Induction of acute rejection by indirect recognition of donor MHC antigens.
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Amino Acid Sequence↗
Biomedical subjects
G Otto
Publications and source records attributed to G Otto.
Importance of the first minutes of reperfusion in hepatic preservation injury.
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Adenosine↗
Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease.
The cellular interactions of advanced glycation end products (AGEs), which have been hypothesized to contribute to the development of vascular lesions, occur, at least in part, through their binding to a novel integral membrane protein, the receptor for AGEs (RAGE). Studies of human vascular segments show that endothelial RAGE expression at the antigen and mRNA level was variable and usually at low levels in samples from healthy individuals. In contrast, patients with a range of peripheral occlusive vascular diseases, with or without underlying diabetes, demonstrated prominent enhancement of endothelial RAGE expression. Smooth muscle cells and nerves in the vessel wall showed constitutively high levels of RAGE expression that were unchanged with aging (from 1 to 92 years) or by the presence of vascular disease. These data suggest that RAGE is likely to have ligands other than AGEs, and that multiple factors in addition to AGEs impact on its expression. Taken together, our findings suggest that RAGE may contribute to the pathogenesis of a range of vascular disorders.
Adult↗
[Resections of recurrence in the liver of primary and secondary liver cancers].
1) Only one third of primary hepatic carcinomas and in particular hepatocellular carcinomas are amenable to liver resection. Approximately half of these patients develop tumor recurrences within the first two years accounting for the poor prognosis of this condition. The liver is the site of first failure in about 80 percent of patients. Secondary liver surgery for intrahepatic recurrence is technically possible in about one third of the patients at low operative mortality (< 5 percent). Long-term prognosis following potentially curative liver reresection for hepatosellular carwinoma compares favourably (5-year survival approximately 50 percent) with the prognosis after resection of the primary tumor. For potentially curative treatment liver transplantation is the only alternative to hepatic reresection, while alcohol injection and chemoembolization are merely palliative procedures. II) Liver resection represents the only potentially curative form of treatment for hepatic metastases from collorectal cancer. Operative mortality is generally less than 5 percent and 5-year survival of 20-40 percent can be expected. Secondary hepatic recurrences following hepatic resection of colorectal metastases are amenable to reresection in approximately 10 percent of patients. Selection criteria for reresection are the same as for primary liver reresection. Median survival following secondary liver resection is 32 months and this is identical to the median survival after the first liver resection for colorectal metastases.
Adolescent↗
Remission of severe alcoholic polyneuropathy after liver transplantation.
Alcoholic polyneuropathy presents with variable severity. Only few very severely disabled patients showed good clinical and electrophysiological improvement after cessation of alcohol abuse. We report a 55 year old patient with polyneuropathy who underwent orthotopic liver transplantation for decompensated alcoholic cirrhosis. After an initial postoperative exacerbation of her neurological disorder the patient developed an impressive remission of her clinical condition during the 4 year post transplantation follow up period. Nine months after surgery the initially wheel chair bound patient regained the ability to walk on her own. The previously severely impaired sensory modalities returned to nearly normal function. Electrophysiological findings also improved. The right tibial nerve conduction velocity increased from 16.8 to 26.7 m/s between the 27th and 37th post transplantation month. We postulate that liver transplantation facilitated the remission of this patient's alcohol-induced polyneuropathy. This observation suggests that alcoholic polyneuropathy, even when severe, should not be considered a contraindication for liver transplantation.
Alcoholism↗
Frequency analysis of donor-reactive cytotoxic T lymphocyte precursors in in allograft recipients. Lack of correlation with clinical outcome.
The frequency of donor-reactive and of third party-reactive cytotoxic T lymphocyte precursors (CTLp) was determined by limiting dilution analysis in the peripheral blood of 13 liver allograft recipients before (pre-tpx) and at various intervals (4 to 22 months) after (post-tpx) transplantation. In 6 of 13 patients with stable graft function, no change of donor-reactive CTLp occurred within 9 to 17 months post-tpx, and high levels of donor-reactive CTLp (frequencies ranging from 1/1024 to 1/13,295) were maintained. In contrast, a 4-11-fold reduction of donor-reactive CTLp frequencies was observed in 5 patients within 4 to 22 months post-tpx; in 3 of these patients the measured frequency of donor-specific CTLp dropped to biologically irrelevant levels (1/43,800 to 1/150,000). However, a 5-7-fold increase of the post-tpx frequency of donor-reactive CTLp was observed in two additional patients with stable graft function. Taken together, these results demonstrate that the frequency analysis of donor-reactive CTLp in the peripheral blood does not closely correlate with the clinical outcome. Thus, stable liver allograft function after > 1 year of transplantation can be associated with a specific deletion, unaltered levels, or even an increase in the frequency of circulating donor-reactive CTLp.
