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John J Fung

Publications and source records attributed to John J Fung.

At least 19 recordsLinked to original sources
PubMed2007

The role of liver-derived regulatory dendritic cells in prevention of type 1 diabetes.

Development of type 1 diabetes has been attributed to T-cell-mediated autoimmunity, which is regulated by antigen-presenting cells. To study the role of liver-derived B220(+) regulatory dendritic cells (DCs) in the development of diabetes in non-obese diabetic (NOD) mice, we found that liver 220(+) DCs could easily be propagated from young NOD mice, but that such propagation was extremely difficult from mice older than 11 weeks, when insulitis began. This was not simply an age-related phenomenon, because liver B220(+) DCs were readily propagated from both young and old congenic non-obese diabetic-resistant (NOR) and normal BALB/c mice. It was therefore speculated that the development of diabetes might be associated with a lack of precursors of B220(+) DC in the liver in this animal model. Unfortunately, the specific marker for precursors of liver B220(+) DC has not been identified. An alternative approach to supplement liver B220(+) DCs by intravenous administration significantly inhibited the development of diabetes by inducing T-cell hyporesponsiveness via enhancement of their apoptotic death. Liver B220(+) DCs were capable of effectively presenting antigens but, unlike plasmacytoid DCs, did not express CD11c and were not interferon-alpha producers. These observations may throw new light on the aetiopathology of type 1 diabetes.

Aging↗
PubMed2006

Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: One- and two-year outcomes.

BACKGROUND: Alemtuzumab (Campath-1H) induction with tacrolimus monotherapy has been shown to provide effective immunosuppression for kidney, liver, lung, and small bowel transplantation. This drug combination was evaluated in pancreas transplant recipients. METHODS: Sixty consecutive pancreas transplants (30 simultaneous pancreas-kidney, 20 pancreas after kidney, and 10 pancreas alone) were carried out under this protocol between July 2003 to January 2005. The mean follow-up was 22 months (range 17-33). RESULTS: One-year patient, pancreas, and kidney allograft survival were 95%, 93%, and 90%, respectively. With 22 months follow-up, patient, pancreas, and kidney survival were 94%, 89%, and 87%, respectively. The rejection rate was 30% (18/60), with four patients (7%) experiencing steroid-resistant rejection. Major infection occurred in three (5%) patients resulting in two (3.3%) deaths from disseminated histoplasmosis and a herpes virus infection. One patient with cryptococcal meningitis was successfully treated. Seven (11.7%) patients experienced cytomegalovirus infection, all of whom responded to treatment with ganciclovir. One (1.7%) case of polymorphic posttransplant lymphoproliferative disease was seen, which regressed with a temporary discontinuation of tacrolimus and high-dose ganciclovir. The mean serum creatinine of the 30 simultaneous pancreas-kidney transplants at one year posttransplant was 1.37+/-0.33 mg/ml. The preexisting creatinine in pancreas after kidney transplants was not adversely affected by this immunosuppressive protocol. CONCLUSION: A single dose of perioperative alemtuzumab followed by daily tacrolimus monotherapy provides effective immunosuppression for pancreas transplantation, but the optimal use of this drug combination is not yet clear.

Alemtuzumab↗
PubMed2006

Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus.

