摘要:

The major role of anti-αGal antibodies in the hyperacute rejection of pig organs by humans and baboons has been clearly demonstrated. Spacered α-galactose disaccharide (Galα1-3Gal) hapten was produced by chemical synthesis and covalently attached to a flexible, hydrophilic polymer (PAA), which in turn was covalently coupled to macroporous glass beads, forming an immunoadsorbent that is mechanically and chemically stable and can be sterilized. The extracorporeal immunoadsorption (EIA) of anti-αGal antibodies using this column has been investigated in vivo in 3 baboons. In Baboon 1 (which had hyperacutely rejected a pig heart transplant 4 months previously, was not splenectomized, and did not receive any pharmacologic immunosuppression) the levels of anti-αGal antibody and antipig IgM and IgG, as well as serum cytotoxicity, fell significantly after each of 3 EIAs but were not eliminated. Serum cytotoxicity, antipig immunoglobulin and anti-αGal antibody rose steeply within 24 hr of the final EIA, suggesting that the return of cytotoxicity was associated with anti-αGal antibody. In Baboons 2 and 3 (which were immunologically naive and splenectomized, and received triple drug immunosuppressive therapy) serum cytotoxicity was totally eliminated and anti-αGal antibody and antipig IgM and IgG levels were greatly reduced by courses of EIA. In Baboon 2, cytotoxicity and all antibody levels remained negligible for approximately one week after the final (fourth) daily EIA. In Baboon 3, cytotoxicity and antibody levels were maintained low by intermittent EIA (over a period of 13 days) for almost 3 weeks, although antipig IgM began to rebound 4 days after the final EIA. We conclude that, in an immunosuppressed, splenectomized baboon, repeated EIA using a specific αGal disaccharide column will reduce antipig and anti-αGal antibody levels and serum cytotoxicity significantly for several days. This reduction in cytotoxicity will almost certainly be sufficient to delay the hyperacute rejection of a transplanted pig organ, but further studies are required to investigate whether it will be sufficient to allow accommodation to develop.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A descriptive study of a new model enabling serial biopsies of ongoing hyperacute rejection of small intestinal discordant xenografts is presented. In a series of guinea-pig-to-Lewis rat small bowel xenotransplants(n=7), aboral free ends of Thierry-Vella loops constructed from the graft were sequentially biopsied at one-minute intervals up to ten minutes post-reperfusion and less frequently thereafter. In a guinea pig-to-guinea pig(n=6) isograft series, biopsy controls for preservation/ischemia-reperfusion injury were obtained. Xenoantibody sequestration in this model was evaluated in a separate series of transplants, utilizing an ELISA assay for rat anti-guinea pig natural antibodies. Pathologic evaluation revealed a unique series of events characterized with microcirculatory failure and thrombosis progressing from the submucosal vasculature to the lumen. Within the system's detection limits, complement deposition and P-selectin expression occurred as early as one minute post-reperfusion, preceding the staining for IgM and IgG. Using rat serum ELISAs, no significant difference in xenoantibody sequestration was detected between the xenograft and isograft groups. The guinea pig-to-rat discordant small bowel xenotransplantation is an efficient small animal model to dissect the very early pathophysiologic events during hyperacute rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Preservation with University of Wisconsin (UW) solution can maintain liver graft function and produces survival rates of recipients higher than that with Euro Collins (EC) solution. To explore the underlying mechanisms, we transplanted rat livers following cold preservation with EC or UW solution for 18 hr, and measured hepatic adenine nucleotide levels, the percentage of water content, lactate levels, and endogenous antioxidant levels (α-tocopherol[α-Toc], reduced coenzyme Q9[CoQ9H2], reduced coenzyme Q10[CoQ10H2] and reduced glutathione [GSH] during preservation and after transplantation. The adenosine triphosphate levels of the liver grafts preserved with UW solution recovered after reperfusion more rapidly and reached a higher level than those preserved with EC solution. UW solution caused a reduction in hepatic water content during preservation. Conversely, EC solution induced remarkable tissue edema. In addition, UW solution reduced the rate of hepatic lactate production both during preservation and after reperfusion. The concentrations of hepatic GSH, α-Toc, CoQ9H2, and CoQ10H2immediately after the graftectomy, and after the 18 hr of preservation with both EC and UW solutions, did not differ from those in the normal liver, and decreased only after transplantation. However, UW solution suppressed significantly the reduction in hepatic GSH, α-Toc, and CoQ9H2after reperfusion, compared with EC solution.These results suggest that long-term cold storage induces tissue edema, reflecting a disturbance of the microcirculation during preservation, followed by parenchymal cell damage mediated by free radicals after reperfusion. The protective effects of UW solution could be attributable to the inhibition of free radical production after reperfusion.