Adolescent↗
Liver transplantation and de novo hepatitis B infection.
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Hepatitis B↗
Soluble tumor necrosis factor receptors in patients with recurrent hepatitis C virus infection after liver transplantation.
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Adult↗
Serum amyloid A protein (SAA): a marker for liver allograft rejection in humans.
Serum amyloid A protein (SAA) concentrations were monitored in 12 consecutive liver transplant recipients until the 70th postoperative day. Fourteen rejection episodes were identified histologically in 42 liver biopsies of the grafts. Of 12 rejections 8 (66.7%) were characterized by pronounced simultaneous increases in SAA concentrations in plasma, the mean peak value being 16.94 +/- 8.82 mg/dl (range 4.58-28.55 mg/dl) compared with a mean normal value of 0.98 +/- 0.42 mg/dl in healthy controls. Of 42 biopsies 28 did not show histological evidence of graft rejection. Of 25 negative biopsies 24 (96.0%) were not accompanied by a parallel SAA increase in plasma. These findings demonstrate that measurements of SAA concentrations may provide a valuable noninvasive aid in identifying acute liver allograft rejection in humans.
Adolescent↗
Short-term T cell receptor directed immunotherapy induces organ specific peripheral tolerance in a strongly incompatible rat model.
We analysed the effect of selective alpha/beta-T cell elimination on allograft survival in a strongly histoincompatible DA-->LEWIS rat model by treatment of recipients with the mouse monoclonal antibody R73 two times before and seven times after transplantation. R73 induced virtually indefinite cardiac allograft survival in 44% of six-week-old LEWIS recipients, whereas donor-type skin allografts were rejected within 11 days. The remaining 56% of animals presented a mean cardiac survival time of 41 +/- 13 days. Graft prolongation was age dependent since in ten-week-old animals the survival time was only of 19 +/- 5 days (untreated controls: 7 +/- 1 days). R73 induced a rapid decrease of R73-positive T cells in the peripheral blood from 70% before treatment to 2%. From the fifth day of treatment a gradual T cell recovery was registered. The T cell marker CD5 decreased from 72% to 17% but recovered already from the second day of treatment. Determination of alpha/beta-TCR, CD3 and CD5 density on T cells during R73 therapy showed that the initial T cell decrease was due to T cell elimination, whereas modulation of alpha/beta-TCR was predominant during the following days. Anti-R73 antibodies appeared regularly during the first week of treatment and blocked R73 activity, indicating their anti-idiotypic nature. The present findings show that short-term R73 therapy is able to induce long-lasting allograft survival. This experimental model can be used to study the basis of peripheral organ specific T cell tolerance.
Animals↗
Biliary tract strictures after orthotopic liver transplantation: diagnosis and management.
Biliary tract complications in 105 patients who had undergone orthotopic liver transplantation were reviewed in order to determine their incidence and localization. In addition, the possible endoscopic and percutaneous management of such complications was evaluated. Signs of cholestasis appeared in 32 of 105 (30.5%) transplant recipients after a mean of 6.5 months (range 1-19 months), and visualization of the biliary system was performed in all. Twenty biliary tract complications were observed in these 32 patients (62.5%). There were multiple strictures, both intrahepatic and extrahepatic, in 11 grafts. Five of the nine extrahepatic strictures were not confined to the site of the bile duct anastomosis, and involved the whole common bile duct of the donor liver, while the remaining four were confined. The multiple intrahepatic and extrahepatic strictures were related either to occlusion of the hepatic artery or to the fact that the graft had been in a cold ischemic state for a prolonged time. In contrast, multiple strictures and necrosis of the whole extrahepatic bile duct were attributed to local ischemia due to the harvesting procedure. Stenoses strictly confined to the site of anastomosis were thought to be due to surgical technique. Ten extrahepatic bile duct stenoses with considerably impaired bile flow were corrected endoscopically (four), percutaneously (three) and by surgery (three). In four patients with complications in the whole intrahepatic and extrahepatic system, retransplantation was necessary. Biliary tract complications in our patients occurred in up to 19% after liver transplantation on long-term follow-up. Complications of only the extrahepatic system can be treated successfully, whereas complications involving multiple stenoses of the intrahepatic bile duct system frequently require retransplantation.
Adolescent↗
Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery.
