Role of xanthine-oxidase system in mucosal injury after intestinal preservation and transplantation.
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Animals↗
Biomedical subjects
S Todo
Publications and source records attributed to S Todo.
Liver allograft rejection in sensitized recipients. Observations in a clinically relevant small animal model.
A sequential analysis of liver allograft rejection in sensitized rats using immunopathological and ultrastructural microscopy is described. Lewis rats were primed with four ACI skin grafts and challenged with an arterialized ACI orthotopic liver allograft 14 to 17 weeks later. The sensitization resulted in a mix of IgG and IgM lymphocytotoxic antibodies at a titer of 1:512 at the time of transplantation. Specificity analysis of pretransplant immune sera revealed a predominance of IgG anti-class I major histocompatibility complex (RT1) antibodies with a minor IgG fraction showing apparent endothelial cell specificity (non-RT1). This level of sensitization was associated with accelerated graft failure in 3 to 5 days from mixed humoral and cellular rejection. Sequential analysis of serial posttransplant graft biopsies revealed diffuse vascular IgG deposition and platelet thrombi in portal veins and periportal sinusoids within 3 minutes after reperfusion. This was followed by endothelial cell hypertrophy and vacuolization, periportal hepatocyte necrosis, arterial spasm, focal large bile duct necrosis, and hilar mast cell infiltration and degranulation. However, the liver allografts did not fail precipitously and hyperacute rejection was not seen. Kupffer cell phagocytosis of the sinusoidal platelets began as early as 30 minutes posttransplant and by 24 hours, the platelet thrombi had decreased. Cholangioles appeared focally at the edge of the limiting plates by 2 to 3 days, apparently in response to earlier periportal hepatocyte damage. A mononuclear portal and perivenular infiltrate became evident at 3 days, and graft failure was attributed to both antibody and cell-mediated rejection (Furuya et al: Preformed lymphocytotoxic antibodies: Hepatology 1992, 16: 1415-1422). The model described resembles observations in crossmatch positive human liver allograft recipients. The mechanisms of hepatic graft resistance to antibody mediated rejection and the possible long term consequences of early damage to the biliary tree are discussed.
Animals↗
Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance.
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Adolescent↗
Clinical intestinal transplantation.
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Adult↗
Orthotopic liver transplantation for urea cycle enzyme deficiency.
Hyperammonemia, abnormalities in plasma amino acids and abnormalities of standard liver functions were corrected by orthotopic liver transplantation in a 14-day-old boy with carbamyl phosphate synthetase-I deficiency and in a 35-yr-old man with argininosuccinic acid synthetase deficiency. The first patient had high plasma glutamine levels and no measurable citrulline, whereas citrulline values were markedly increased in Patient 2. Enzyme analysis of the original livers showed undetectable activity of carbamyl phosphate synthetase-I in Patient 1 and argininosuccinic acid synthetase in Patient 2. Both patients were comatose before surgery. Intellectual recovery of patient 1 has been slightly retarded because of a brain abscess caused by Aspergillus infection after surgery. Both patients are well at 34 and 40 mo, respectively, after surgery. Our experience has shown that orthotopic liver transplantation corrects the life-threatening metabolic abnormalities caused by deficiencies in the urea cycle enzymes carbamyl phosphate synthetase-I and argininosuccinic acid synthetase. Seven other patients--six with ornithine transcarbamylase deficiency and another with carbamyl phosphate synthetase-I deficiency--are known to have been treated elsewhere with liver transplantation 1 1/2 yr or longer ago. Four of these seven recipients also are well, with follow-ups of 1 1/2 to 5 yr. Thus liver transplantation corrects the metabolic abnormalities of three of the six urea cycle enzyme deficiencies, and presumably would correct all.
Adult↗
Preformed lymphocytotoxic antibodies: the effects of class, titer and specificity on liver vs. heart allografts.
The effect on liver and heart allograft survival (ACI rats to Lewis rats) was studied after three methods of recipient presensitization and after different intervals between sensitization and transplantation. With comparable lymphocytotoxic antibody titers, liver allografts always survived longer than heart grafts. The titer, class and specificity of the antibodies varied with the method of sensitization. Four skin grafts produced IgG and IgM lymphocytotoxic antibody titers of 1:2,000 to 4,000. The IgG fraction was shown to have hepatic vascular endothelial specificity by indirect immunofluorescence. These primed recipients hyperacutely rejected both heart and liver allografts, which showed vascular deposition of IgG antibodies. Survival of either kind of graft was inversely proportional to the lymphocytotoxic antibody titer and length of time after placement of the last skin graft. Presensitization with a single heterotopic heart graft produced an even higher mixed IgG and IgM lymphocytotoxic antibody titer of 1:8,000 but with less IgG vascular endothelial specificity. These animals also hyperacutely rejected heart or liver grafts with tissue deposition of IgG but less consistently and with a weaker correlation with lymphocytotoxic antibody titers and time after sensitization. Sensitization with two pretransplant blood transfusions produced the lowest titer (1:500 to 1,000) and the least IgG vascular endothelial specificity. Liver allograft survival was routinely enhanced in these animals, and little effect was seen on heart grafts. Collectively, the experiments showed that the liver is not only resistant to antibody-mediated rejection relative to the heart but is more easily enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pediatric liver transplantation from neonatal donors.
Sixteen recipients of neonatal liver grafts were compared with 114 contemporaneous pediatric recipients of grafts from older donors. Graft and patient survival were worse in the neonatal group although the differences were not statistically significant. Patients with neonatal livers who had no technical complications required a longer time postoperatively to correct jaundice and a prolonged prothrombin time. These functional differences were limited to the 1st postoperative month and the end result was the same as with liver transplantation from older donors.
Adolescent↗
Liver transplantation for arteriohepatic dysplasia (Alagille's syndrome).
Thirteen out of 268 children (less than 18 years old) underwent hepatic transplantation (OLT) for end-stage liver disease (ESLD) associated with arteriohepatic dysplasia (AHD). Seven children are alive and well with normal liver function. Six children died, four within 11 days of the operation and the other two at 4 and 10 months after the OLT. Vascular complications with associated septicemia were responsible for the deaths of three children. Two died of heart failure and circulatory collapse, secondary to pulmonary hypertension and congenital heart disease. The remaining patient died of overwhelming sepsis not associated with technical complications. Seven patients had a portoenterostomy or portocholecystostomy early in life; five of these died after the OLT. Severe cardiovascular abnormalities in some of our patients suggest that complete hemodynamic monitoring with invasive studies should be performed in all patients with AHD, especially in cases of documented hypertrophy of the right ventricle. The improved quality of life in our surviving patients confirms the validity of OLT as a treatment of choice in cases of ESLD due to AHD.
Adolescent↗
Incidence, prevalence, and clinical course of hepatitis C following liver transplantation.
Hepatitis C virus (HCV) is the agent responsible for posttransfusion hepatitis. The incidence, timing, and clinical course of HCV positive hepatitis in liver transplant recipients are unknown. Three hundred and seventeen donor-recipient liver transplant pairs were grouped on the basis of their pretransplant HCV antibody status. The biopsy findings were examined. Four distinct groups were identified on the basis of HCV serology: group I, both were negative; group II, donor was negative and recipient was positive; group III, donor was positive and recipient was negative; group IV, both were positive. The prevalence of anti-HCV positivity in recipients was 13.6%. The rate of seroconversion was 9.2%. Histologic hepatitis not ascribable to any specific cause other than non-A, non-B (NANB) hepatitis occurred in 13.8%. The incidence of histologic chronic active hepatitis was 1.6%, and none progressed to cirrhosis. The concordance rate for a positive anti-HCV serology and NANB hepatitis was 2.8%. Of the 35 patients (group II and IV) with positive anti-HCV serology pretransplant, only 17 were positive posttransplantation. Based on these data it can be concluded that posttransplant NANB hepatitis occurred in 13.8% of liver recipients. Twenty percent of these were anti-HCV positive. Progression to histologic chronic active hepatitis occurs over a period of 1-5 years in 1.6% of cases.
Adolescent↗
An improved technique for isolated perfusion of rat livers and an evaluation of perfusates.
