHC. The study population consisted of 670 adults with CHC, including 155 with advanced cirrhosis, and 237 non-HCV-infected controls. Serological testing for HLA class I antigens was performed via microlymphocytotoxicity assay. Peptide expression was defined as heterozygous (i.e., a different allele at each locus) or homozygous. Fibrosis staging was determined using METAVIR classification. Heterozygosity at the B locus (fibrosis progression rate [FPR] 0.08 vs. 0.06 units/yr; P = .04) and homozygosity at the A locus (FPR 0.10 vs. 0.08 units/yr; P = .04) predicted a higher median FPR. Age at infection, genotype, and duration of infection were also predictors of FPR. A higher proportion of patients with stage F2-F4 expressed HLA-B18 compared with controls (OR 2.2, 95% CI 1.17-4.23; P = .02). These differences were not observed in patients with advanced cirrhosis. HLA zygosity at 1, 2, or 3 alleles was not associated with fibrosis stage, liver inflammation, or treatment outcome. In conclusion, HLA class I allelic diversity has a minor influence on FPRs and disease severity in CHC.

Adult↗
PubMed2005

Liver transplantation for HCV-related cirrhosis in a patient with gastric mucosa-associated lymphoma (MALToma) pretreated with rituximab.

End-stage liver disease due to chronic hepatitis C virus (HCV) infection is now the most frequent indication for liver transplantation. HCV infection is associated with extrahepatic disease including cryoglobulinemia and lymphoma. The number of patients requiring liver transplantation (LT) for cirrhosis secondary to HCV infection has increased over the past 10 years; consequently, associated extrahepatic manifestations (in particular hematological malignancies) will be more commonly observed in this patient group. The management of patients with both end-stage liver disease and significant HCV-related extrahepatic disease is undefined. We report a 59-year-old man in whom extranodal marginal-zone B-cell lymphoma arising in gastric mucosa-associated lymphoid tissue (MALToma) was successfully eradicated by rituximab administration and gastrectomy at LT for HCV-related cirrhosis. Our experience with rituximab in this patient suggests that it can be used safely in the setting of severe liver disease due to HCV infection. Rituximab may be useful in preventing progression of NHL until surgical extirpation is possible.

Antibodies, Monoclonal↗
PubMed2004

Hepatitis B virus genotype A and D and clinical outcomes of liver transplantation for HBV-related disease.

Hepatitis B virus (HBV) genotypes have been associated with specific patterns of disease and response to antiviral therapy. We investigated the effect of HBV genotype on HBV recurrence and mortality after liver transplantation (LT). Pretransplant sera of 45 hepatitis B surface antigen (HBsAg) positive adults were submitted for HBV genotyping by a reverse-phase hybridization line probe assay with genotype-specific probes. Data were correlated with clinical outcomes after transplantation. Genotype A (n =15), D (n = 13) and A/D (n = 12) accounted for 89% of all genotypes. Coinfection with two HBV genotypes was encountered in 14 (31.1%) patients. Eighteen patients (40 %) developed HBV recurrence at a median of 10 months posttransplant (range, 1-53) and 10 patients (22 %) died at a median of 24 months (range, 3-63). Genotype D patients were more likely to develop HBV recurrence or die compared with genotype A patients, although this did not reach statistical significance. Dual infection with genotype A/D resulted in mortality similar to that of genotype A but recurrence similar to that of genotype D. Active viral replication at time of transplantation was the only independent factor (P = 0.03) that predicted HBV recurrence. In conclusion, HBV genotype A and D did not have a significant impact on clinical outcomes of LT for HBV-related liver disease in patients of European origin. These data do not support routine HBV genotyping in liver transplantation.

Adolescent↗
PubMed2004

Mitochondrial toxicity associated with HAART following liver transplantation in an HIV-infected recipient.

Antiretroviral therapy is not uncommonly associated with drug toxicities, and hepatotoxicity occurs in approximately 20% of individuals prescribed antiretroviral therapy. Mitochondrial toxicity causing lactic acidosis is a rare but fatal complication that has been described in some HIV-infected patients treated with nucleoside analogue reverse transcriptase inhibitors. In this report, we describe the course of an HIV-infected patient receiving antiretroviral therapy who developed lactic acidosis after liver transplantation for HCV-induced liver disease.