Mutations or loss of the APC tumor-suppressor gene is important for the development of colorectal polyps and cancers, but little is known about the function of this gene in normal tissue. To study the role of APC and other genes in colonocytes in vivo, a system was developed whereby transient expression of genes is established in normal rodent colonic epithelium, using liposomal gene delivery by rectal catheter infusion. Expression of a beta-galactosidase reporter gene and of the human APC gene under a constitutive promoter is demonstrated. A high efficiency of transfection is maintained, with close to 100% of epithelial cells expressing the introduced gene. Expression is transient and does not persist beyond 4 days, consistent with the normal turnover time of gut epithelium, but it can be maintained by repeated treatments. Human APC was expressed for three weeks under these conditions at approximately one-tenth the level of the endogenous APC gene, and no toxicity was observed beyond that attributed to repeated rectal enemas. These results reveal that in vivo expression of exogenous gene is feasible using a liposomal delivery system and suggest a method to further study the physiologic role of APC or other genes in the interrelated process of colonic epithelial proliferation and differentiation.
Animals↗
Focus on intractable rejection: 6-month results of the European multicentre liver study of FK 506 and cyclosporin A.
The incidence of intractable rejection was evaluated during the course of a multicentre, randomised, parallel-group study comparing the efficacy and safety of FK 506 and conventional cyclosporin A-based immunosuppressive regimens in patients undergoing primary liver transplantation. A diagnosis of intractable rejection was made if there was histological evidence of unchanged or worsening acute rejection, or chronic rejection after two discrete courses of antirejection therapy. Antirejection regimens were specific to each centre. Patients who experienced intractable rejection could be withdrawn from the study. Patients who were withdrawn from the cyclosporin A treatment group could subsequently receive FK 506 therapy and vice-versa. Intractable rejection was diagnosed in 32/540 patients (5.9%): 7/267 patients (2.6%) in the FK 506 treatment group and 25/273 patients (9.2%) receiving cyclosporin A therapy (P < 0.01). Of these 32 patients, 25 were withdrawn from the study: 3 and 22, from the FK 506 and cyclosporin A treatment groups, respectively. All three patients withdrawn from the FK 506 treatment group are alive: two having undergone retransplantation. Of the 22 patients withdrawn from the cyclosporin A group and converted to FK 506 therapy, 6 were retransplanted, 4 of whom subsequently died. A further two patients died without retransplantation. Thus, in 14 of the 16 patients who were still alive at 6 months, the liver graft was saved after conversion to FK 506 treatment. The reduced incidence of intractable rejection in patients receiving treatment with FK 506, together with the successful rescue of patients developing intractable rejection while receiving cyclosporin A, suggests that FK 506 is an effective immunosuppressive agent following orthotopic liver transplantation.
Adolescent↗
Corticosteroids and concomitant medication in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation.
The steroid-sparing effect and the use of concomitant medication during the treatment of liver transplant patients with the novel immunosuppressant FK 506 were evaluated within the European multicentre, randomized, parallel-group study in liver transplantation. Patients undergoing primary liver transplantation were randomized to treatment with FK 506 (n = 267) or with a cyclosporin-based immunosuppressive regimen (n = 273). The total cumulative steroid usage was significantly reduced in the FK 506 treatment group, which is likely to have resulted from the lower incidence of acute rejection in these patients. The number of patients receiving antidiabetic, diuretic and antihypertensive therapy did not differ between the two treatment groups, even though the incidence of diabetes mellitus and oliguria was significantly higher in the FK 506 group. It can, therefore, be assumed that in a number of such cases the severity of these events was very mild necessitating no specific therapy.
Adrenal Cortex Hormones↗
Glucose metabolism in liver transplant recipients treated with FK 506 or cyclosporin in the European multicentre study.
From September 1990 to January 1992, 545 liver transplant patients were randomised to treatment with either FK506 and prednisolone or a conventional cyclosporin-based immunosuppressive regimen (CBIR). Eight European centres participated in the study. Adverse events were reported as defined by each centre. Hyperglycaemia was reported as an adverse event in 30.7% of patients receiving FK 506 compared with 20.5% in the CBIR group (P < 0.01). Diabetes mellitus was reported in 17.2% of patients treated with FK 506 and 9.5% of CBIR-treated patients (P < 0.05). Treatment with insulin was required in 12.0% of patients in the DK 506 treatment group and in 5% in the CBIR group at 6 months. Initially, higher doses of FK 506 were used. During the study, the protocol was changed to allow a lower dose of FK 506. When the early and late cohorts of patients were compared, the incidence of diabetes mellitus fell from 23.9% to 10.5% in FK 506-treated patients but remained relatively constant in the CBIR group (10.4% to 8.7%). The median cumulative doses of i.v. and p.o. corticosteroids were significantly greater in the CBIR group. Thus, in the overall series, the incidence of diabetes mellitus was significantly greater in the FK 506 group as compared with the CBIR group. However, when a lower FK 506 dose was used during the second half of the study, the difference in the incidence of diabetes mellitus disappeared.
