Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders.
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Early diagnosis of Epstein-Barr Virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is important because many patients respond to reduction in immunosuppression, especially if PTLD is detected at an early stage. Previous studies have found elevated EBV DNA levels in blood from patients with PTLD, but these assays required isolation of cellular blood fractions and quantitation. We evaluated the presence of cell-free EBV DNA in serum from solid-organ transplant recipients as a marker for PTLD. Five of 6 transplant recipients with histopathologically documented PTLD had EBV DNA detected in serum at the time of diagnosis (sensitivity = 83%), compared with 0 of 16 matched transplant recipients without PTLD (specificity = 100%) (P < 0.001 [Fisher's exact test]). Furthermore, EBV DNA was detected in serum 8 and 52 months prior to the diagnosis of PTLD in two of three patients for whom stored sera were analyzed. Detection of EBV DNA in serum appears to be a useful marker for the early detection of PTLD in solid-organ transplant recipients. Further studies to define the role of such assays in evaluating solid-organ transplant patients at risk for PTLD are warranted. (+info)
Long-term results of pancreas transplantation under tacrolius immunosuppression.
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BACKGROUND: The long-term safety and efficacy of tacrolimus in pancreas transplantation has not yet been demonstrated. The observation of prolonged pancreatic graft function under tacrolimus would indicate that any potential islet toxicity is short-lived and clinically insignificant. We report herein the results of pancreas transplantation in patients receiving primary tacrolimus immunosuppression for a minimum of 2 years. METHODS: From July 4, 1994 until April 18, 1996, 60 patients received either simultaneous pancreas-kidney transplant (n=55), pancreas transplant only (n=4), or pancreas after kidney transplantation (n=1). Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Azathioprine was used as a third agent in 51 patients and mycophenolate mofetil in 9. Rejection episodes within the first 6 months occurred in 48 (80%) patients and were treated with high-dose corticosteroids. Antilymphocyte antibody was required in eight (13%) patients with steroid-resistant rejection. RESULTS: With a mean follow-up of 35.1+/-5.9 months (range: 24.3-45.7 months), 6-month and 1-, 2-, and 33-year graft survival is 88%, 82%, 80%, and 80% (pancreas) and 98%, 96%, 93%, and 91% (kidney), respectively. Six-month and 1-, 2-, and 3-year patient survival is 100%, 98%, 98%, and 96.5%. Mean fasting glucose is 91.6+/-13.8 mg/dl, and mean glycosylated hemoglobin is 5.1+/-0.7% (normal range: 4.3-6.1%). Mean tacrolimus dose is 6.5+/-2.6 mg/day and mean prednisone dose 2.0+/-2.9 mg/day at follow-up. Complete steroid withdrawal was possible in 31 (65%) of the 48 patients with functioning pancreases. CONCLUSIONS: These data show for the first time that tacrolimus is a safe and effective long-term primary agent in pancreas transplantation and provides excellent long-term islet function without evidence of toxicity while permitting steroid withdrawal in the majority of patients. (+info)
Prevention of autoimmune recurrence and rejection by adenovirus-mediated CTLA4Ig gene transfer to the pancreatic graft in BB rat.
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Type 1 diabetes is the result of a selective destruction of pancreatic islets by autoreactive T-cells. Therefore, in the context of islet or pancreas transplantation, newly transplanted beta-cells are threatened by both recurrent autoimmune and alloimmune responses in recipients with type 1 diabetes. In the present study, using spontaneously diabetic BB rats, we demonstrate that whereas isolated islets are susceptible to autoimmune recurrence and rejection, pancreaticoduodenal grafts are resistant to these biological processes. This resistance is mediated by lymphohematopoietic cells transplanted with the graft, since inactivation of these passenger cells by irradiation uniformly rendered the pancreaticoduodenal grafts susceptible to recurrent autoimmunity. We further studied the impact of local immunomodulation on autoimmune recurrence and rejection by ex vivo adenovirus-mediated CTLA4Ig gene transfer to pancreaticoduodenal grafts. Syngeneic DR-BB pancreaticoduodenal grafts transduced with AdmCTLA4Ig were rescued from recurrent autoimmunity. In fully histoincompatible LEW-->BB transplants, in which rejection and recurrence should be able to act synergistically, AdmCTLA4Ig transduced LEW-pancreaticoduodenal allografts enjoyed markedly prolonged survival in diabetic BB recipients. In situ reverse transcription-polymerase chain reaction revealed that transferred CTLA4Ig gene was strongly expressed in both endocrine and exocrine tissues on day 3. These results indicate the potential utility of local CD28-B7 costimulatory blockade for prevention of alloimmune and autoimmune destruction of pancreatic grafts in type 1 diabetic hosts. (+info)
Treatment of upper abdominal malignancies with organ cluster procedures.
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Upper abdominal exenteration for upper abdominal malignancies was carried out in 15 patients with removal of the liver, spleen, pancreas, duodendum, all or part of the stomach, proximal jejunum and ascending and transverse colon. Organ replacement was with the liver, pancreas and duodenum plus, in some cases, a short segment of jejunum. Eleven of the 15 patients survived for more than 4 months; 2 died, after 61/2 and 10 months, of recurrent tumor. Of the 9 patients who are surviving after 61/2 to 14 months, recurrent tumor is suspected in only 1 and proven in none. Four patients with sarcomas and carcinoid tumors (2 each) have had no recurrences. The other 5 survivors had duct cell cancers (3 examples), a cholangiocarcinoma (1 example), and a hepatoma (1 example). The experience so far supports further cautious trials with this drastic cancer operation. (+info)
Evolution in pancreas transplantation techniques: simultaneous kidney-pancreas transplantation using portal-enteric drainage without antilymphocyte induction.
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OBJECTIVE: To report initial experience with the combination of a novel technique of portal-enteric pancreas transplantation with newer immunosuppressive strategies that eliminate antilymphocyte induction therapy. BACKGROUND: A new surgical technique of pancreas transplantation has been developed with portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric). The introduction of potent immunosuppressive agents may allow simultaneous kidney and pancreas transplants (SKPT) to be performed without antilymphocyte induction. METHODS: From September 1996 to November 1998, the authors performed 28 primary SKPTs with portal-enteric drainage and no antilymphocyte induction. All patients received triple immunosuppression with tacrolimus, mycophenolate mofetil, and steroids. The study group had a mean age of 38 years and a mean preoperative duration of diabetes of 25 years. Four patients (14%) had prior kidney transplants. RESULTS: All patients had immediate renal allograft function. Actual patient, kidney, and pancreas graft survival rates were 86%, 82%, and 82%, respectively, after a mean follow-up of 12 months. Four patients died, three as a result of cardiac events unrelated to SKPT. Five kidney and five pancreas grafts were lost, including five deaths with function and three cases of chronic rejection. The mean length of stay and total charges for the initial hospital stay were 12.5 days and $99,517. The mean number of readmissions was 2.9, and 10 patients (36%) had no readmissions. Six patients (21 %) developed acute rejection, with five (18%) receiving antilymphocyte therapy. Seven patients (25%) underwent relaparotomy, including two (7%) for intraabdominal infection. Nine patients (32%) had major infections, including three (11%) with cytomegaloviral infection. Of the 24 surviving patients, 22 (92%) are both dialysis- and insulin-free. CONCLUSION: These preliminary results suggest that SKPT with portal-enteric drainage without antilymphocyte induction can be performed with excellent outcomes. (+info)
Lipids increase after solitary pancreas transplantation.
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OBJECTIVE: The aims of this study were to determine 1) changes in lipids after solitary pancreas transplantation (SPTX) in patients with type 1 diabetes and 2) factors that influence those changes. RESEARCH DESIGN AND METHODS: Lipids were evaluated prospectively in 24 patients who underwent SPTX. Three were excluded because of early graft failure. The remaining patients (n = 21; 13 men, 8 women) were studied for changes in lipids over time (pre-SPTX, 0-2, 3-6, 7-12, and > 12 months). Glycohemoglobin, serum creatinine, BMI, and medications were also analyzed for their effects on lipid changes. RESULTS: Cholesterol, HDL, and LDL decreased in the immediate postoperative period (0-2 months), whereas triglycerides (TGs) increased (P < 0.05). At 3-6 months, cholesterol, HDL, and TG were higher than before the SPTX, whereas LDL returned to pre-SPTX levels. After 12 months, HDL and TG remained higher than their pre-SPTX levels (P < 0.05). During the study, systolic and diastolic blood pressure increased, renal function decreased, glyco-hemoglobin improved, and weight was unchanged. Changes in cholesterol/HDL ratio, HDL, and TG correlated with changes in prednisone dose (P < 0.05), and changes in TG correlated with changes in creatinine (P < 0.05). The same pattern of lipids occurred in patients prescribed or not prescribed hypolipidemic agents. CONCLUSIONS: Lipids do not improve within the 1st year after SPTX, despite improved glycemic control and blood pressure control, and renal function is worse. These results are in contrast to those reported for combined kidney-pancreas transplantation, where lipids, blood pressure, and renal function improved immediately after transplant. Further studies are needed to determine whether lipids continue to change with time after SPTX. The impact of these changes after SPTX on overall cardiovascular risk is unknown. (+info)
Activation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease.
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The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBV-specific CTL lines from these patients and show their potential use for immunotherapy against PTLD in solid organ transplant patients. Peripheral blood mononuclear cells from a panel of solid organ transplant recipients with and without active PTLD were used to assess EBV-specific memory CTL responses. The activation protocol involved cocultivation of peripheral blood mononuclear cells with an autologous lymphoblastoid cell line under conditions that favored expansion of virus-specific CTL and hindered the proliferation of allospecific T cells. These CTL consistently showed (i) strong EBV-specificity, including reactivity through defined epitopes in spite of concurrent immunosuppressive therapy, and (ii) no alloreactivity toward donor alloantigens. More importantly, adoptive transfer of these autologous CTLs into a single patient with active PTLD was coincident with a very significant regression of the PTLD. These results demonstrate that a potent EBV-specific memory response can be expanded from solid organ recipients who have acquired their primary EBV infection under high levels of immunosuppressive therapy and that these T cells may have therapeutic potential against PTLD. (+info)
Normoglycemia and preserved insulin secretory reserve in diabetic patients 10-18 years after pancreas transplantation.
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Pancreas transplantation is a controversial form of therapy for type I diabetes. A major obstacle to acceptance of this procedure for many physicians is the lack of demonstrable long-term success. We performed these studies to assess the hypothesis that successful pancreas transplantation is efficacious in normalizing endogenous insulin secretion and glycemia in the long term (1-2 decades). Sixteen patients with a history of diabetic complications who had undergone a transplant 10-18 years earlier involving either a whole or a segment of pancreas were recruited for measurements of fasting plasma glucose, HbA1c, intravenous glucose tolerance, and insulin secretory reserve. All patients were taking immunosuppressive drugs, but none was using insulin or other hypoglycemic agents. All recipients had normal levels of fasting blood glucose, intravenous glucose tolerance, and HbA1c, and 15 of 16 stated that their quality of life had improved after transplantation. They had intact acute insulin responses to intravenous pulses of glucose and to arginine and insulin secretory reserve. Glucose potentiation of arginine-induced insulin secretion, the measure of insulin secretory reserve, correlated significantly (r = 0.095, P < 0.001) with the acute insulin response to intravenous glucose, rendering the latter a much simpler and valid measure of functional beta-cell mass. We conclude that successful pancreas transplants are efficacious for periods as long as 1-2 decades in returning euglycemia to type 1 diabetic patients by restoring endogenous insulin secretion and insulin secretory reserve. Thus, concern about long-term deterioration, as distinct from rejection, should not be a major obstacle when deciding whether to recommend pancreas transplantation. (+info)