We have modified the apparatus for isolated rat liver perfusion (IPRL) in order to be able to perform two perfusions simultaneously. In addition, we studied the quality and stability of livers by comparison of five different perfusates: Blood (Group A), Original Krebs Henseleit buffer (Group B), Krebs buffer with glucose (Group C) or bovine serum albumin (BSA) added, (Group D). In a last group (E) albumin, glucose, and taurocholic acid were added to Krebs. After 180 min of perfusion, livers perfused with solutions including 2% albumin (Group D, E) had a significantly higher release of hepatocellular and endothelial cell (purine nucleoside phosphorylase) enzymes and lower bile production as compared to Groups A, B, and C (P less than 0.0001). Increasing levels of purine nucleoside phosphorylase (PNP), a reflection of damage to the microvascular endothelium preceded the increases in hepatocellular enzymes. Histologically, damages of sinusoidal endothelial cells and hepatocytes are appreciated moderate to severe in Groups D and E, slight to mild in Groups A and B, and not significant in Group C. These results suggest that BSA may have toxic effects to the perfused rat liver. These data also confirm that the IPRL modified for simultaneous perfusion of two livers is efficient, and that with this technique the rat liver can be optimally perfused for up to 3 hr with oxygenated Krebs Henseleit buffer without additives (Group B) and without blood. These two improvements should allow those performing studies with perfused rat livers to obtain data in a more efficient, accurate, and inexpensive fashion.
Animals↗
Effect of FK506 on insulin secretion in normal dogs.
In this report, we describe the effect of FK506 on glucose-mediated insulin release in normal dogs. Dogs were placed into one of two groups, group 1 dogs received FK506 (1 mg/kg/d orally) for 2 weeks, and group 2 dogs received FK506 at the same dose, but for 4 weeks. Following the treatment period, both groups of dogs were allowed a recovery period during which time no FK506 was administered. Intravenous glucose tolerance tests (IVGTT) were performed (0.5 mg/kg IV) before FK506 treatment, after 2 or 4 weeks of treatment, and following the recovery periods. Complete blood cell counts (CBC) and serum chemistries were also obtained at these times. Following FK506 treatment for either 2 or 4 weeks, the dogs experienced a delay in glucose disappearance in response to IV glucose injection. Insulin secretion during IVGTT was unchanged in dogs treated for only 2 weeks, but was significantly decreased in dogs treated for 4 weeks. Following the recovery period, glucose disappearance during IVGTT returned to normal in dogs that were treated for 2 weeks, and was more rapid than normal in dogs that had been treated for 4 weeks. Insulin secretion after the recovery period remained unchanged in group 1 dogs, but continued to be significantly reduced in group 2 dogs that had received FK506 for 4 weeks. No significant change was detected in the CBCs or serum chemistries.
Animals↗
Immunopathology of antibodies as effectors of orthotopic liver allograft rejection.
We have come a long way in our understanding of antibodies as effectors of liver graft damage, but we still have much to learn. Animal heterografts provided the first evidence that livers are susceptible to antibody-mediated damage. The pathophysiologic events are similar to those of extrahepatic organ grafts, but the liver is relatively resistant and rapidity of graft destruction is slower, if it occurs at all. Nevertheless, the ABO isoagglutinins can predictably cause human liver allograft failure, often in a quickened, but rarely a hyperacute fashion. The liver is more resistant to lymphocytotoxins, and in many cases will suffer no apparent damage. However, when present, a spectrum of graft pathologic changes can be seen. Early manifestations include hemorrhagic necrosis and lesions mimicking "preservation" injury. Later on, ischemic biliary necrosis and small bile duct loss may be seen. The variability is likely related to a balance between destructive antibody class, specificity, and titers and the ability of the liver to withstand the assault. More precise characterization of lymphocytotoxic antibodies is needed in clinical practice. In addition, antigen distribution in the graft, release of soluble MHC antigens, the role of Kupffer cells and other mechanisms of liver resistance are likely areas of fruitful investigation.
ABO Blood-Group System↗
Intestinal transplantation in composite visceral grafts or alone.
Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft-versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection.
Adult↗
Logistics and technique for combined hepatic-intestinal retrieval.
During a 13-month period, en bloc liver-small bowel cadaveric grafts were procured for seven children and one adult. All liver grafts functioned immediately, and all but one of the recipient patients recovered. Return of absorptive small bowel function was slow, but the integrity of the bacterial intestinal barrier was not disrupted. The described technique allows the procurement of other abdominothoracic organs, with the exception of the whole pancreas.
Adolescent↗
Cadaveric small bowel and small bowel-liver transplantation in humans.