BACKGROUND: Administration of immature dendritic cells (DC) prolongs but does not result in indefinite allograft survival. We attempted to achieve this goal by adding a sub-therapeutic dose of immunosuppression. METHODS: DC propagated from B10 (H-2(b)) mouse bone marrow (BM) were transfected with nuclear factor-kappaB (NF-kappaB)-binding-site-specific oligodeoxyribonucleotide (ODN). The allostimulatory activity of transfected and normal DC were examined in mixed-lymphocyte reaction (MLR) and cytotoxic T-lymphocyte (CTL) assays in vitro, and their influence on allograft survival by systemic administration of DC in vivo. RESULTS: Transfection of DC with NF-kappaB ODN resulted in complete abrogation of NF-kappaB activity and inhibition of co-stimulation. Allogeneic (C3H, H-2(k)) T cells stimulated by ODN DC demonstrated impairment in MLR and CTL activity. Administration of ODN DC significantly prolonged B10 allograft survival. In contrast to cyclosporine, which failed to enhance the effect of ODN DC, a combination of ODN DC with sirolimus at 6 mg/kg/day for 6 days achieved long-term survival in all allografts. This was associated with low CTL activity of either graft-infiltrating cells or splenic T cells and increased TUNEL-positive cells in T-cell areas of recipient mesenteric lymph nodes. Analysis of transcription factor nuclear translocation with Cellomics indicated that stimulation with ODN DC showed inhibited T-cell nuclear translocation of signal transducer and activator of transcription (Stat)1 and Stat3, extracellular signal-related kinase (ERK) and activating transcription factor (ATF)-2, but not NF-kappaB and P38, compared with mature DC. The selective inhibition was enhanced by sirolimus, but not cyclosporine. CONCLUSIONS: Sirolimus enhances immature DC tolerogenicity by induction of T-cell apoptosis, and promotes immature DC-induced inhibition of Stat1, ERK and ATF-2 activation.

Animals↗
PubMed2006

A randomized trial of inhaled cyclosporine in lung-transplant recipients.

BACKGROUND: Conventional regimens of immunosuppressive drugs often do not prevent chronic rejection after lung transplantation. Topical delivery of cyclosporine in addition to conventional systemic immunosuppression might help prevent acute and chronic rejection events. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial of inhaled cyclosporine initiated within six weeks after transplantation and given in addition to systemic immunosuppression. A total of 58 patients were randomly assigned to inhale either 300 mg of aerosol cyclosporine (28 patients) or aerosol placebo (30 patients) three days a week for the first two years after transplantation. The primary end point was the rate of histologic acute rejection. RESULTS: The rates of acute rejection of grade 2 or higher were similar in the cyclosporine and placebo groups: 0.44 episode (95 percent confidence interval, 0.31 to 0.62) vs. 0.46 episode (95 percent confidence interval, 0.33 to 0.64) per patient per year, respectively (P=0.87 by Poisson regression). Survival was improved with aerosolized cyclosporine, with 3 deaths among patients receiving cyclosporine and 14 deaths among patients receiving placebo (relative risk of death, 0.20; 95 percent confidence interval, 0.06 to 0.70; P=0.01). Chronic rejection-free survival also improved with cyclosporine, as determined by spirometric analysis (10 events in the cyclosporine group and 20 events in the placebo group; relative risk of chronic rejection, 0.38; 95 percent confidence interval, 0.18 to 0.82; P=0.01) and histologic analysis (6 vs. 19 events, respectively; relative risk, 0.27; 95 percent confidence interval, 0.11 to 0.67; P=0.005). The risks of nephrotoxic effects and opportunistic infection were similar for patients in the cyclosporine group and the placebo group. CONCLUSIONS: Inhaled cyclosporine did not improve the rate of acute rejection, but it did improve survival and extend periods of chronic rejection-free survival. (ClinicalTrials.gov number, NCT00268515.).

Acute Disease↗
PubMed2006

In vivo immune modulatory activity of hepatic stellate cells in mice.

Accumulating data suggest that hepatic tolerance, initially demonstrated by spontaneous acceptance of liver allografts in many species, results from an immune regulatory activity occurring in the liver. However, the responsible cellular and molecular components have not been completely understood. We have recently described profound T cell inhibitory activity of hepatic stellate cells (HSCs) in vitro. In this study, we demonstrate in vivo evidence of immune modulatory activity of HSCs in mice using an islet transplantation model. Co-transplanted HSCs effectively protected islet allografts from rejection, forming a multi-layered capsule, which reduced allograft immunocyte infiltrates by enhancement of apoptotic death. The immune modulation by HSCs appeared to be a local effect, and regulated by inducible expression of B7-H1, an inhibitory molecule of B7 family. This may reflect an intrinsic mechanism of immune inhibition mediated by liver-derived tissue cells. In conclusion, these results may lead to better understanding of liver immunobiology and development of new strategies for treatment of liver diseases.

Animals↗
PubMed2006

Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease.

For patients who receive a liver transplant (LTX) for alcoholic liver disease (ALD), investigators are focusing beyond survival to determine specific alcohol use outcomes. Studies suggest the use of alcohol ranges from 8 to 22% for the first post-transplant year with cumulative rates reaching 30 to 40% by 5 years following transplantation. Yet while investigators are interested in determining specific rates of alcohol use and predictors of use, only three studies since 1990 have been prospective. In 1998, we began a prospective study of post-LTX alcohol consumption in ALD recipients using multiple repeated measures of alcohol use. After 5 years of follow-up, we found that 22% had used any alcohol by the first year and 42% had a drink by 5 years. By 5 years, 26% drank at a heavier use (binge) pattern and 20% drank in a frequent pattern. In a univariate model, predictors of alcohol use included pre-transplant length of sobriety, a diagnosis of alcohol dependence, a history of other substance use, and prior alcohol rehabilitation.

Adult↗
PubMed2006

Caroli's disease and orthotopic liver transplantation.

Caroli's disease is a rare congenital hepatic disease, characterized by segmental dilatation of the biliary tree. Patients who have recurrent bouts of biliary infection, particularly those with complications related to portal hypertension, may require orthotopic liver transplantation (OLT). Few case reports have described the outcome of OLT in patients with Caroli's disease and to date there is no large series reported in the literature. We retrospectively analyzed the outcome of OLT in patients with Caroli's disease who underwent OLT between 1982 and 2002 at Starzl Transplantation Institute, University of Pittsburgh. Patients were identified and data was collected by computerized search of the electronic database system. All patients had confirmation of diagnosis by histopathology of explanted liver. A total of 33 patients with Caroli's disease were listed for liver transplantation, 3 of whom were excluded, as they were not transplanted. A total of 90% had signs of hepatic decompensation at the time of OLT. Median posttransplantation follow-up was 7.7 yr. Short-term graft and patient survival at 1 month was 83% and 86%, whereas overall long-term graft survival rates at 1, 5, and 10 yr were 73%, 62%, and 53%, respectively, and patient survival rates were 76%, 65%, and 56%, respectively. Long-term outcome in patients who survived the first year after transplantation was significantly better. Their survival rate at 5 and 10 yr was 90% and 78%. On univariable analysis, recipient age, donor male gender, coexistent congenital hepatic fibrosis, and re-OLT were associated with poor patient survival. Eight patients were retransplanted, 3 of whom had primary nonfunction. A total of 13 patients died; the most common cause of death being sepsis and cardiovascular complications. Patients who died of sepsis had cholangitis pre-OLT. In conclusion, OLT is a form of curative and life-saving therapy in patients with Caroli's disease, especially in those with decompensated liver disease. Overall survival is better with liver transplantation and is comparable with the survival of recipients who undergo OLT for other etiologies of chronic liver disease. Survival was poor in patients with congenital hepatic fibrosis (Caroli's syndrome) and in those who had cholangitis at the time OLT.

Adult↗
PubMed2006

Isolated right hepatic vein obstruction after piggyback liver transplantation.

The "piggyback" technique for liver transplantation has gained worldwide acceptance. Still, complications such as outflow obstruction have been observed, usually attributable to technical errors such as small-caliber anastomosis of the suprahepatic vena cava, twisting, or kinking. Iatrogenic Budd-Chiari syndrome after piggyback liver transplantation has been reported as a consequence of obstruction involving the entire anastomosis (usually the 3 hepatic veins). Here we describe technical issues, clinical presentation, diagnosis, and treatment of 3 cases in which outflow obstruction affected only the right hepatic vein. In conclusion, all 3 patients developed recurrent ascites requiring angioplasty and/or stent placement across the right hepatic vein to alleviate the symptoms.

Budd-Chiari Syndrome↗
PubMed2006

In vivo expansion of two distinct dendritic cells in mouse livers and its impact on liver immune regulation.

