摘要:

The extreme demand for human organs or tissues for transplantation has driven the search for viable alternatives. Pigs are considered a possible source of tissue for a number of reasons including shared physiology, plentiful supply, short gestation, and, more recently, the generation of transgenic animals. Porcine islets show promise as a source of islets for the treatment of type 1 diabetes mellitus. Porcine islets regulate glucose levels in the same physiologic range as humans, and porcine insulin has been used for years as an exogenous source of insulin for glucose control. In this review, we discuss the advantages and disadvantages of the use of adult or neonatal porcine islets, the immunologic challenges facing transplantation of xenogeneic islets, and the concerns regarding transmission of infectious agents between species. Porcine islets isolated from both adult and neonatal pigs are capable of restoring euglycemia in experimental animal models of diabetes. Adult islets are more difficult to isolate, whereas neonatal islets have great proliferation potential but require several weeks to function posttransplantation. Xenogeneic islets are susceptible to complement-mediated lysis after the binding of preformed natural antibodies and cellular immunity involving both macrophages and CD4+ T cells. In addition, the potential for transmission of porcine endogenous retroviruses, porcine cytomegalovirus, and porcine lymphotropic herpesvirus type 1 are all concerns that must be addressed. Despite the challenges facing xenotransplantation, the extreme need for donor organs and tissues continues to drive progress toward overcoming the unique issues associated with transplantation between species.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Endothelial injury plays a central role in the pathophysiologic mechanisms underlying cardiac allograft vasculopathy (CAV). Although the accelerated course of CAV and its localization to the allograft support an important role for the alloimmune response, there is considerable evidence implicating lipoprotein abnormalities, metabolic disturbances, viral infections, and systemic inflammation in the process. This multifactorial basis for CAV may be put into a pathophysiologic context in which endothelial cell injury is the triggering event that initiates and drives the proliferative and fibrotic processes characteristic of CAV. In the transplant setting, endothelial cell injury is induced by multiple factors, including brain death, ischemia-reperfusion, alloimmune responses, and viral infections. Once initiated, propagation of the proliferative processes that ultimately lead to vascular occlusion is enhanced by the abnormal metabolic environment of elevated lipoproteins and insulin resistance encountered in most patients. This review examines the evidence for the role of potential triggers of endothelial injury in the pathophysiology of CAV and discusses the central role of the nitric oxide pathway in the disease process.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Animal cloning techniques have enabled gene disruption in several species. Here, we report the first successful disruption of the &agr;1,3-galactosyltransferase (&agr;1,3-GT) gene in cattle.Methods.The &agr;1,3-GTgene of the Japanese Black cow (JBC) was used to construct pGT-6, a targeting vector for the bovine &agr;1,3-GTgene, and pGT-6 was introduced into the fetal fibroblast cell line JBC906 by the lipofection method. Four polymerase chain reaction (PCR)-positive colonies were obtained from 797 G418-resistant colonies, and Southern blot analysis revealed successful homologous recombination at the &agr;1,3-GTlocus in one of the four colonies. Nuclear transfer was performed, and the four embryos were transferred to a heifer.Results.To establish fetal fibroblasts that were heterozygously disrupted at the &agr;1,3-GTlocus, one of the fetuses was recovered at 5 weeks of pregnancy, and PCR and Southern blot analysis of the fetal fibroblasts established from it showed definite homologous recombination of the &agr;1,3-GTgene.Conclusions.Heterozygous knockout of the &agr;1,3-GTgene was performed in JBC, and production of a homozygous &agr;1,3-GTknockout JBC by a second round of targeting 906htGT is currently in progress. The technique described here can be applied to disruption of other genes in cattle.