Acidosis, Lactic↗
PubMed2004

Outcomes of liver transplantation in HIV-infected individuals: the impact of HCV and HBV infection.

Liver transplantation (LT) in human immunodeficiency virus (HIV)-positive individuals is considered to be an experimental therapy with limited reported worldwide experience, and little long-term survival data. Published data suggest that the short-term outcome is encouraging in selected patients. Here, we report our experience in 14 HIV-infected liver allograft recipients, and compare outcomes between those coinfected with hepatitis C virus (HCV) and the non-HCV group. A total of 14 HIV-infected patients (12 male, 2 female, age range 26-59 years) underwent LT between January 1995 and April 2003. Indications for LT were HCV (n = 7), hepatitis B virus (HBV; n = 4), alcohol-induced liver disease (n = 2), and seronegative hepatitis (n = 1); 3 patients presented with acute liver failure. At LT, CD4 cell counts (T-helper cells that are targets for HIV) ranged from 124 to 500 cells/microL (mean 264), and HIV viral loads from <50 to 197,000 copies/mL. Nine of 12 patients were exposed to highly active antiretroviral therapy (HAART) before LT. In the non-HCV group (n = 7), all patients are alive, all surviving more than 365 days (range 668-2,661 days). No patient has experienced HBV recurrence, and graft function is normal in all 7 patients. However, 5 of 7 HCV-infected patients died after LT at 95-784 days (median 161 days). A total of 4 patients died of complications due to recurrent HCV infection and sepsis, despite antiviral therapy in 3 of them. A total of 3 patients experienced complications relating to HAART therapy. In conclusion, outcome of LT in HIV-infected patients with HBV or other causes of chronic liver disease indicates that LT is an acceptable therapeutic option in selected patients. However, longer follow-up in larger series is required before a conclusive directive can be provided for HCV / HIV coinfected patients requiring LT.

Adult↗
PubMed2004

Distinct subpopulations of gamma delta T cells are present in normal and tumor-bearing human liver.

Gamma delta T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and characterized hepatic and peripheral blood gamma delta T cells from 11 normal and 13 unresolved tumor-bearing human liver specimens. gamma delta T cells are enriched in normal liver (6.6% of T cells) relative to matched blood (0.9%; P = 0.008). The majority express CD4(-)CD8(-) phenotypes and many express CD56 and/or CD161. In vitro, hepatic gamma delta T cells can be induced to kill tumor cell lines and release interferon-gamma, tumor necrosis factor-alpha, interleukin-2 and interleukin-4. Analysis of V gamma and V delta chain usage indicated that V delta 3(+) cells are expanded in normal livers (21.2% of gamma delta T cells) compared to blood (0.5%; P = 0.001). Tumor-bearing livers had significant expansions and depletions of gamma delta T cell subsets but normal cytolytic activity. This study identifies novel populations of liver T cells that may play a role in immunity against tumors.

Adolescent↗
PubMed2003

Expansion of innate CD5pos B cells expressing high levels of CD81 in hepatitis C virus infected liver.

BACKGROUND/AIMS: Association of hepatitis C virus (HCV) with increased autoantibodies, mixed cryoglobulinaemia, non-Hodgkin's B-cell lymphoma and increased peripheral innate (CD5(pos)) B cells suggests a role for B-lymphocytes in the pathogenesis of HCV-infection. METHODS: Flow cytometry was used to estimate CD5(pos) B cell levels and CD81 co-expression in chronic HCV infection. Viral load was assessed using PCR. RESULTS: We demonstrate expansion of innate B cells in HCV-infected liver from patients with fibrosis score less than stage II (39%, % of total B cells, P=0.002) and end stage HCV cirrhosis (20%, P<0.05) compared with normal liver (8%). Expression of CD81, a signal transducing molecule and putative HCV receptor, was significantly increased on peripheral blood CD5(pos) B cells compared with conventional B cells (P=0.0001). Higher levels of CD81 on CD5(pos) B cells were more dramatic in the liver of HCV-infected individuals. However, no significant difference was observed in the viral load of CD5(pos)CD81(High) B cells and CD5(neg)CD81(Low) B cells. CONCLUSIONS: Increased expression of CD81 on innate B cells, a population that is expanded in the livers and peripheral blood of chronic HCV-infected patients, suggests a role in viral specific activation and clonal proliferation in chronic HCV infection.