Liver transplant tolerance in pigs, rats, and mice has been disclosed for decades, but the underlying mechanisms are not completely understood. Accumulating data indicate that residing dendritic cells (DC) are important in determining direction of immune responses in the liver. However, our knowledge remains very limited due to the difficulties in obtaining sufficient liver DC. Most of the previous studies were dependent on DC propagated in vitro with growth factors and cytokines. In this study, we adopted an approach to transfect genes into the mouse liver by tail vein injection of plasmid DNA. Transfection with plasmid granulocyte-macrophage colony-stimulating factor markedly expanded liver CD11c(+) DC mainly located in portal regions, while liver B220(+) DC were dramatically generated after injection with plasmid interleukin (IL)-3/CD40L largely present in the lobules. Although both were phenotypically mature and strong T-cell stimulators, CD11c(+)DC induced potent T-cell response while B220(+)DC induced T-cell hyporesponsiveness. Administration of CD11c(+)DC accelerated cardiac allograft rejection, while B220(+)DC significantly prolonged graft survival. This hyporesponsiveness is not due to inhibition of DC/T-cell interaction, but rather through an active process of stimulating T-cell apoptosis. Compared to B220(+) DC that expressed messenger RNA of (TLR) 1, 2, 6, 7, and 9, CD11c(+)DC expressed all TLR 1 to 9. TLR 9 ligation stimulated very high IL-12 in CD11c(+) DC, but high IL-10 and no IL-12 in B220(+) DC. In conclusion, through these mechanisms, liver DC may be actively involved in immune regulation in the liver.

Animals↗
PubMed2006

Immune regulatory activity of liver-derived dendritic cells generated in vivo.

Hepatic tolerance is demonstrated by spontaneous acceptance of liver allografts in mice. Hepatic dendritic cells (DC) play a crucial role in determining immunity or tolerance. In this study, we adopted an approach to transfect gene(s) into the mouse liver by tail-vein injection of plasmid-carrying genes. Transfection with GM-CSF expanded liver CD11c+ myeloid DC (LMDC), while liver B220+CD11c- lymphoid DC (LLDC) were expanded after transfection of IL-3 and CD40L. Flow analysis revealed that these liver DC subsets were phenotypically mature following overnight culture. However, in contrast to LMDC, LLDC induced hyporesponsiveness in allogeneic T-cells, with suppressed secretion of both IL-2 and IFN-gamma, and prolonged cardiac allograft survival. This immune regulatory DC population in the liver may play a role in modulating T-cell immunity in the liver.

Animals↗
PubMed2006

Regulatory dendritic cells modulate immune responses via induction of T-cell apoptotic death.

We describe a regulatory lymphoid dendritic cell (LDC) population propagated from mouse liver nonparenchymal cells (NPC) in IL-3 and anti-CD40 monoclonal antibody that are phenotypically mature, and induce T-cell hyporesponsiveness by promoting T-cell apoptotic death, which is partially caspase-dependent, but is unlikely to be mediated by soluble factor(s). In vivo administration of liver LDC significantly prolonged the survival of vascularized cardiac allografts in an alloantigen-specific manner. This is associated with enhanced T-cell death in secondary lymphoid organs.

Animals↗
PubMed2006

Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome.