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.MO2ART (monitoring of 2-hr absorption in renal transplantation) is the first prospective, multicenter trial of cyclosporine (CsA) blood level 2 hr postdose (C2) monitoring in de novo kidney recipients receiving CsA microemulsion (ME) (Neoral; Novartis, Basel, Switzerland). Efficacy and safety results from the first 3 months are presented here.Methods.MO2ART is a 12-month, open-label, randomized study involving 296 patients. In all patients, the dose of CsA-ME was adjusted to achieve protocol-defined C2targets of 1.6 to 2.0 &mgr;g/mL for the first month, with subsequent tapering. Randomization into two target groups occurred at 3 months. All patients received steroids and mycophenolate mofetil (89%) or azathioprine. For patients with delayed graft function, the protocol permitted reduced C2targets and prophylactic administration of antibodies.Results.At 3 months, overall incidence of biopsy-proven acute rejection was 11.5%. Median serum creatinine was 132 &mgr;mol/L. Patient and graft survival were 96.6% and 91.2%, respectively. C2levels greater than 1.6 &mgr;g/mL were achieved within 5 days by 60.6% of patients with immediate graft function and 19.5% of patients with delayed graft function. Prophylactic antibodies were used in 15% of the total population. Twenty-four patients (8.1%) experienced serious adverse events with a suspected relation to CsA, and 26 patients (8.8%) discontinued the study because of adverse events (n=15) or after a switch in immunosuppression after rejection episodes (n=11).Conclusions.Patient management by C2monitoring resulted in a low incidence of biopsy-proven acute rejection in standard risk de novo kidney recipients, 85% of whom did not receive prophylactic antibodies. CsA-ME with C2monitoring provides excellent short-term efficacy and safety among de novo renal transplant patients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.A major obstacle to successful small bowel transplantation is that of bacterial infection. The aim of this study was to preserve the small bowel mucosal barrier by using oxygenated luminal perfusion with a proven amino acid (AA)-based solution.Methods.Rat small bowel (n=4) was flushed vascularly with modified University of Wisconsin solution and flushed luminally as follows: group 1, none (control); group 2, AA solution; group 3, 1-hr perfusion then storage with AA; group 4, continuous perfusion with AA. Energetics, malondialdehyde (MDA), glutathione (reduced), and histology were assessed over 24 hr at 4°C.Results.Within 4 hr, adenosine triphosphate (ATP) dropped by 25% to 65% in all groups except for group 4, which remained unchanged from fresh tissue values throughout 12 hr. After 12 hr, ATP in groups 1 through 3 had dropped to 0.5 to 0.9 &mgr;mol/g, compared with 1.5 &mgr;mol/g for group 4. Even after 24 hr, group 4 levels were more than twofold greater than groups 1 through 3. MDA increased transiently in tissues subjected to simple flush (no perfusion), whereas levels in perfused tissues remained elevated throughout the 24-hr period. Glutathione in group 1 dropped by greater than 50% from fresh tissue values but increased over 24 hr in groups 2 and 3 by 50% to 55%. Overall, histologic injury was markedly less in groups 2 through 4; however, after 24 hr, the lowest injury was observed in group 3 (median, grade 2) compared with groups 1 and 4 (grades 7 and 4).Conclusions.Our data indicate that perfusion clearly improves tissue energetics. However, mucosal integrity is markedly superior, with only a brief 1-hr period of perfusion; oxidative and mechanical stress are the factors likely responsible for injury resulting from continuous perfusion.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective.With newer immunosuppressive agents, acute rejection and graft loss resulting from acute rejection have become less common for pancreas transplant recipients. As long-term graft survival rates have improved, an increasing number of grafts are being lost to chronic rejection (CR). We studied the incidence of CR and identified risk factors.Methods.We retrospectively analyzed all cadaver pancreas transplants performed at the University of Minnesota between June 19, 1994, and December 31, 2002. We determined the causes of graft loss, the incidence of graft loss to CR and, using multivariate techniques, the major risk factors for CR.Results.A total of 914 cadaver pancreas transplants were performed in the following three categories: simultaneous pancreas-kidney (SPK) (n=321), pancreas after kidney (PAK) (n=389), and pancreas transplant alone (PTA) (n=204). The mean recipient age was 41.3 years and the mean donor age was 30.1 years. Of the 914 pancreas grafts, 643 (70.3%) continue to function (mean length of follow-up, 39 months). The most common cause of graft loss was technical failure, accounting for 118 (12.9%) of the failed grafts. The second most common cause was CR, accounting for 80 (8.8%) of the failed grafts. The incidence of graft loss to CR was highest for PTA (n=23 [11.3%]) and PAK (n=45 [11.6%]) recipients and lowest for SPK recipients (n=12 [3.7%]) (P=0.002). By multivariate analysis, the most significant risk factors for graft loss to CR were a previous episode of acute rejection (relative risk [RR]=4.41,P<0.0001), an isolated (vs. simultaneous) transplant (PAK or PTA [vs. SPK], RR=3.02,P=0.002), cytomegalovirus infection posttransplant (RR=2.41,P=0.001), a retransplant (versus primary transplant) (RR=2.27,P=0.004), and one or two (vs. zero) antigen mismatches at the B loci (RR=1.68,P=0.04).Conclusions.As short-term pancreas transplant results improve and as isolated (PAK or PTA) pancreas transplants gain in popularity, CR will become increasingly common as a cause of pancreas graft loss.