Five patients had complete cadaveric small bowel transplants under FK506 immunosuppression, one as an isolated graft and the other 4 in continuity with a liver. Three were children and two were adults. The five patients are living 2-13 months posttransplantation with complete alimentation by the intestine. The typical postoperative course was stormy, with sluggish resumption of gastrointestinal function. The patient with small intestinal transplantation alone had the most difficult course of the five, including two severe rejections, bacterial and fungal translocation with bacteremia, renal failure with the rejections, and permanent consignment to renal dialysis. The first four patients (studies on the fifth were incomplete) had replacement of the lymphoreticular cells in the graft lamina propria by their own lymphoreticular cells. Although the surgical and after-care of these patients was difficult, the eventual uniform success suggests that intestinal transplantation has moved toward becoming a practical clinical service.
Cadaver↗
The adverse impact on liver transplantation of using positive cytotoxic crossmatch donors.
Because of the liver graft's ability to resist cytotoxic antibody-mediated rejection, it has become dogma that the conventional transplant crossmatch used to avoid hyperacute rejection of other organs is irrelevant to the liver. We examined this hypothesis in a consecutive series of adult primary liver recipients treated with FK506 and low-dose steroids. Twenty-five of 231 (10.8%) patients received a liver from a cytotoxic-positive crossmatch donor (more than 50% of donor T lymphocytes were killed by dithiothreitol-pretreated recipient serum). The outcome was compared with that of 50 negative crossmatch patients who had their transplantations just before and after the crossmatch positive cases. The one-year graft and patient survivals were 56% and 68%, for positive and 82% and 86% for negative crossmatch patients (P = 0.004, P = 0.03, respectively). The difference between patient and first graft survival was accounted for by retransplantation, which was 4 times more frequent in the positive-crossmatch cases. Histologically, failed allografts obtained at the time of retransplantation revealed a spectrum of pathologic findings related to vascular injury. This study showed a higher difficulty of intraoperative blood product management, a degraded prognosis, and a poorer average quality of ultimate graft function when liver transplantation was performed against positive cytotoxic crossmatches. In such patients for whom crossmatch-negative donors may never be found because of the broad extent and intensity of sensitization, special therapeutic strategies perioperatively must be evolved if results are to improve.
Adult↗
The effect of bile duct ligation and bile diversion on FK506 pharmacokinetics in dogs.
Mongrel or beagle dogs were submitted to bile duct ligation, or to extraenteric biliary diversion by means of choledochoureterostomy. The kinetics of intravenously administered FK506 was not changed from control status two weeks after bile duct ligation, but the bioavailability of orally administered FK506 was nearly quadrupled. Following oral administration, the absorption of FK506 was highly variable. The results indicate that in dogs FK506 is absorbed from the intestine just as efficiently in the absence of enteric bile and in presence of exogenous bile salt supplement when compared with its absorption in presence of normal bile drainage. These findings with FK506 are different from those with cyclosporine after biliary obstruction or diversion and will have important practical as well as experimental ramifications.
Animals↗
The protective effect of FK506 pretreatment against renal ischemia/reperfusion injury in rats.
The effect of pretreatment with FK506 on renal ischemia and reperfusion (I/R) injury was investigated using a rat model. Animals were assigned to one of two groups (20 rats each). Group 1 animals (controls) received 0.5 ml saline while group 2 animals received FK506 (0.3 mg/kg), administered intravenously 24 hr prior to the induction of renal ischemia. A 60-min period of ischemia of the right kidney was induced, and upon reperfusion a left nephrectomy was performed. Blood samples for estimation of BUN, creatinine, and tumor necrosis factor were collected on days 0 (preischemia), 1, 2, 3, 5, 7, and 10 (postischemia). Rats were sacrificed after day 10 and renal tissue was examined histologically. All animals survived the ischemic episode. FK506 pretreatment significantly reduced the serum levels of BUN (P less than 0.02), creatinine (P less than 0.02), and TNF (P less than 0.05) as compared with that seen in controls. Histologically, at day 10, the kidneys showed the expected sequelae of prior renal I/R with various degrees of tubular damage. However, no objective differences were evident between the two groups. Based upon these data, it can be concluded that (1) FK506 pretreatment ameliorates the functional renal injury associated with I/R, (2) renal ischemia induces the release of TNF, and (3) FK506 pretreatment results in a significant inhibition of TNF production. These data suggest that the release of TNF may be responsible for the increasing of BUN and creatinine levels seen after renal I/R and that pretreatment of renal donors with FK506 may improve renal function in the immediate post-transplant period.
Animals↗