In an attempt to more completely define the histopathologic features of the portal vein hyperperfusion or small-for-size syndrome (PHP/SFSS), we strictly identified 5 PHP/SFSS cases among 39 (5/39; 13%) adult living donor liver transplants (ALDLT) completed between 11/01 and 09/03. Living donor segments consisting of 3 right lobes, 1 left lobe, and 1 left lateral segment, with a mean allograft-to-recipient weight ratio (GRWR) of 1.0 +/- 0.3 (range 0.6 to 1.4), were transplanted without complications, initially, into 6 relatively healthy 25 to 63-year-old recipients. However, all recipients developed otherwise unexplained jaundice, coagulopathy, and ascites within 5 days after transplantation. Examination of sequential posttransplant biopsies and 3 failed allografts with clinicopathologic correlation was used in an attempt to reconstruct the sequence of events. Early findings included: (1) portal hyperperfusion resulting in portal vein and periportal sinusoidal endothelial denudation and focal hemorrhage into the portal tract connective tissue, which dissected into the periportal hepatic parenchyma when severe; and (2) poor hepatic arterial flow and vasospasm, which in severe cases, led to functional dearterialization, ischemic cholangitis, and parenchymal infarcts. Late sequelae in grafts surviving the initial events included small portal vein branch thrombosis with occasional luminal obliteration or recanalization, nodular regenerative hyperplasia, and biliary strictures. These findings suggest that portal hyperperfusion, venous pathology, and the arterial buffer response importantly contribute to early and late clinical and histopathologic manifestations of the small-for-size syndrome.

Adult↗
PubMed2005

Rituximab (chimeric anti-CD20 antibody) for posttransplant lymphoproliferative disorder after solid organ transplantation in adults: long-term experience from a single center.

BACKGROUND: Occurrence of posttransplant lymphoproliferative disorder (PTLD) after transplantation is known. Drastic reduction or withdrawal of immunosuppression with anti-viral therapy for Ebstein-Barr virus (EBV) is the primary treatment for all PTLD. Many PTLD are B cell in origin have CD20 antigen on the cell surface. Rituximab is a chimeric anti CD20 antibody, which has been used to treat PTLD with variable success. This study aims to report long-term experience with rituximab for PTLD from a single center. METHODS: Seventeen patients (13 male, 4 female, mean age 51.2 years) received rituximab to treat PTLD. Five patients received rituximab with drastic reduction in immunosuppression (primary). Nine patients received rituximab after failure of primary therapy (rescue) and three patients received it after resolution of PTLD (prophylactic). Mean follow-up period was 60 months. RESULTS: Overall 1-, 3-, and 5-year patient survivals were 64.7%, 47.1% and 35.3%, respectively. In the primary group, three patients had complete and one had partial response; however, only two (40%) patients are currently alive. In the rescue group, none of the patients had a complete response, four patients had partial response, and only two (22%) patients are currently alive. In the prophylactic group, two patients died at 28 and 41 months due to recurrence and graft failure, respectively. CONCLUSION: Sixty percent (3 of 5) of patients who received rituximab as primary therapy had complete resolution, and 44% (4 of 9) of patients who received it as rescue therapy had partial response. Overall 5-year patient survival was a disappointing 35%.

Antibodies, Monoclonal↗
PubMed2005

EBV-specific memory CD8+ T cell phenotype and function in stable solid organ transplant patients.

Immune responses to EBV in immunosuppressed (IS) solid organ transplant (SOTx) recipients have not been well characterized. Here we evaluate the phenotype and function of EBV-specific CD8+ T cells in peripheral blood isolated from "stable" IS SOTx recipients. The EBV-specific CD8+ T cell memory subset distribution in the peripheral blood of patients was examined by flow cytometric analysis using HLA-A2 tetramers incorporating BMLF1 (lytic), and LMP2 and EBNA3A (latent)-derived peptides, in conjunction with mAbs against the CD45RO, CD45RA, and CD62L markers. The ability of CD8+ T cells to produce IFN-gamma in response to the same EBV-derived peptides was measured by ELISPOT assay. Patients and healthy normal donors exhibited similar anti-EBV CD8+ T cell frequencies and specificities against the EBV epitopes evaluated. When compared to healthy normal donors, an overall significant expansion of the CD8+ T cell "effector memory" (CD45RO+/CD62L-) pool, including that of EBV "latent" (LMP2 and EBNA3A)-specific CD8+ T cells was detected in IS SOTx patients. However, the patients' EBV-specific CD8+ T cells showed decreased IFN-gamma production to the EBV-peptide stimulation. These results indicate that the impairment of EBV-specific CD8+ T cell activity is not due to clonal depletion, but is mainly due to impaired functional activation.

Antigens, Viral↗