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Blood coagulation equilibrium in the hepatic sinusoids may be deranged after orthotopic liver transplantation, since tissue factor activity increases in Kupffer cells and thrombomodulin expression disappears in sinusoidal endothelial cells in orthotopically transplanted rat liver. The presence of sinusoidal blood coagulopathy and its contribution to the development of early graft failure following orthotopic liver transplantation were investigated in rats. Orthotopic liver transplantation was performed using livers preserved in cold UW solution, according to the method of Kamada, in rats. Abnormalities in the hepatic sinusoids were evaluated electron-microscopically. Anticoagulation therapy was done using antithrombin III concentrate infused immediately and 12 hr after operation. Fibrin deposition and endothelial cell destruction in the hepatic sinusoids were observed in transplanted rats 5 hr after operation. In these rats, plasma antithrombin III activity was decreased to less than 40% of normal levels, and massive hepatic necrosis developed with increased plasma thrombin-antithrombin III complex concentration 24 hr after operation. Anticoagulation therapy significantly attenuated the extent of hepatic necrosis, with normalization of plasma antithrombin III activity and further increase in plasma thrombin-antithrombin III complex concentration. A hypercoagulative state exists after orthotopic liver transplantation in rats. Fibrin deposition in the hepatic sinusoids associated with this state may contribute to the development of early graft injury.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Transplant arteriosclerosis is the major factor influencing allograft survival after the first year posttransplantation. The host's immunologic response is one of the principal effectors responsible for the constitution of this vascular wall lesion, but the effector pathway and the factors influencing the immune injury are not clear. In a rat abdominal aortic allograft model, we used a skin priming method to study the influence of sensitization on the occurence of vascular wall lesions. Primed rats developed transplant arteriosclerosis lesions involving medial decellularization and intimal proliferation before the 21st day, whereas naive animals had the same lesions at 2 months posttransplantation. A significant difference between primed and naive rats was found for medial thickness (48.00±2.85 μm versus 79.34±2.55 μm,P<0.001) and smooth muscle cell content (160±28 cell/mm versus 466±19 cell/mm,P<0.001) at 21 days posttransplantation, and intimal hyperplasia was seen in primed animals at that time, whereas it was not observed in naive rats until the 60th day. The immune profile in naive and primed animals was different. The immune cells infiltrating the arterial wall in naive rats, were principally macrophages and CD8+ T-lymphocytes. No Ig or complement deposition was detected. IgG and complement activated fraction were present in the media of primed animals as early as the fifth day posttransplantation and CD4+ T lymphocytes were the dominant immune cell population. In conclusion, sensitization influences the immune mechanisms responsible for the development of transplant arteriosclerosis and alters the rate of its evolution.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Preemptive cadaveric renal transplantation (PCRT) maximizes the chance of maintaining high quality of life and may avoid the morbidity of dialysis and the associated financial costs. These benefits are offset by disadvantages, which include the possibility of transplantation many months before the need for dialysis, resulting in wasted organ function; an immediate risk of graft failure with conversion to a dialysis-dependent state; and uncertainty of the safety of PCRT. Patients who underwent PCRT between June 1976 and December 1994 at the Oxford Transplant Centre were compared with a matched cohort of first cadaveric transplant recipients who were dialysis-dependent when transplanted. The 116 patients in the PCRT cohort were well matched to the control group with respect to sex, age, blood group, HLA match, degree of sensitization, donor age, immunosuppression, and year of transplantation. Patient and graft survival were significantly better in the PCRT group. The difference in graft survival did not appear to be completely explained by better patient survival, as suggested by a trend toward better graft survival after excluding death with a functioning graft as a cause of failure. Among surviving grafts there were no significant differences in graft function as assessed by 1, 2, and 3 year plasma creatinine levels. In conclusion, PCRT appears to be safe and may even be associated with superior graft survival when compared with conventional transplantation. Early inclusion on a transplant waiting list with a view to PCRT can be justified with respect to the clinical outcome but the financial costs and implications for the utilization of cadaveric donor kidneys must also be considered.