Adolescent↗
Renal complications and development of hypertension in the European study of FK 506 and cyclosporin in primary liver transplant recipients.
We examined the occurrence of renal complications and hypertension in 540 primary liver recipients entered into the European liver trial comparing primary FK 506 to a cyclosporin A based immunosuppression regimen (CBIR). No difference in serious renal impairment or mean creatinine levels was observed with similar rates of "kidney failure" (FK 506 9.4% vs. CBIR 7.3%) and dialysis requirements (FK 506 12% vs. CBIR 11%). "Abnormal kidney function", a less serious parameter of renal impairment, was reported in 89 recipients (33%) in the FK 506 group versus 58 (21%) in the CBIR group (P < 0.01). Development of this complication was associated with elevated intravenous FK 506 dosing schedules, with the mean cumulative dose 43% higher than treated patients with unaffected kidney function. In a later cohort of patients where intravenous dosing was lower, no significant difference in renal complications was detectable. The 6-month prevalence rate of systemic arterial hypertension was noted to be lower in the FK 506-treated patients compared to the CBIR group [33 (17.2%) vs. 47 (25.7%)].
Adolescent↗
Neurological complications in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation.
Neurological complications were examined in a multicentre, randomized, parallel-group study of 545 patients undergoing primary liver transplantation to compare the efficacy and safety of FK 506- and cyclosporin A-based immunosuppressive regimens (CBIR). In an additional analysis, patients were divided into early and late randomized cohorts to detect the influence of protocol amendements that allowed for FK 506 dose reductions. Initial follow-up was for 6 months. Tremor, headache and insomnia were the most frequently reported adverse events involving the neurological system. Whereas these neurological symptoms were observed significantly more often in FK 506-treated patients (P < 0.05 vs. CsA for the overall population), this was no longer the case for the late FK 506 and CBIR cohorts. The risk of FK 506-treated patients developing tremor was related to the initial i.v. dose, the rate of administration of the i.v. dose and the daily dose (P < 0.01). Headache was significantly correlated with the FK 506 dose (P < 0.05), and insomnia was not related to any dosing variable. Major neurological symptoms, including psychosis, convulsion, coma, aphasia and intracranial haemorrhage, were reported with a low frequency (0.4-5.2%), and differences between both treatment groups were neither significant for the overall population nor for the early and late cohorts of FK 506 and CBIR. Data from the late cohorts showed no differences in the overall incidence of neurological adverse events between FK 506- and CBIR-treated patients.
Cyclosporine↗
Optimal FK 506 dosage in patients under primary immunosuppression following liver transplantation.
In a retrospective study, we analysed the FK 506 dosage used in primary liver graft recipients enrolled in the European FK 506 multicenter trial conducted from September 1990 to January 1992. In addition, a second cohort of patients treated more recently in a single centre was investigated. The impact of different dosing strategies on the clinical course of the patients was analysed with special emphasis on the incidence of rejection episodes and FK 506 side-effects. Among the patients enrolled in the European FK 506 multicenter trial, those patients enrolled during the "early" phase of the study received a higher oral FK 506 dose [mean oral dosage on day 7 = 0.19 mg/kg body weight (bw) per day, n = 134] compared to patients enrolled during the "late" period of the study (mean oral dosage on day 7 = 0.14 mg/kg bw per day, n = 133). This lower dosage was the result of several protocol amendments performed to reduce the incidence of FK 506 side-effects. Lowering of the FK 506 dosage was accompanied by a reduction in the long-term prevalence of side-effects such as diabetes (n. s.) or hypertension (P < 0.05), while patient survival and rejection frequency remained constant. Patients treated in centres with online FK 506 blood level monitoring experienced significantly less hypertension, less episodes of diabetes and less rejection episodes compared to patients treated in centres without. The clinical course of those patients enrolled in the multicentre trial was compared with the course of a cohort of liver-grafted patients treated with FK 506 more recently in a single centre. These patients had a further reduction in the FK 506 dosage (0.10 mg/kg bw per day p.o. or less according to whole blood levels, with no intravenous FK 506 administration). When compared to patients enrolled in the multicentre trial, these patients experienced less side-effects (nephrotoxicity, hypertension, serious early neurotoxicity) while adaequate immunosuppression was maintained.
Administration, Oral↗