The response to the treatment with pegylated interferon (PEG IFN)-α combined with ribavirin in ch... more The response to the treatment with pegylated interferon (PEG IFN)-α combined with ribavirin in chronic hepatitis C virus (HCV) infection varies with some patients having a rapid or early response which is not sustained.
In the mid 1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotyp... more In the mid 1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection following administration of contaminated anti-D immunoglobulin in 1977-79. We describe their disease history and estimate the effect of selected host and treatment factors on disease progression. We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. 682 participants were included in the study. Among chronically infected participants (n=374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected participants had developed cirrhosis, hepatocellular carcinoma, and liver-related death, ...
To examine the results of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HC... more To examine the results of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) in Ireland over a 14-year period. Cases of HCC receiving OLT between January 1995 and September 2009 in the Irish Liver Transplant Unit were reviewed from a prospectively maintained database. Outcome measures included overall and recurrence free survival, alpha-fetoprotein (AFP) and tumour pathological features. On explant pathology, 57 patients had HCC. The median follow-up time was 42.7 mo. The overall 1, 3 and 5 years survival was 87.7%, 72.1% and 72.4%. There was no difference in survival when compared to patients undergoing OLT without malignancy. The tumour recurrence rate was 14%. The Milan criteria were exceeded in 32% of cases but this did not predict overall survival or recurrence. On multivariate analysis pre-operative AFP > 100 ng/mL was an independent risk factor for recurrence (RR = 5.2, CI: 1.1-24.3, P = 0.036). Patients undergoing OLT for HCC had excellent survival ...
Natural killer (NK) and CD56(+) T cells are thought to play a central role in antitumour immunity... more 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 KIR3D...
The intrahepatic immune system is likely to play a key role in determining the outcome of hepatit... more 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. 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. 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 pre...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1999
The human liver contains significant numbers of T cells, NK cells, and lymphocytes that coexpress... more The human liver contains significant numbers of T cells, NK cells, and lymphocytes that coexpress T and NK cell receptors. To evaluate their functional activities, we have compared the cytotoxic activities and cytokines produced by normal adult hepatic CD3+CD56- (T) cells, CD3-CD56+ (NK) cells, and CD3+CD56+ (natural T (NT)) cells. In cytotoxicity assays using immunomagnetic bead-purified NK cell, T cell, and NT cell subpopulations as effectors, fresh hepatic NK cells lysed K562 targets, while NT cells could be induced to do so by culturing with IL-2. Both NT and T cells were capable of redirected cytolysis of P815 cells using Abs to CD3. Flow cytometric analysis of cytokine production by fresh hepatic lymphocyte subsets activated by CD3 cross-linking or PMA and ionomycin stimulation indicated that NT cells and T cells could produce IFN-gamma, TNF-alpha, IL-2, and/or IL-4, but little or no IL-5, while NK cells produced IFN-gamma and/or TNF-alpha only. The majority of NT cells produc...
Concanavalin A-activated T-lymphocyte suppression of IgG production was found to be significantly... more Concanavalin A-activated T-lymphocyte suppression of IgG production was found to be significantly impaired in patients with untreated active autoimmune chronic hepatitis when compared to normals or patients with inactive disease. When the dose-response effect of TP-1, a calf thymic extract, on in vitro suppressor cell activity was assessed, lymphocytes from six out of eight patients with previously reduced suppressor cell function showed a significant improvement, while over a similar range the suppressor cell activity of most normal controls declined. These results support the possibility that defective immunoregulation in patients with autoimmune chronic active hepatitis may be related to a deficiency in thymic hormone levels.
Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity are ... more Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity are variable, and diagnosis relies on a combination of clinical evaluation, biochemical testing, and radiologic assessment. Identifying patients who have early disease is critical, and the administration of ursodeoxycholic acid appears to be beneficial. The pathogenesis is incompletely understood, and factors that contribute to the variability in incidence and severity are unknown. Fortunately, only a small proportion of individuals progress to advanced liver disease; however, in this population, there is significant morbidity and impairment in quality of life. Liver transplantation can be performed successfully in patients with end-stage liver disease. Future treatments involve targeted gene therapy and activation of mutant forms of the cystic fibrosis transmembrane conductance regulator.
gy T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and... more gy T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and characterized hepatic and peripheral blood gy T cells from 11 normal and 13 unresolved tumor-bearing human liver specimens. gy T cells are enriched in normal liver (6.6% of T cells) relative to matched blood (0.9%; P = 0.008). The majority express CD4CD8 phenotypes and
Veno-occlusive disease of the liver is a serious and often life-threatening complication after bo... more Veno-occlusive disease of the liver is a serious and often life-threatening complication after bone marrow transplantation. Although risk factors for the development of veno-occlusive disease have been postulated, there is no precise method for accurately identifying those patients who are at risk and for whom early intervention and treatment would have maximum potential benefit. Liver transplantation has been advocated as a treatment for veno-occlusive disease in selected patients. In this report, we describe a patient who underwent liver transplantation for life-threatening veno-occlusive disease after autologous bone marrow transplantation for acute lymphoblastic leukemia. Liver engraftment was achieved, but the patient developed Pneumocystis pneumonia, which failed to respond to pentamidine. The patient died 6 months after liver transplantation. While acknowledging the limited experience of orthotropic liver transplantation in this patient population, we suggest its consideration as a feasible, potentially beneficial treatment option in patients with severe veno-occlusive disease after bone marrow transplantation.