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Patients with chronic hepatitis run the risk of developing progressive liver disease during immunosuppressive therapy after kidney transplantation. To determine the impact of chronic hepatitis C on morbidity and mortality we analyzed 162 anti-HCV positive of 1241 renal-grafted patients(prevalence 13.1%; 84.9% HCV RNA positive) regularly surveyed in our outpatient clinic between 1992 and 1994. The mean age at transplantation was 44.5 (6-69) years, and follow-up after grafting was 7.4 (0.1-23.9) years. The immunosuppressive regimen and frequency of rejection episodes in HCV-infected patients were comparable to the total population. Only 4.3% (5/117) of the anti-HCV positive, HBV negative patients living with functioning grafts developed a markedly compromised liver function. Fifteen (9.3%) of the HCV-infected patients died, but none suffered from posthepatitic cirrhosis. An additional retrospective analysis of causes of death after transplantation prior to 1992 revealed that liver disease had only been responsible for 2% of the deaths (7 of 324) in the HBsAg negative population (n=1901). In contrast, the predominant cause of death in the HBsAg positive population (n=76) was posthepatitic cirrhosis in 58% (15 of 26). Thus, kidney transplantation in patients with replicative hepatitis C and normal liver function appears to be justified because of low early and late morbidity and mortality due to chronic liver disease. HBV infection and hemosiderosis substantially increase the risk of chronic liver disease in renal transplant recipients with hepatitis C.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A maintenance immunosuppressive regimen of cyclosporine and steroids after renal transplantation has proven to be a successful policy to obtain long-term graft survival. However, serious side-effects are associated with this therapy; these include an increased risk for infections, cancer, and cardiovascular morbidity and mortality. Therefore, this pilot study was conducted to investigate the possibility of reducing the immunosuppressive load after transplantation. To this end, we tried to develop an in vitro assay to predict graft rejection after withdrawing steroids from the immunosuppressive therapy. Patients who had stable renal function at least one year after transplantation were randomly divided into a group that continued to receive standard immunosuppression of cyclosporine and steroids and a group to be withdrawn from steroid therapy, the latter group being the subject of the present study. Patients withdrawn from steroids were monitored closely and when a biopsyproven rejection occurred, steroid treatment was reestablished. Blood was collected from patients preceding steroid withdrawal and at fixed time points thereafter. In case of suspected rejection, blood was also taken before biopsy, before steroid treatment was reestablished. In the in vitro limiting dilution analysis-assays cytotoxic T lymphocyte precursor frequencies directed against kidney donor HLA-antigens were determined, in the absence or presence of cyclosporine and several concentrations of prednisolone and the combination of these agents. Confirming earlier results, we found that the number of cyclosporineresistant cytotoxic T lymphocytes increased prior to a rejection crisis, while they did not change or even decreased in patients who retained normal graft function after steroid withdrawal. More importantly, the results show that 10-7M prednisolone in vitro differentially affected donor-specific cytotoxic T lymphocyte precursor frequencies in patients who experienced a rejection crisis after steroid withdrawal, compared with those who remained to do well. This heterogeneity could be detected before the start of steroid withdrawal. Therefore, we conclude that the present data justify a prospective clinical trial to investigate the possible application of this in vitro assay to predict for which patients steroid withdrawal might be considered.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection(P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection(P<0.01). High short-term variability in cyclosporine concentrations was weakly associated with risk of rejection(P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 μg L-1provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We have attempted to quantify the optimal clinical use of cyclosporine during the first 3 months after heart-lung transplantation. We used multiple logistic regression to investigate the influence of blood cyclosporine concentrations and other potential risk factors on histologically confirmed acute lung rejection in 50 heart-lung transplant recipients. A 50% increase in cyclosporine concentration was associated with a 25% reduction in risk of rejection in the subsequent 5 days (P=0.008). Increasing oral corticosteroid dose also protected against rejection(P=0.006). Rejection was over 4 times more likely to occur during the first 20 postoperative days (P=0.002). After 20 days, an FEV1≤ 70% of the age-, sex-, and height-adjusted expected score was associated with a 4-fold increase in risk of rejection (P=0.01). Patients who had multiple previous rejection episodes were also predisposed to further rejection(P=0.005). An investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that cyclosporine concentrations above 500 μg L-1provide optimal protection against acute lung allograft rejection. This result provides an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart-lung transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID