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Biomedical subjects

A Shaked

Publications and source records attributed to A Shaked.

At least 19 recordsLinked to original sources
PubMed2001

Pattern of alloimmune response in second same donor allografts after induction of tolerance using CTLA4Ig.

BACKGROUND: The pattern of allograft acceptance in the presence of costimulatory blockade is manifested by the sequential appearance of Th1 cells, followed by Th2 cells. The aim of this study was to examine whether this phenomenon repeats itself after second same donor allotransplantation, hoping to determine whether acceptance in this setting provokes a predominance of the Th2 response. METHODS: Tolerance was achieved by transplantation of CTLA4Ig-transduced ACI liver allografts in Lewis recipients. Recipient long-term survivors received a second transplant, consisting of a cervical heterotopic heart from the same ACI donor strain. Animals were sacrificed at predetermined intervals following the second transplant and the heart and liver were processed for histology and cytokine mRNA expression. RESULTS: Recipients of CTLA4Ig-transduced livers survived indefinitely. Rechallenge with same donor strain second allograft was manifested by an anergic immune response in the second cardiac allograft, and a very mild transient infiltrate within the first accepted liver graft. Cardiac function was maintained with resolution of all infiltrates. The cytokine cascade was activated within the allografts; however, the pattern of acceptance was not associated with predominance of a specific Th subtype. CONCLUSIONS: The pattern of acceptance of an allograft following CTLA4Ig-mediated costimulatory blockade is not related to long-term predominance of Th2 cells, a phenomenon that may be unique to the setting of a tolerant liver. It may be likely that the infiltrating lymphocytes that are dominant in the second graft are suppressed by other memory mechanisms.

Abatacept↗
PubMed2001

Modified AdCTLA-4 vector blocks alloimmune response in vitro.

BACKGROUND: Gene transfer of the costimulatory blockade molecule CTLA-4Ig into cold-preserved rat liver allografts results in indefinite allograft survival. Despite local delivery, this mode of immunomodulation is associated with systemic immunosuppression. In an effort to restrict immunosuppression to the graft, we have constructed a novel adenoviral vector, AdCTLA-4ex-TAG, in which the Ig sequence of CTLA-4Ig DNA has been deleted to destabilize the gene product to promote rapid extrahepatic degradation while maintaining its immunosuppressive activity within the graft milieu. METHODS: (1) Vector construction. CTLA-4 extracellular binding domain (CTLA-4ex) was prepared by PCR-based cloning methods and fused in frame to a genetic element encoding an epitope TAG allowing identification of the transgene product CTLA-4exTAG. CTLA-4exTAG was subcloned into a shuttle vector enabling isolation of AdCTLA-4exTAG. (2) In vitro transfection: AdCTLA-4exTAG was transfected into MH(1)C(1) cells and then supernatant was recovered for Western blot analysis. (3) In vitro alloimmune response was characterized by CFSE proliferation assay. (4) Extrahepatic effect of AdCTLA-4exTAG was characterized by the ability to control tumor growth after implantation of a regressive, immune sensitive cancer cell line (REGb) in the skin of BDIX rats after liver transduction with AdCTLA-4exTAG. RESULTS: Expression and secretion of the recombinant protein were documented by Western blot after infection of the MH(1)C(1) cell line() with AdCTLA-4exTAG. Addition of infected MH(1)C(1) cell supernatant resulted in abrogation of alloimmune response as shown by markedly diminished division of CD4(+) T cells in a CFSE proliferation assay. Extrahepatic tumor regressed normally after liver transduction with AdCTLA-4exTAG. CONCLUSIONS: These results show efficient in vitro expression of CTLA-4exTAG after transfection with AdCTLA-4exTAG. The modified protein retains its ability to abrogate in vitro alloimmune response. Efficient control of extrahepatic tumor growth after liver-directed delivery of AdCTLA-4exTAG suggests that the immunosuppressive effect of this vector is restricted to the liver. These results set the ground for the utilization of this novel adenoviral vector in the transplant setting.

Abatacept↗
PubMed2001

Partnership.

Individuals are called partners when it is in their best interest to help each other, if by doing so they increase the probability of being together in the future when, for similar reasons, they will continue to help each other. Kinsmen or individuals who often face (hedonic) situations in which helping is the dominating strategy are committed to help each other. Partnership may develop among them since the loss of the other means the loss of a guaranteed helper. Thus, they may be willing to take additional risks to help each other. Partnership may occur among unrelated individuals and with no hedonic situations. Partnership creates bonds between partners which may be much stronger than those between kinsmen; an individual may take more risks for his partner than he will ever take for a kin. Partnership may evolve without the sophistication and memory required for reciprocation altruism. Although kin selection, partnership and reciprocation are likely to appear fused as the causes for altruism, we argue that it may be possible to distinguish between them in some situations. We show that as the partners get older partnership may become less important to them. We also show that like cooperation, and for analogous reasons, malice may evolve among partners so that each will be willing to take additional risks in order to eliminate the other.

Aging↗
PubMed2001

Role of plasmapheresis in the management of acute hepatic failure in children.

OBJECTIVE: To assess the efficacy of plasmapheresis in the treatment of children with acute hepatic failure. SUMMARY BACKGROUND DATA: Acute liver failure is expressed with severe encephalopathy, coagulopathy, and subsequent multisystem organ failure, resulting in a high death rate. Liver transplantation is considered the best option, with long-term 1-year survival rates exceeding 88%. It has been suggested that plasmapheresis may improve coagulopathy and prevent bleeding complications while maintaining adequate fluid, electrolyte, and acid-base balance. METHODS: Forty-nine patients with acute liver failure underwent a total of 243 therapeutic plasma exchanges (TPE). Indications for treatment included candidacy for liver transplant and prolonged prothrombin time. Pheresis was performed daily until the patient recovered, died, or was transplanted. Four patients were anhepatic during pheresis. RESULTS: Coagulation profiles after TPE significantly improved compared with mean preexchange values while maintaining euvolemia. No bleeding episodes were observed during the course of treatment. There was no sustained improvement in neurologic function. Spontaneous recovery was observed in three patients; the remaining either underwent transplantation (32/49) or were not considered transplant candidates because of irreversible neurologic insults (11/49) or sepsis (3/49). CONCLUSION: For children with acute liver failure, TPE is extremely effective in preventing life-threatening bleeding while maintaining appropriate volume status in small children. This method of treatment has no effect on the neurologic complications of liver failure and has no impact on the ability of the liver to regenerate.

Acute Disease↗
PubMed2001

Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients.

The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme-linked immunosorbent assay (ELISA) for monitoring whole-blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7-day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients.

Administration, Oral↗
PubMed2000

The fate of liver grafts declined for subjective reasons and transplanted out of a local organ procurement organization.

BACKGROUND: Decisions made by transplant surgeons to decline liver grafts for local use are based on both objective and ill-defined subjective parameters. These livers may be offered and subsequently transplanted at non-local centers. We analyzed the fate of these exported livers, focusing on the outcome of grafts declined for subjective reasons. The aim is to determine whether local surgeons' concerns about inferior graft function are justified. METHODS: Over a 3-year period, 13.3% of 555 livers in our organ procurement organization (OPO) were exported and transplanted out of the local area. Donor data and reason for decline were obtained from an extensive OPO database. Objective reasons for decline were based on no appropriate matched recipient due to donor size, serologies, or malignancy with potential for spread. Subjective parameters were related to the procuring surgeon's assessment and included variables such as medical and social history, abnormal liver enzymes, older age, organ visualization, and biopsy. Recipient data were obtained from questionnaires sent to outside transplant centers. RESULTS: There was a significantly higher rate of nonfunction in the subjective group (17.1%), compared to the objective group (0%). One-year graft and patient survival were 79 and 83% for the objective group and 59 and 68% for the subjective group (P=NS). When donors declined for medical/social history were excluded from the subjective group, leaving only grafts declined based solely on the surgeon's assessment of graft quality, there is a significant difference in graft survival (79% for objective and 46% for this subjective subgroup, P=0.03). CONCLUSIONS: Livers declined for local use based on subjective assessment by the procuring surgeon have a high nonfunction rate, associated with a high morbidity. Therefore, the use of these grafts should be restricted to recipients at the most urgent status.

Adolescent↗
PubMed2000

Endoscopic management of postoperative biliary complications in orthotopic liver transplantation.

