摘要:

Advances in molecular biology and in techniques of gene transfer have resulted in the development of practical approaches to human gene therapy.Many applications are of relevance to manipulation of the immune system and have potential in organ and cell transplantation. For example, gene therapy approaches may facilitate the induction of immunological tolerance to a donor organ or protect it locally against the host’s immune response. Based on a comprehensive review of the world literature, examples of current research efforts in both allogeneic and xenogeneic transplantation are presented and discussed.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Introduction.Leukocyte function-associated antigen-1 (LFA-1, CD11a) monoclonal antibody (mAb) affects many leukocyte functions without cell depletion. We hypothesized that the use of a humanized, anti-rhesus modified LFA-1 mAb (H2C12) in rhesus monkeys would cause: (1) prolonged heart allograft survival, (2) inhibition of primary but not secondary antibody responses, and (3) minimal drug toxicity.Methods and Results.Control (n=5) and H2C12-treated (n=7) (8–20 mg/kg i.v. on day −1 followed by 10 mg/kg/day) adult male rhesus recipients were inoculated with GP120 protein antigen on day −28 and −1 and grafted with heterotopic abdominal hearts (day 0). Donor-recipient pairs were equally MLR mismatched (4329.8±1124.1 CPM controls vs. 7289.0±1926.5 treated,P=NS). Mean heart allograft survival as evaluated by daily abdominal palpation was significantly prolonged in high dose recipients (23.0±2.6, n=4) vesus controls (8.2±1.3, n=5,P<0.02, Mann-WhitneyUtest). H2C12 treatment did not produce signs of cytokine release or toxicity, was nondepleting, but down-modulated PBL CD11a expression to 43.4±3.6% (n=4) of control levels (n=5) at day 7 as demonstrated by flow cytometry. It had no effect on postoperative Con A or MLR and did not prevent mAb clearance due to the rhesus-antihuman antibody response. The addition of mycophenolate mofitil prevented rhesus-antihuman antibody response with therapeutic H2C12 levels seen for >35 days.Conclusions.The use of this mAb to block CD11a had the benefit of being a well tolerated, highly targeted therapy. These are the first results showing that monotherapy with anti-leukocyte function-associated antigen-1 mAb prolonged survival of MLR mismatched allogenic cardiac grafts in primates.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Myocardial preconditioning with brief coronary artery occlusions before a sustained ischemic period is reported to reduce infarct size. We wished to evaluate whether ischemic preconditioning (IP) is efficient in an experimental brain death (BD) model in the rabbit.Methods.Rabbits were randomized into four experimental groups of eight animals each. In the control group (CTRL), anaesthetized rabbits were subjected to 30 min of left coronary marginal branch occlusion and 90 min of reperfusion without any pretreatment. In the CTRL+IP group, anaesthetized rabbits were preconditioned with a 3-min ischemia and 3-min reperfusion sequence before coronary occlusion. In the BD group, rabbits were subjected to 90 min of BD before 30 min of coronary occlusion and 90 min of reperfusion. In the BD+IP group, BD rabbits were preconditioned as in the CTRL+IP group before coronary occlusion. BD was induced by rapid inflation of an intracranial balloon and was validated by clinical and electroencephalographic examinations. At the termination of the experiment, left ventricular volume (LVV), myocardial volume at risk (VAR) and infarct volume (IV) were determined with methylene blue and tetrazolium staining and were measured using planimetry.Results.LVV was not significantly different among the four experimental groups (CTRL, 6.54±0.90 cm3; CTRL+IP, 5.92±0.60 cm3; BD, 5.87±0.81 cm3; BD+IP, 6.16±0.95 cm3;P=ns). Furthermore, myocardial VAR, expressed as a percentage of LVV, was not significantly different between groups (CTRL, 20.0±4.2%; CTRL+IP, 22.32±2.25%; BD, 21.38±3.36%; BD+IP, 21.64±3.39%;P=NS). IV, expressed as a percentage of VAR, was significantly reduced in the CTRL+IP group compared with the CTRL group (15.76±8.47% vs. 49.95±1.51%; P<0.0001). In contrast, there was no significant difference in IV, expressed as a percentage of VAR, between the BD and the BD+IP groups (50.0±1.52% vs. 49.72±1.58%;P=NS).Conclusion.The data indicate that the infarct-limiting effect of IP is lost in BD rabbits. Thus, the clinical potential of IP in the context of organ transplantation seems to be severely compromised.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.The use of lung grafts from non-heart-beating donors (NHBD) is one way of solving the donor organ shortage problem. In this experiment, we studied the effect of retrograde flush (RF) from the left atrium before harvest, inhaled nitric oxide (NO), and gabexate mesilate (FOY), a protease inhibitor, in the lung grafts from NHBD.Methods.Forty-eight Lee-Sung, small-ear, miniature pigs (15–20 kg) were divided into 24 pairs (donor and recipient) and four groups. The donor lungs were flushed and harvested 90 min after cardiac arrest. No i.v. heparin was administered until the time before flush and harvest. Left single lung transplantation was undertaken, and the recipients were observed for 18 hr. The grafts warm and cold ischemia times were 90 (controlled) and 183±23.4 min. Group 1 (untreated control, UC, n=6) had core perfusion through a Swan-Ganz catheter followed by a single, antegrade flush with modified Euro-Collin’s solution containing heparin, urokinase, and PGE1. Group 2 (RF group, n=6) had the same as group 1, except that one additive retrograde flush through the left atrium was administered. Group 3 (NO group, n=6) had the same as group 1, except that 20 parts per million (ppm) inhaled NO was administered for the cadaver donors before the graft harvest, and for the recipients after the grafts reperfusion. Group 4 (FOY group, n=6) had the same as group 1, except that the recipients received FOY i.v. infusion from the beginning of the recipient’s operation and continuously throughout the experiments.Results.Compared with the group 1 (control), group 2 (RF) had significantly (P<0.05) lower mean pulmonary artery pressure, pulmonary vascular resistance (PVR), lung wet/dry ratio, histological lung injury score, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 3 (NO) had significantly lower mean pulmonary arterial pressure, PVR, lung injury score, degree of tissue neutrophils infiltration (histological and myeloperoxidase assay), bronchoalveolar lavage fluid protein content and neutrophils (PMNs) percentage, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 4 (FOY) had significantly lower PMNs infiltration, lung injury score, wet/dry ratio, bronchoalveolar lavage fluid protein and PMNs percentage, and higher PaO2/FiO2. Group 2 (RF) revealed better gas exchange (PaO2/FiO2) than the control (group 1) at earlier reperfusion periods (1st and 5th hr). On the contrary, group 4 (FOY) had higher PaO2/FiO2 than group 1 only at later period (18th hr). Pathologically, retrograde flush (group 2, RF) inhibited the intravascular thrombi formation more effectively than the NO or FOY treatment. However, the NO or FOY treatment inhibited the neutrophil infiltration more effectively than did the retrograde flush.Conclusion.The retrograde flush, inhaled NO and FOY infusion are beneficial to the protection of the NHBD lung grafts at an early reperfusion period, through different mechanisms. The use of these treatments in combination might help us to find a better way to protect the NHBD grafts against the preservation and reperfusion injury.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Fatty liver is associated with primary nonfunction after liver transplantation, contributing a shortage of suitable liver grafts. Because extensive investigation of mechanisms underlying such nonfunction has been limited largely to rodents, we made a new fatty liver model in dogs and studied primary nonfunction after warm ischemia.Methods.We developed a diet rich in fat but deficient in choline to induce fatty change in canine liver and investigated effects of 60 min of warm ischemia and reperfusion in dogs with such fatty livers.Results.Microscopically evident steatosis increased with duration of dietary manipulation (up to12 weeks), as did hepatic total lipid and triglyceride levels. No dog with >30% of steatotic hepatocytes, >445 mg/g hepatic total lipid or >145 mg/g hepatic triglyceride survived after 60 min of warm ischemia. Arterial ketone body ratios decreased and blood endotoxin increased after reperfusion in nonsurvivors. The main histologic finding in livers of nonsurvivors was marked sinusoidal congestion.Conclusions.Damage to hepatocytes and nonparenchymal cells after warm ischemia and reperfusion was thought to be closely related to sinusoidal microcirculatory disturbances in fatty livers. The canine fatty liver model reported here may be useful in studying the pathology of primary nonfunction and in establishing criteria for allowable degrees of fatty change in potential liver grafts.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Recently, specific immunonutrients were found to increase experimental allograft survival when combined with cyclosporine A (CsA). This study compared the effect on rat cardiac allograft survival when nutritional immunomodulation was used with CsA, rapamycin (Rapa), or tacrolimus (FK506).Methods.Intra-abdominal ACI to Lewis cardiac allografts were performed and assessed daily by palpation. Study groups included untreated controls and those receiving CsA, Rapa, or FK506. Rats were fed ad libitum with Impact diet (fortified with fish oil, arginine, and RNA) or standard rat food. Further study groups were transplanted that received a donor-specific transfusion in addition to immunosuppression and diet.Results.Allograft survival was extended by combining Impact with CsA (45.3±19 days) and Rapa (165.3±52 days), but not FK506 (12.4±3.2 days). Mean graft survival in the Rapa/Impact group met criteria for functional tolerance. The addition of a donor-specific transfusion did not lead to graft survival advantages over similar groups not receiving a donor-specific transfusion.Conclusions.The use of immunonutrients improves transplant outcome in animals treated with short courses of CsA and Rapa, but not FK506. These findings highlight the potential differences in the effects of nutritional immunomodulation with different immunosuppressive drugs in the treatment of transplant patients.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID