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S W Chung

Publications and source records attributed to S W Chung.

At least 19 recordsLinked to original sources
PubMed1997

The effect of immunomodulation of stimulator antigen presenting cells on subsequent responder T-cell function.

In this study, we examined whether lipopolysaccharide (LPS)-, interferon-gamma (IFN-gamma) or 16,16-dimethyl prostaglandin E2 (dmPGE2)-pretreatment of stimulator spleen cells from C57BL6 (B6) mice affects effector function of responder T-lymphocyte from C3H/HeJ mice. Stimulation of B6-derived splenic mononuclear cells (SMNCs) with LPS (10 micrograms/ml) prior to their utilization as stimulator cells in a mixed lymphocyte culture (MLC) resulted in an increase in responder T-lymphocyte proliferation compared to utilization of unstimulated SMNC (P < 0.05). IFN-gamma demonstrated similar effects in a dose dependent fashion with maximal stimulatory effect seen at 1000 U/ml. In contrast, pretreatment of stimulator SMNC with dmPGE2 resulted in dose-dependent inhibition of the responder T-lymphocyte proliferation with maximum inhibitory effect seen using a concentration of dmPGE2 of 10(-5) M. The presence of indomethacin in the MLC did not reverse this effect. These data demonstrate the effect of immunomodulation of stimulator spleen cells on subsequent T-lymphocyte function.

16,16-Dimethylprostaglandin E2↗
PubMed1997

Evaluation of liver transplantation for high-risk indications.

BACKGROUND: Appropriate use of orthotopic liver transplantation (OLT) requires continued assessment of the indications for transplantation as a number of diseases are associated with a poor prognosis. High-risk patients are those who have a poor survival or high incidence of recurrent disease (patients with tumours, hepatitis B- or hepatitis C-induced cirrhosis, fulminant hepatic failure or primary graft non-function). In addition, retransplantation may be associated with a poor outcome. METHODS: A retrospective review was made of the records of all adult patients undergoing OLT at this hospital between October 1985 and July 1994. RESULTS: A total of 396 liver transplants were performed in 364 patients. The 1- and 3-year actuarial survival rates were 81 and 69 per cent respectively. The overall survival rate of high-risk patients was significantly lower than that for all OLT recipients (P < 0.05). While no patients transplanted for hepatitis C have developed graft failure, recurrent hepatitis occurred in 15 of 35 patients. CONCLUSION: Strict selection criteria and appropriate perioperative investigations and interventions are required to improve the results of OLT in these high-risk patients.

Adolescent↗
PubMed1996

A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation.

A microemulsion formulation of cyclosporine (CsA) has improved absorption compared with the original form. The purpose of this case control study was to assess the safety and efficacy of the microemulsion without intravenous CsA for induction immunosuppression in adult liver transplantation. Twenty-one consecutive patients receiving induction immunosuppression with the microemulsion 15 mg/kg/day were compared with 20 patients receiving intravenous CsA and the original oral form. Both groups received the same dose of methylprednisilone. Twenty of 21 patients receiving the microemulsion required no intravenous CsA to achieve target CsA levels. All patients receiving the original form received initial intravenous CsA. There was no difference in trough CsA levels between the two groups at 24 and 48 hours. The microemulsion group had 24 hr and 48 hr trough CsA levels of 227+/-15 and 520+/-300 ng/ml by monoclonal RIA while the intravenous CsA group had 24 and 48 hr trough levels of 293+/-18 and 405+/-91 ng/ml. CsA levels analyzed by HPLC were 20% lower than by RIA. The frequency of adverse events resulting in reduction of drug dosage was similar for the microemulsion and the original form: neurotoxicity (23 vs. 40%, P=.30); nephrotoxicity (25 vs. 45%, P=.32), and no patients required dialysis. There was no difference in septic complications. One patient required discontinuation of the microemulsion in an attempt to reverse severe neurotoxicity. A total of 75% of microemulsion patients were rejection free at 3 months while only 35% of CsA patients remained rejection free (P=0.02). These data suggest that the use of the microemulsion without intravenous CsA in liver transplantation is safe and efficacious, and may result in decreased episodes of acute rejection.

Adult↗
PubMed1996

Activation of quiescent ABL-transduced hemopoietic stem cells.