BACKGROUND: Surgery, percutaneous cholangiography, and endoscopic retrograde cholangiopancreatography (ERCP) have been used in the management of biliary complications after orthotopic liver transplantation with varied results. We assessed the role of ERCP in the diagnosis, treatment, and outcome of post-orthotopic liver transplantation biliary complications. METHODS: We retrospectively reviewed the records of 260 patients who underwent orthotopic liver transplantation. We examined the number of patients referred for ERCP and the indication, diagnosis, therapeutic intervention, success, and complication rate of ERCP post orthotopic liver transplantation. We compared the survival and retransplantation rates of the patients who underwent ERCP with a control group of post-orthotopic liver transplantation patients not undergoing ERCP. RESULTS: Of the 260 patients undergoing orthotopic liver transplantation, 64 (24.6%) underwent 137 ERCPs. Two categories of indications for ERCP were identified: bile leak (n = 31) and obstruction (n = 39). ERCP identified the site of the bile leak in 27 of 31 cases (87.1%) and the leak was treated by endoscopic means in 26 of 31 (83.9%). Treatment success differed significantly based on location of the leak (T tube, 95.2% vs. anastomosis, 42.9%; p = 0. 009). ERCP identified the site of obstruction in 37 of 39 cases (94. 9%) and obstruction was relieved by endoscopic means in 25 of 35 cases (71.4%). ERCP was significantly less successful in the treatment of biliary casts (25.0%, p = 0.048). There was no difference in survival or retransplantation between patients who did and did not undergo ERCP. CONCLUSION: ERCP should be the primary method for diagnosis and treatment of post-orthotopic liver transplantation biliary complications. Endoscopic therapy is safe and effective for the majority of post-orthotopic liver transplantation complications and temporizes management for those complications that may require surgery.

Adolescent↗
PubMed1999

Supraceliac aortic pseudoaneurysms after liver transplantation in infants.

BACKGROUND: Reconstruction of the hepatic artery in infants undergoing liver transplantation presents challenging vascular situations. Microvascular techniques ensure arterial blood flow via small caliber vessels but are insufficient when inflow is poor. In these situations, the use of allogeneic grafts to the supraceliac aorta have been advocated. The development of a pseudoaneurysm at the supraceliac aortic suture line requires urgent repair and restoration of arterial flow to the graft. METHODS: Our study was based on case reports and review of the literature. RESULTS: Definitive diagnosis and successful repair of supraceliac pseudoaneurysm was accomplished in two infants after transplantation. CONCLUSION: We advocate a thoracoabdominal retroperitoneal approach, which provides safe control of the aorta and primary repair or patching of the diseased aortic segment, and also provides access for hepatic revascularization via placement of an infrarenal graft. Thrombosis of the artery and subsequent liver necrosis are indications for retransplantation.

Aneurysm, False↗
PubMed1999

Liver transplantation at the University of Pennsylvania and the Children's Hospital of Philadelphia.

The liver transplant program at the University of Pennsylvania and the Children's Hospital of Philadelphia experienced healthy growth in its clinical activity in the past 5 years. Patterns of referral and patient evaluation were established, care of patients while waiting on the list or being followed after transplantation was streamlined. We are now achieving excellent outcomes while transplanting relatively sicker patients. Innovative surgical procedures are implemented resulting in more efficient utilization of cadaveric and living-donor liver grafts. The protocols that are used for patient care are more standard, yet flexible and accommodate recent advancement in transplantation immunobiology. This progress of the clinical program was enhanced by careful preservation of the academic mission of the institution, which encourages the liver transplant faculty to be involved in NIH-supported clinical and basic science research.

Adult↗
PubMed1998

Percutaneous thrombolysis and stent placement for the treatment of portal vein thrombosis after liver transplantation: long-term follow-up.

BACKGROUND: The durable use of percutaneous minimally invasive techniques for the treatment of portal venous thrombosis after liver transplant has not been widely described. This report illustrates two cases in which percutaneous thrombolysis, angioplasty, and endovascular stent placement were successfully used to treat portal vein thrombosis in patients with recent liver transplants. METHODS: Liver dysfunction was initially manifested by the elevation of liver enzymes or the development of marked ascites and confirmed in both cases by sonography and angiography. The occluded portal vein was accessed by either a transjugular transhepatic puncture or direct transhepatic catheterization. Intraportal thrombolytic infusion, angioplasty, and stent placement were accomplished without complication. RESULTS: At the most recent follow-up, portal vein patency had been maintained for 2.5 and 4.5 years. CONCLUSIONS: These results demonstrate the technical feasibility and long-term patency of angioplasty and endovascular stent placement for the treatment of portal vein thrombosis in liver transplant recipients.

Adult↗
PubMed1998

Organ transplantation in the twenty-first century.

Major advances in the understanding of the immunologic process responsible for organ or cellular transplant rejection, a dramatic improvement in available immunosuppressive drugs, development of more sophisticated surgical techniques, and important progress in posttransplant intensive care over the last 30 years have led to a remarkable improvement in success following organ transplantation. Whereas excellent short-term survival of most transplanted organs is readily achieved, graft loss because of chronic rejection and the worsening problem of organ donor shortage remain major concerns in the field of transplantation. Recent advances in immunosuppressive drugs, induction of immunologic tolerance, and gene therapy strategies may help to prolong organ allograft survival in the future. Revised criteria for organ donation and xenotransplantation may one day solve the problem of organ supply. Today, as we approach the next millennium, we are optimistic that the elusive goal of immunologic tolerance will be achieved and perhaps applied to animal tissue. Such will certainly be the challenge for the next century.

Forecasting↗
PubMed1998

Adenovirus-mediated gene transfer into cold-preserved liver allografts: survival pattern and unresponsiveness following transduction with CTLA4Ig.

The immune response of liver transplant recipients was modulated via adenovirus-mediated transduction of the cold-preserved liver with sequences encoding CTLA4Ig. Transplanted allografts demonstrated rapid transient local expression and recombinant protein production shortly after revascularization, resulting in intact liver function, indefinite survival of the recipient, and the development of donor-specific unresponsiveness. Lymphocytic infiltration of the graft was mainly of the T helper 2 (Th2) subset and was not associated with injury to primary cellular targets of the alloimmune response. These findings demonstrate a successful outcome of a feasible and potentially clinically relevant system of gene delivery of sequences encoding proteins capable of inhibiting the alloimmune response.

Abatacept↗
PubMed1997

Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen.

Although adenoviral vectors are attractive for gene transfer, their effectiveness is limited by host antiviral immune responses. In this study, we determined if host antiallograft and antiviral immunity could be diminished with an adenoviral vector encoding the immunosuppressive cytokine viral interleukin-10 (vIL-10). AdSV40vIL-10, a vIL-10-expressing adenoviral vector with an SV40 promoter, induced significant prolongation of murine cardiac allograft survival to 32.2 +/- 1.7 days compared to 14.2 +/- 1.0 days for controls (p < 0.01). This effect was specific for vIL-10 encoding vector and could be inhibited by anti-vIL-10 monoclonal antibody (mAb). In vivo administration of adenovirus facilitated the generation of adenovirus-specific cytotoxic T lymphocytes (CTL), whereas treatment with AdSV40vIL-10 prevented CTL priming and generation of virus-specific immunity. AdSV40vIL-10 also induced extended expression of a beta-galactosidase reporter from a co-injected LacZ-encoding adenoviral vector. These results demonstrate that adenovirus-mediated gene transfer and expression of vIL-10 prolong allograft survival and inhibit the immune response to adenoviral antigens, thereby improving the persistence of the vector and extending transgene expression. The efficacy of adenoviral vectors can be improved by incorporating immunosuppressive genes into the vector.

Adenoviridae↗
PubMed1997

Randomized controlled trial to evaluate flush and reperfusion techniques in liver transplantation.

To determine the impact of different flush and reperfusion techniques on postreperfusion syndrome (PRS) and postoperative graft function, 100 transplants were randomly assigned into four groups as follows: group 1 (n=31), portal vein flush, no vena caval venting; group 2 (n=21), hepatic arterial flush, no vena caval venting; group 3 (n=29), portal vein flush with vena caval venting; and group 4 (n=19), hepatic artery flush with vena caval venting. Donor and recipient characteristics were similar. Extensive intraoperative and postoperative monitoring was performed and measurements were documented immediately before reperfusion and at 1, 5, 15, and 30 min after reperfusion. PRS was defined by three criteria: mean arterial pressure (MAP) <60 mmHg at 1 min after reperfusion, MAP <60 mmHg at 5 min after reperfusion, and a decrease of 30% or more for the MAP percent area under the curve during the initial 5 min after reperfusion (%AUC). Using these definitions, the overall incidence of PRS was 21%, 8%, and 43%, respectively. Group 1 was the most hemodynamically stable; the incidence of PRS in group 1 was 2/31 (7%) at 1 min and 8/31 (25%) using %AUC criteria compared with 7/21 (33%) at 1 min and 12/21 (57%) using %AUC criteria for group 2 (P<0.05). The patients in groups 3 and 4 (vena caval venting) demonstrated smaller percentage increases in serum potassium levels (as determined by %AUC; 4.3+/-6.8 and 0.3+/-5.4, vs. 15.1+/-8.1 for group 1 and 22.9+/-8.2 for group 2). The difference between group 4 and group 2 was statistically significant (P<0.05). The increases in serum potassium did not translate into increased cardiac or hemodynamic instability. Combining all data obtained over the first 30 min after reperfusion, there was no statistically significant difference in hemodynamic or biochemical changes noted among the four groups. Postoperative liver function was similar among the four groups. We conclude that portal vein flush without vena caval venting provided a lower incidence of PRS than any other technique. Vena caval venting decreased the release of potassium into the circulation. Postoperative graft function was not significantly affected by flush and reperfusion techniques.

Adult↗