Adult↗
PubMed2002

Selective reduction of natural killer cells and T cells expressing inhibitory receptors for MHC class I in the livers of patients with hepatic malignancy.

Natural killer (NK) and CD56(+) T cells are thought to play a central role in antitumour immunity. Their cytolytic activities are controlled by a variety of receptors including CD94 and killer immunoglobulin-like receptors (KIR), which bind to major histocompatibility complex (MHC) class I molecules on target cells and mediate cell activation or inhibition. We have examined the numbers, phenotypes and antitumour cytotoxic functions of hepatic NK and CD56(+) T cells isolated from 22 patients with hepatic malignancy and 19 healthy donors. Flow cytometry revealed that NK cell numbers were increased among hepatic mononuclear cells in malignancy compared to histologically normal livers (mean: 38% vs 27%; P=0.03), but CD56(+) T cell numbers were not (28% vs 27%). NK cells and CD56(+) T cells from tumour-bearing livers exhibited lymphokine-activated killing of K562 targets and T cell receptor-mediated lysis of P815 cells. The expression of CD94 and the KIR isotypes CD158a, CD158b and KIR3DL1 by CD56(+) T cells and NK cells was significantly and consistently reduced in tumour-bearing livers compared to healthy livers ( P<0.05 in all cases). Simultaneous ligation of CD158a, CD158b and KIR3DL1 caused an overall partial inhibition of CD56(+) T cell cytotoxic activity, suggesting that the observed reductions in KIR(+) cell numbers in malignancy are likely to lead to enhanced cytotoxicity. Our results suggest that, while hepatic CD56(+) T cells are not expanded in malignancy, downregulation of KIR and CD94 expression may be a mechanism by which the hepatic immune system can be activated to facilitate tumour rejection.

Adenocarcinoma↗
PubMed2002

Cytomegalovirus infection after liver transplantation: viral load as a guide to treating clinical infection.

BACKGROUND: Quantitative commercial assays for early and accurate detection of active cytomegalovirus (CMV) infection after liver transplantation are widely available. However, meaningful interpretation of viral load measurements is hampered by the lack of definitive cutoff points that correlate with clinically significant disease. METHODS: One hundred fifty liver allograft recipients were prospectively monitored for the presence of CMV DNA for the first 12 weeks after orthotopic liver transplantation using the Murex hybrid capture system. The first CMV DNA value after liver transplantation, a weekly rise in CMV DNA (gradient value), and the CMV DNA value on clinical detection of active infection (critical value) were analyzed as risk factors for CMV infection. RESULTS: Forty-four (29.3%) of 150 patients had detectable CMV DNA within 12 weeks of transplantation, and 20 (13.3%) experienced symptomatic CMV infection. Multiple regression analysis demonstrated that baseline CMV DNA level above 10 pg/mL, positive weekly increase in CMV DNA level, and critical CMV DNA level above 13 pg/mL were independent risk factors for clinically significant infection. Using Cox's multiple regression model, the hazard ratio was 13.9 for baseline CMV DNA above 10 (P =0.0001; 95% confidence interval, 3.5-54) and 13 for a weekly increase in the gradient (P =0.0003; 95% confidence interval, 3.5-50). Critical CMV DNA level above 13 correlated with active infection (100% sensitivity, 98% specificity, 90% positive predictive value, 100% negative predictive value). CONCLUSION: Baseline and gradient CMV DNA viral load levels correlate with active CMV infection in liver allograft recipients. These data indicate that CMV viral load detection by hybridization methodology is useful in predicting active CMV infection and could be used in a preemptive strategy in liver allograft recipients.