Chronic myelogenous leukemia (CML) is a hemopoietic stem cell disorder in which an activated ABL oncogene is expressed and has been shown to play an important role in disease pathogenesis. A mouse model has been established in which hemopoietic stem cells (HSCs) transduced with a retrovirus vector carrying an activated ABL oncogene can be analysed. Using this model, we now report that abl-transduced HSCs can be quiescent without causing a disease for an extended period of time. Recipient mice were able to survive more than one treatment of 5-fluorouracil (5-FU) at a dose that normally eliminates cycling hemopoietic progenitor cells; subsequently, transduced HSCs could become activated and undergo clonal expansion, resulting in abl-induced leukemic development. The disease developed in these mice was transplantable. Upon engraftment into secondary mice, previously unidentified abl-transduced HSC clones appeared. These data suggest the presence of an abl-suppressive mechanism in HSCs and have important implications to the pathogenesis of stem cell diseases and leukemic clonal evolution.

Animals↗
PubMed1996

A pilot study of ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation.

Ribavirin is a guanosine analogue that normalizes serum liver enzymes in most nontransplant patients with chronic hepatitis C virus (HCV) infection. We conducted an uncontrolled pilot study of ribavirin in 9 liver transplantation recipients that had persistently elevated liver enzymes, active hepatitis by liver biopsy, and HCV RNA in serum by polymerase chain reaction. Ribavirin was given orally at dosages of 800-1200 mg per day for 3 mo. All 9 patients promptly responded to ribavirin: mean (+/- SD) ALT decreased from 392 +/- 377 IU/L immediately before treatment to 199 +/- 185 and 68 +/- 37 IU/L after 1 and 12 weeks of treatment, respectively, complete normalization of enzymes occurred in 4 patients. None of the patients cleared the virus from their serum during therapy, and biochemical relapse occurred in all patients 4 +/- 4.2 weeks after cessation of therapy. The hepatitis activity index of liver biopsy specimens obtained before and at the cessation of therapy was similar. Ribavirin treatment was resumed in 4 patients because of increasing fatigue (2 patients), rising bilirubin (3), or increasing necroinflammation on liver biopsy (2); the biochemical response to the second course of therapy was similar to the first course in all 4 patients. Ribavirin caused reversible hemolysis in all patients, including symptomatic anemia in 3 patients that resolved after reduction of drug dosage. These results suggest that ribavirin may be of benefit in the treatment of HCV infection after liver transplantation. Further studies are needed to determine the optimal dosage and duration of therapy.

Adult↗
PubMed1996

Resistance of naive mice to murine hepatitis virus strain 3 requires development of a Th1, but not a Th2, response, whereas pre-existing antibody partially protects against primary infection.

Murine hepatitis virus strain 3 (MHV-3) produces a strain-dependent spectrum of disease. The development of liver necrosis has been shown to be related to production of a unique macrophage procoagulant activity (PCA), encoded by the gene fgl-2, in susceptible mice. These studies were designed to examine the influence of Th1/Th2 cells on resistance/susceptibility and production of macrophage PCA in resistant (A/J) and susceptible (BALB/cJ) strains of mice following infection with MHV-3. Immunization of A/J mice with MHV-3 induced a Th1 cellular immune response, and one Th1 cell line (3E9.1) protected susceptible mice and inhibited PCA production by macrophages both in vitro and in vivo. In contrast, immunization of BALB/cJ mice with an attenuated variant of MHV-3 derived from passaging MHV-3 in YAC-1 cells resulted in a Th2 response. Transfer of spleen cells and T cell lines from immunized BALB/cJ mice failed to protect naive susceptible syngeneic mice from infection with MHV-3 and augmented macrophage PCA production to MHV-3 in vitro. However, serum from immunized BALB/cJ mice contained high titrated neutralizing Ab that protected naive BALB/cJ animals from lethal primary MHV-3 infection. These results demonstrate that susceptible BALB/cJ mice generate a Th2 response following MHV-3 infection and that these Th2 cells neither inhibit MHV-3-induced macrophage PCA production nor protect naive mice from MHV-3 infection. The results suggest that Ab protects against primary infection but cannot eradicate ongoing infection. Thus, these data define the differential role of Th1/Th2 lymphocytes in primary and secondary MHV-3 infection and emphasize the importance of PCA in the pathogenesis of MHV-3 infection.

Animals↗
PubMed1996

The role of ICAM-1 in the induction of antigen-specific T cell hyporesponsiveness.

We have previously demonstrated that pre-transplant transfusion of allogeneic splenic mononuclear cells from B10.BR mice to C3H/HeJ recipient mice resulted in subsequent antigen specific skin graft prolongation and an associated predominance of IL-4-producing T lymphocytes. In this report, we examined the role of ICAM-1 in the induction of T cell hyporesponsiveness and skin graft prolongation following intrahepatic alloantigen delivery. C3H/HeJ mice receiving splenic cells from B10.BR mice intrahepatically showed antigen-specific enhanced skin graft survival. This graft survival was further prolonged following pre-treatment of infused cells with anti-ICAM-1. No such prolongation was seen following intravenous administration of cells in the presence or absence of anti-ICAM-1 pre-treatment. Anti-ICAM-1 infusion alone similarly had no effect when given intrahepatically or peripherally. T lymphocytes from the mice receiving intrahepatic splenic cells and anti-ICAM-1 produced significantly higher amounts of IL-4 compared to mice receiving intrahepatic cells alone or intravenous cells. PCR analysis of ICAM-1 mRNA transcripts demonstrated an increased expression of ICAM-1 in the spleen compared to the liver. These results suggest that ICAM-1 plays an important role in the induction of T cell hyporesponsiveness and allograft prolongation following the intrahepatic encounter of alloantigen.

Animals↗
PubMed1996

Correlation of peripheral blood lymphocyte and intragraft cytokine mRNA expression with rejection in orthotopic liver transplantation.

BACKGROUND: Regulation of allograft rejection mediated by CD4+ T lymphocytes is dependent on the pattern of cytokines produced by these cells. The purpose of this study was to examine liver transplant recipients to determine whether peripheral blood lymphocyte (PBL), intragraft cytokine production, or both correlated with histologic assessment of graft rejection. METHODS: PBL and liver biopsy specimens from transplant recipients were examined at varying times after transplantation. Biopsy samples were examined histologically. Messenger RNA was extracted from PBL and liver biopsy specimens and was then amplified by polymerase chain reaction with oligo-specific primer pairs for interleukin (IL)-2, IL-4, IL-6, transforming growth factor-beta, interferon-gamma, and beta-actin. RESULTS: PBL transcription of IL-2, IL-6, and interferon-gamma was significantly increased in transplant recipients with rejection compared with that in recipients without rejection or healthy individuals who did not undergo transplantation (p < 0.05). Equivalent transcription of IL-4 and transforming growth factor-beta was observed in all patients regardless of rejection status. Graft specimens exhibited quantitative increases in IL-2 and interferon-gamma transcription during rejection with increased IL-4 transcription in the absence of rejection. CONCLUSIONS: Our data show that specific patterns of peripheral and intragraft cytokine production play a role in the regulation of rejection in liver transplantation.

Adult↗
PubMed1996

Restoration of lipopolysaccharide-mediated B-cell response after expression of a cDNA encoding a GTP-binding protein.

Previous analysis of hybrid progeny derived from lipopolysaccharide (LPS) responder and nonresponder inbred mouse strains demonstrated that a single genetic locus controlled responsiveness to LPS. Using a differential functional screening approach, we report the isolation of a cDNA that has sequence homology to a GTP-binding protein. Expression of the cDNA in splenic B cells of C3H/HeJ nonresponder, endotoxin-resistant mice resulted in polyclonal B-cell activation in response to LPS stimulation. Thus a GTP-binding protein may be involved in LPS stimulation in B cells and perhaps other cell types.

Amino Acid Sequence↗
PubMed1996

The ABL genes in normal and abnormal cell development.

Genetic alteration of the c-abl protooncogene has led to abnormal cellular development, primarily within the hemopoietic system. Different forms of oncogenic alteration have variations in biological strength for cellular transformation. The abnormal Abl oncoproteins are known to suppress apoptosis, which may be the basis for causing leukemia development. However, recent evidence also shows that c-abl proto-oncoprotein can inhibit apoptosis. Expression of the Abl oncoprotein in hemopoietic stem cells (HSCs) also results in alteration in the expression of certain cell surface molecules such that the interaction between HSCs and their marrow stroma microenvironment has become abnormal. The basis for the genetic alteration of the c-abl protooncogene in patients with chronic myelogenous leukemia may or may not be due to genetic imprinting.

Animals↗
PubMed1996

Isoform-specific functions of c-abl: type I is necessary for differentiation, and type IV is inhibitory to apoptosis.

The c-abl proto-oncogene is expressed ubiquitously during development. There are two predominant isoforms, type I and type IV. Their biological functions in cell growth and development are unknown. To examine their respective biological roles, we transduced 70Z/3 lymphoid cells with antisense sequences specific to each respective isotype. When the cells were incubated with antisense oligonucleotides against type IV c-abl but not against type I c-abl, induction of apoptosis was observed, as measured by either DNA fragmentation, cell proliferation, or colony formation. Immunoprecipitation showed that antisense-treated cells had reduced amounts of c-abl as compared to the untreated cells. When stimulated with lipopolysaccharide (LPS), 70Z/3 cells underwent proliferation and differentiation. When antisense oligonucleotides against type IV were added to the cell cultures, with LPS stimulation, induction of apoptosis continued to occur. When antisense oligonucleotides against type I were added in the cultures, in the presence of LPS, cell differentiation was inhibited, but cell proliferation continued to occur. This inhibition of differentiation was evident by a lack of immunoglobulin light chain production by cells that otherwise would produce immunoglobulin when they are stimulated with LPS. These data therefore show that type I c-abl allows cell differentiation to occur, whereas type IV c-abl suppresses apoptosis.

Animals↗
PubMed1995

Identification of a unique membrane-bound molecule on a hemopoietic stem cell line and on multipotent progenitor cells.

Hemopoietic stem cells are a distinct population of cells that can differentiate into multilineages of hemopoietic cells and have long-term repopulation capability. A few membrane-bound molecules have been found to be preferentially, but not uniquely, present on the surface of these primitive cells. We report here the identification of a unique 105-kDa glycoprotein on the surface of hemopoietic stem cell line BL3. This molecule, recognized by the absorbed antiserum, is not present on the surface of myeloid progenitors 32D and FDC-P1 cells, EL4 T cells, and NIH 3T3 fibroblasts. This antiserum can also be used to block the proliferation of BL3 cells even in the presence of mitogen-stimulated spleen cell conditioned medium, which is known to have a stimulating activity on BL3 cells. It can also inhibit development of in vitro, fetal liver cell-derived multilineage colonies, but not other types of colonies, and of in vivo bone marrow cell-derived colony-forming unit spleen foci. These data suggest that gp105 plays an important role in hemopoietic stem cell differentiation.

Animals↗
PubMed1995

Deregulation of c-abl mediated cell growth after retroviral transfer and expression of antisense sequences.

To determine the role of c-abl during cell growth, we constructed a retrovirus vector alpha A, capable of expressing an antisense RNA directed against the abl mRNA. Based on v-abl-mediated 3T3 transformation assay, we showed that the number of transformed foci was reduced 50-94% when alpha A-infected 3T3 cells were superinfected with A-MuLV. Up to a 100% of inhibition could be observed when the time of infection was lengthened. Introduction of the antisense sequence into NIH3T3 cells resulted in reduction of growth rate. These cells entered into S phase from G1 phase of the cell cycle earlier in time than untransduced cells. Thus c-abl serves as a checkpoint during G1/S transition in the cell cycle, and its reduction resulted in deregulation of cell growth.

3T3 Cells↗
PubMed1995

Effect of alterations in early signal transduction events on the induction of procoagulant activity by murine hepatitis virus strain 3 in vitro.

The induction of macrophage procoagulant activity (PCA) has been shown to correlate with the development of fulminant hepatic necrosis after infection with murine hepatitis virus strain 3 (MHV-3). However, comparatively little is known about the early events in cells after viral infection leading to PCA expression. Accordingly, we investigated the early cellular events in the induction of macrophage PCA by MHV-3. MHV-3 stimulation of macrophages did not result in a detectable increase in intracellular calcium levels nor did stimulation of macrophages by calcium ionophores result in induction of PCA, suggesting that calcium transients were neither necessary nor sufficient for induction of PCA by MHV-3. Treatment of cells with phorbol myristate acetate had no effect on PCA induction; however, inhibition of protein kinase C (PKC) by staurosporine or H7 resulted in attenuation of macrophage PCA following MHV-3 stimulation (P < 0.05 compared with untreated macrophages), suggesting that although activation of PKC alone is insufficient for PCA induction, PKC may be an integral component of PCA induction by MHV-3. We have previously demonstrated that dimethyl prostaglandin E2 inhibited induction of PCA by MHV-3. In this study, treatment of cells by agents that increase intracellular cAMP (forskolin, isobutylmethyl xanthine) significantly inhibited PCA induction (P < 0.02). These results demonstrate that induction of macrophage PCA by MHV-3 involves PKC, but proceeds independently of changes in intracellular calcium, and that PCA expression is down-regulated by increases in intracellular cAMP.

16,16-Dimethylprostaglandin E2↗
PubMed1995

Induction of T-cell hyporesponsiveness by intrahepatic modulation of donor antigen-presenting cells.

In this study, we examined the ability of varying populations of donor cells from B6 mice to induce hyporesponsiveness in T lymphocytes from C3H mice in vitro and in vivo. Small, resting B lymphocytes were inefficient stimulators of T-lymphocyte proliferation compared to splenic mononuclear cells (SMNC) and lipopolysaccharide (LPS)-induced B-cell blasts in vitro (P < 0.05). Pretreatment of SMNC with anti-B7-1 or anti-intracellular adhesion molecule-1 (ICAM-1) monoclonal antibodies (mAb) similarly resulted in inefficient stimulation of T-cell proliferation in vitro (P < 0.05). However, in vivo, only intrahepatic, but not intravenous, injection of donor cells into C3H mice resulted in decreased T-lymphocyte proliferation in response to restimulation by alloantigen. This effect was most pronounced following intrahepatic injection of resting B lymphocytes or SMNC pretreated with anti-ICAM-1 mAb compared to uninjected or intravenously injected mice (P < 0.05). The hyporesponsiveness was associated with an increased production of interleukin-4 (IL-4) by the responder T lymphocytes and correlated with enhanced skin allograft survival. These data demonstrate that intrahepatic injection of donor-derived cells induces T-lymphocyte hyporesponsiveness. The mechanism appears to be modulated by an ICAM-1-mediated signal resulting in expansion of an IL-4-producing T-lymphocyte population.

Animals↗
PubMed1994

Prostaglandin E in the treatment of recurrent hepatitis B infection after orthotopic liver transplantation.

While orthotopic liver transplantation (OLT) has become the treatment of choice for most irreversible end-stage liver diseases, its role in patients with hepatitis B (HBV) infection is controversial. A high risk of reinfection of the transplanted graft, associated with significant morbidity and mortality, has been reported. Although passive and active immunization can delay reappearance of the virus in the allograft, there is not yet an effective therapy for recurrent HBV infection in liver transplant recipients. Between October 1985 and March 25, 1991, 28 OLT in 25 patients with acute and chronic HBV infections were performed. Twelve of the patients were HBV DNA-negative, six were HBV DNA-positive, and seven were not tested prior to transplantation. Only the 19 patients surviving more than 100 days after transplantation were considered to have sufficient duration of follow-up (mean 734 days; range 500-1545) to include in analysis of recurrence. Five (26%) were free of recurrent disease at the time of last follow-up (mean 1031 days, range 526 to 1770 days. Recurrent HBV in the allograft, as defined by positive immunoperoxidase stains of biopsy sections for viral antigens, was detected in 74% (13 male, 1 female; 7 Asian, 7 white) at a mean of 134 days posttransplantation. Histological changes of viral hepatitis, first appearing an average of 157 days (range 95-326) posttransplantation, were evident in 13 of 14 with positive immunostaining. Twelve of the 14 patients were treated, on an open trial basis, with intravenous and oral prostaglandin E (PGE) because of deteriorating clinical condition. Eleven of the twelve responded to PGE with an initial drop in serum transaminases, improvement in coagulopathy and resolution of encephalopathy. One patient failed to respond and died of a myocardial infarction within 9 days of institution of therapy. Three of the eleven patients with an initial response relapsed and died in liver failure as a direct result of recurrent HBV after 13, 16, and 37 days of treatment in association with generalized sepsis. Eight of the 12 patients (67%) had a sustained favorable response to PGE therapy (mean follow-up 737 days, range 403-1545). All patients with a sustained response had accompanying improvement in histology and reduction in viral antigen staining in hepatocytes. Treatment with PGE appeared to be of benefit in recurrent HBV infection of the transplanted liver with an initial response rate of 92% and a sustained response rate of 67%.

Administration, Oral↗
PubMed1994

Liver transplantation for hepatocellular carcinoma.

Twenty-nine patients with hepatocellular carcinoma (HCC) underwent orthotopic liver transplantation (OLTx) at the University of Toronto. Four patients did not have cirrhosis. Of the 25 patients with cirrhosis, 19 had known or suspected HCC before OLTx. Eleven patients tested positive for the hepatitis B surface antigen (HBsAg). No patients received adjuvant chemotherapy. None of the patients have developed recurrent HCC in a follow-up of 9 to 87 months (mean: 33 months). The actuarial post-transplant survival of all patients at 3 months, 1 year and 3 years was 75%, 61%, and 46%, respectively. The survival of HBsAg-negative patients was 69% at 3 years, whereas HBsAg-negative patients had a 3-year survival of 18% (p = 0.045). These results suggest that OLTx for carefully selected patients with otherwise unresectable HCC is associated with a low risk of recurrence. HBsAg-positive patients with HCC have a high mortality, suggesting that they make poor candidates for OLTx.

Adult↗