The response to the treatment with pegylated interferon (PEG IFN)-α combined with ribavirin in ch... more The response to the treatment with pegylated interferon (PEG IFN)-α combined with ribavirin in chronic hepatitis C virus (HCV) infection varies with some patients having a rapid or early response which is not sustained.
In the mid 1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotyp... more In the mid 1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection following administration of contaminated anti-D immunoglobulin in 1977-79. We describe their disease history and estimate the effect of selected host and treatment factors on disease progression. We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. 682 participants were included in the study. Among chronically infected participants (n=374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected participants had developed cirrhosis, hepatocellular carcinoma, and liver-related death, ...
To examine the results of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HC... more To examine the results of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) in Ireland over a 14-year period. Cases of HCC receiving OLT between January 1995 and September 2009 in the Irish Liver Transplant Unit were reviewed from a prospectively maintained database. Outcome measures included overall and recurrence free survival, alpha-fetoprotein (AFP) and tumour pathological features. On explant pathology, 57 patients had HCC. The median follow-up time was 42.7 mo. The overall 1, 3 and 5 years survival was 87.7%, 72.1% and 72.4%. There was no difference in survival when compared to patients undergoing OLT without malignancy. The tumour recurrence rate was 14%. The Milan criteria were exceeded in 32% of cases but this did not predict overall survival or recurrence. On multivariate analysis pre-operative AFP > 100 ng/mL was an independent risk factor for recurrence (RR = 5.2, CI: 1.1-24.3, P = 0.036). Patients undergoing OLT for HCC had excellent survival ...
Natural killer (NK) and CD56(+) T cells are thought to play a central role in antitumour immunity... more 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 KIR3D...
The intrahepatic immune system is likely to play a key role in determining the outcome of hepatit... more 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. 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. 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 pre...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1999
The human liver contains significant numbers of T cells, NK cells, and lymphocytes that coexpress... more The human liver contains significant numbers of T cells, NK cells, and lymphocytes that coexpress T and NK cell receptors. To evaluate their functional activities, we have compared the cytotoxic activities and cytokines produced by normal adult hepatic CD3+CD56- (T) cells, CD3-CD56+ (NK) cells, and CD3+CD56+ (natural T (NT)) cells. In cytotoxicity assays using immunomagnetic bead-purified NK cell, T cell, and NT cell subpopulations as effectors, fresh hepatic NK cells lysed K562 targets, while NT cells could be induced to do so by culturing with IL-2. Both NT and T cells were capable of redirected cytolysis of P815 cells using Abs to CD3. Flow cytometric analysis of cytokine production by fresh hepatic lymphocyte subsets activated by CD3 cross-linking or PMA and ionomycin stimulation indicated that NT cells and T cells could produce IFN-gamma, TNF-alpha, IL-2, and/or IL-4, but little or no IL-5, while NK cells produced IFN-gamma and/or TNF-alpha only. The majority of NT cells produc...
Concanavalin A-activated T-lymphocyte suppression of IgG production was found to be significantly... more Concanavalin A-activated T-lymphocyte suppression of IgG production was found to be significantly impaired in patients with untreated active autoimmune chronic hepatitis when compared to normals or patients with inactive disease. When the dose-response effect of TP-1, a calf thymic extract, on in vitro suppressor cell activity was assessed, lymphocytes from six out of eight patients with previously reduced suppressor cell function showed a significant improvement, while over a similar range the suppressor cell activity of most normal controls declined. These results support the possibility that defective immunoregulation in patients with autoimmune chronic active hepatitis may be related to a deficiency in thymic hormone levels.
Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity are ... more Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity are variable, and diagnosis relies on a combination of clinical evaluation, biochemical testing, and radiologic assessment. Identifying patients who have early disease is critical, and the administration of ursodeoxycholic acid appears to be beneficial. The pathogenesis is incompletely understood, and factors that contribute to the variability in incidence and severity are unknown. Fortunately, only a small proportion of individuals progress to advanced liver disease; however, in this population, there is significant morbidity and impairment in quality of life. Liver transplantation can be performed successfully in patients with end-stage liver disease. Future treatments involve targeted gene therapy and activation of mutant forms of the cystic fibrosis transmembrane conductance regulator.
gy T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and... more gy T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and characterized hepatic and peripheral blood gy T cells from 11 normal and 13 unresolved tumor-bearing human liver specimens. gy T cells are enriched in normal liver (6.6% of T cells) relative to matched blood (0.9%; P = 0.008). The majority express CD4CD8 phenotypes and
Veno-occlusive disease of the liver is a serious and often life-threatening complication after bo... more Veno-occlusive disease of the liver is a serious and often life-threatening complication after bone marrow transplantation. Although risk factors for the development of veno-occlusive disease have been postulated, there is no precise method for accurately identifying those patients who are at risk and for whom early intervention and treatment would have maximum potential benefit. Liver transplantation has been advocated as a treatment for veno-occlusive disease in selected patients. In this report, we describe a patient who underwent liver transplantation for life-threatening veno-occlusive disease after autologous bone marrow transplantation for acute lymphoblastic leukemia. Liver engraftment was achieved, but the patient developed Pneumocystis pneumonia, which failed to respond to pentamidine. The patient died 6 months after liver transplantation. While acknowledging the limited experience of orthotropic liver transplantation in this patient population, we suggest its consideration as a feasible, potentially beneficial treatment option in patients with severe veno-occlusive disease after bone marrow transplantation.
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