Adult↗
PubMed2002

Decrease in hepatic CD56(+) T cells and V alpha 24(+) natural killer T cells in chronic hepatitis C viral infection.

BACKGROUND/AIMS: The intrahepatic immune system is likely to play a key role in determining the outcome of hepatitis C virus (HCV) infection. The hepatic lymphocyte repertoire is characterised by high CD8/CD4 T cell ratios and large numbers of gamma delta T cells, natural killer (NK) cells, NK T cells and NK receptor-positive T cells. It is not known which of these populations contribute to immunity against HCV or immune pathology. METHODS: To explore the relative contributions of lymphocyte subpopulations, we have compared the intrahepatic lymphocyte repertoires and cytokine expression in 13 patients with mild chronic hepatitis C infection, 14 with end-stage hepatitis C cirrhosis and five histologically normal livers by flow cytometry and immunohistochemistry. RESULTS: CD4(+) T cells bearing alpha beta T cell receptors (TCR) were significantly expanded in livers with chronic HCV infection while CD56(+) alpha beta T cells and V alpha 24 TCR-positive T cells were significantly depleted. Expanded CD4(+)T cells were predominantly Th1 cells, producing interferon-gamma but not interleukin-4. CONCLUSIONS: Failure to resolve HCV infection may be due to deficient innate and/or memory immune responses, while Th1 cells may mediate immune pathology.

Adult↗
PubMed2002

Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis.

BACKGROUND/AIMS: Toxicity and efficacy of azathioprine is governed partly by the activity of thiopurine methyltransferase (TPMT). Azathioprine has been used for many years, with corticosteroids or alone, for the treatment of autoimmune hepatitis (AIH) but no studies of TPMT phenotype and genotype in relation to response to the drug in AIH have been published. METHODS: Erythrocyte TPMT activities were measured by a radioincorporation assay in 72 consecutive outpatients with AIH, 53 of whom were genotyped for the commonest defective alleles in Europeans (TPMT*3A, *3B and *3C) by restriction fragment length polymorphism analysis. RESULTS: TPMT activities were significantly lower in patients intolerant of azathioprine (group I, n=15) than in those who sustained remission on azathioprine alone (group II, n=28; P=0.003) and those who tolerated azathioprine but continued to require corticosteroids (group III, n=29; P<0.0001), and were higher in group III than in group II (P=0.034). Ten patients with defective alleles (all heterozygotes) had significantly lower TPMT activities (P=0.002). However, in 25% there was discordance between phenotype and/or genotype and response to azathioprine. CONCLUSIONS: TPMT phenotyping or genotyping may be advisable before institution of azathioprine therapy in AIH but neither approach invariably predicts response to the drug.

Adolescent↗
PubMed2002

Evidence of differential risk for posttransplantation malignancy based on pretransplantation cause in patients undergoing liver transplantation.

Organ transplant recipients are considered to be at greater risk for developing malignancy because of the prolonged immunosuppression associated with organ grafting. The purpose of this study is to determine risk factors, clinical characteristics, and outcomes of de novo nonlymphoid malignancies after liver transplantation from a large single-center series. All patients undergoing liver transplantation at the King's College Hospital (London, UK) between January 1988 and December 1999 were analyzed retrospectively for the development of de novo malignancy in the posttransplantation period. Records were evaluated for age at diagnosis of malignancy, cause of liver disease, interval from transplantation to diagnosis of malignancy, predisposing factors for the development of cancer, immunosuppression regimen, treatment of malignancy, rejection episodes, and patient survival. Of 1,140 patients undergoing 1,271 liver transplantations, 30 patients (2.6%) developed de novo nonlymphoid malignancy after transplantation. Skin cancers were the most common (n = 13), followed by oropharyngeal carcinoma (n = 2), bladder carcinoma (n = 2), acute leukemia (n = 2), breast carcinoma (n = 2), and various other malignancies (n = 9). The mean time of presentation of the malignancy after transplantation was 45.1 +/- 32 months (range, 6 to 133 months), and mean age at diagnosis of malignancy was 55 years (range, 34 to 71 years). The incidence of de novo malignancy was significantly greater in patients who underwent transplantation for alcoholic liver disease compared with other groups (P <.001). Although the incidence of de novo nonlymphoid malignancy after liver transplantation is low, patients who underwent transplantation for alcoholic cirrhosis appear to have an increased risk for developing posttransplantation malignancy.

Adult↗
PubMed2002

Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Genetic susceptibility to primary sclerosing cholangitis is associated with several different HLA haplotypes, though a single "shared" susceptibility allele has yet to be identified. Most recently, attention has focussed on the MICA alleles in close proximity to the HLA class I, B locus. However, although there are strong associations with MICA*008, implicating this or a closely linked allele as major risk factors, this explanation alone does not account for all of the MHC-encoded susceptibility and resistance to PSC. The present study re-examines HLA class II associations in a large single centre series of well-characterised PSC patients. The specific aims of the study were to test existing associations and to develop hypotheses which together may account for all, or the majority, of the MHC-encoded susceptibility in PSC. METHODS: A total of 148 adult white northern European patients and 134 control subjects were studied. HLA DRB1, DQA1, DQB1 alleles and DRB1*04, DRB1*13 and DRB3 subtypes were determined by standard PCR-genotyping. RESULTS: The primary associations with the DRB3*0101--DRB1*0301--DQA1*0501--DQB1*0201 and DRB1*1301--DQA1*0103--DQB1*0603 haplotypes were confirmed (O.R. = 2.69, p < 0.0000025 and O.R. = 3.8, p < 0.0005). In addition the strong protective influence of the DRB1*04--DQB1*0302 haplotype was reaffirmed (O.R. = 0.26, p < 0.000025) and a previously unreported negative (i.e. protective) association with the DRB1*0701--DQB1*0303 haplotype was also demonstrated (O.R. = 0.15, p < 0.005). Further analysis suggested that susceptibility/resistance encoded by the second and third susceptibility haplotypes and by the two resistance haplotypes may be determined by specific amino acids at DQbeta-87 and DQbeta-55, respectively.

Amino Acid Motifs↗
PubMedDate not supplied

Hepatic expression of IL-15 mRNA is associated with liver graft acceptance.

BACKGROUND: Acute allograft rejection continues to be a major cause of morbidity following organ transplantation. The aim of this study was to investigate the local expression of a range of immunomodulatory molecules which may be mediating rejection of, or tolerance to, liver allografts. METHODS: RNA was extracted from 31 protocol liver biopsies taken 7-10 days post-transplantation, reverse transcribed and screened by a sensitive RT-PCR for a wide range of cytokines and other immunomodulatory molecules. The mRNA profile of each biopsy was subsequently related to the histological and clinical status of the graft. Samples of RNA isolated from activated leukocytes and T cell clones, and from normal liver, were used as controls to compare to the 'immunological snapshot' obtained from the biopsies. RESULTS: Presence of tumour necrosis factor-alpha, fas ligand, granzyme B and perforin mRNA in most of the liver biopsies reflected the occurrence of cell-mediated immune reactions. However, the expression of only one cytokine, interleukin-15 (IL-15), was significantly more frequent in allografts that showed no histological or biochemical signs of rejection during the early post-transplant period. Using an in vitro model it was demonstrated that recombinant IL-15 expands tenfold the number of CD3(+)CD56(+) (natural T; NT) cells from peripheral blood mononuclear cells cultures. Conditioning with IL-15 also increased cytotoxic activity of lymphocytes against leukaemic target cells. CONCLUSIONS: Although considerable evidence for cell-mediated immunity was shown for all liver allografts, the only clinical association was for IL-15 mRNA expression and graft acceptance. An in vitro model suggested that IL-15 may be enhancing the numbers and the activity of local regulatory cells, in particular resident NT cells in the liver, which may have a role in killing activated lymphocytes such as graft-reactive host T cells.

Adjuvants, Immunologic↗