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation.Methods.Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,62H2glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide(GIP) concentrations were compared after intravenous and oral glucose.Results.After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P<0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P<0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose.Conclusions.First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the &bgr;-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Non-Hodgkin’s lymphoma is the second most frequent neoplasia following solid-organ transplantation. The objective of this study is to describe the clinical, histologic, and radiologic features of primary posttransplantation brain lymphomas (PTBL) in addition to their outcome.Methods.Twenty-five kidney transplant patients with histologically proven PTBL from 11 French centers were retrospectively investigated.Results.Immunosuppressive regimen included induction with antithymocyte globulins (ATG) in 20 patients. Median overall delay between transplantation and lymphoma was 18 months (4–264). Six of 10 patients with late posttransplantation brain lymphomas (PTBL) occurrence (>3 years) had been recently switched from azathioprine to mycophenolate mofetil (median switch lymphoma delay 14 months). Cerebral computed tomography (CT) scans and magnetic resonance imaging (MRI) revealed multifocal lesions (n=18), with a ring contrast enhancement (n=20) similar to cerebral abscesses, as observed in HIV-related brain lymphomas. Histology showed large B-cell non-Hodgkin’s lymphoma in 87.5% of cases; Epstein-Barr virus (EBV) was detected in 95%. After lymphoma diagnosis, immunosuppressive treatment was reduced in all patients, and all but one received complementary treatment by surgery (n=2), anti-CD21 antibodies (n=2), chemotherapy including high-dose intravenous methotrexate (n=7), encephalic radiotherapy (n=5), or chemotherapy plus radiotherapy (n=8). Median overall survival was 26 months. Patients with a radiotherapy-based regimen seemed to have a longer survival (36vs.7 months,P<0.005).Conclusions.Our study showed that PTBL are EBV-induced large B-cell lymphomas, which mimic cerebral abscesses on imaging and whose occurrence may be influenced by immunosuppression modifications. Treatment by radiotherapy is associated with better survival.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Withdrawal of corticosteroids from the immunosuppressive regimens of kidney transplant recipients has been associated with an increased risk of acute and chronic allograft rejection. Previous studies indicate that the risk of rejection is particularly high in African Americans.Methods.We prospectively enrolled 44 African American kidney transplant recipients to participate in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids. No patient received antibody induction therapy. Prednisone was withdrawn from eligible patients free of acute rejection beginning as early as 3 months posttransplant, and followed for a minimum of 9 months posttransplant. Patients were followed for acute rejection and for changes in blood pressure, body weight, and serum creatinine concentrations before and after withdrawal of steroids.Results.Thirty of 44 patients (68%) were weaned off of prednisone. Follow-up after withdrawal of prednisone ranged from 3 to 26 months (mean, 14.3±7.7 months). Two of 30 patients (6.7%) developed acute rejection. At last follow-up, 27 of 30 patients (90%) remain steroid-free. Steroid withdrawal was associated with significant reductions in blood pressure.Conclusions.Use of sirolimus and tacrolimus, without the use of induction antibody therapy, allows withdrawal of prednisone as early as 3 months posttransplant with low rates of subsequent acute rejection in African American kidney transplant recipients. Withdrawal of prednisone was associated with lower blood pressures and the need for fewer antihypertensive medications.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID