The goal of transplantation is the induction of immunologic tolerance. At present, nonspecific immunosuppression is used to prevent graft rejection and, commonly, graft-versus-host disease (GVHD). Nevertheless, nonspecific immunosuppressive therapy is frequently complicated by infection, malignant tumors, and drug toxicity. In order to examine whether hematopoietic chimerism can be used to induce specific allograft tolerance, we have reconstituted lethally irradiated Lewis rats with ACI bone marrow that has been depleted of T cells with use of immunomagnetic beads. This technique consists of binding OX-19, a mouse anti-rat pan-T lymphocyte monoclonal antibody, to magnetic polymer beads. Mixing of bone marrow or splenocytes with the bead/OX-19 complexes, followed by magnetic separation, results in significant depletion of T cells with minimal nonspecific cell loss. Immunomagnetic T-cell depletion of bone marrow, followed by reconstitution of a lethally irradiated host, allows for the development of stable, mixed hematopoietic chimerae without evidence of GVHD. These hosts are immunocompetent by clinical criteria. Recipients of untreated donor bone marrow that did or did not receive nonspecific immunosuppression demonstrated varying degrees of GVHD and reduced survival. The ability to rapidly and simply deplete T lymphocytes from bone marrow and produce stable, immunocompetent hematopoietic chimerae without GVHD may be an important method for tolerance induction to vascularized allografts.

Animals↗

PubMed1989

Accelerated graft arteriosclerosis is enhanced by sensitization of the recipient to donor lymphocytes.

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Animals↗

PubMed1989

Significance of lecithin:cholesterol acyltransferase activity as a prognostic indicator of early allograft function in clinical liver transplantation.

Rapid and accurate assessment of allograft function in the early postoperative period is critical for successful liver transplantation. This study evaluated the efficacy of lecithin:cholesterol acyltransferase (LCAT) activity as an indicator of early allograft function in human orthotopic liver transplantation (OLTx). During a three-month period between September and November 1987, 9 of 11 adult OLTx recipients whose graft exhibited poor function were studied. Poor graft function was defined as primary nonfunction, need for retransplantation within a week after OLTx, or elevation of the prothrombin time over 20 sec early after OLTx. Plasma LCAT activities (measured pretransplant and at 0, 6, 12, 18, and 24 hr, as well as 3 days, after OLTx) and pretransplant clinical variables were compared with those of 15 control patients whose graft exhibited good function. A significant correlation was found between mean LCAT activities during the first 24-hr after OLTx and early allograft function (P less than 0.05, chi 2 = 5.23). When pretransplant histological findings of the 6 grafts with poor function and the 15 controls together were correlated with the mean LCAT activity within 24 hr following OLTx, a significant association was demonstrated (P less than 0.05). This study suggests that plasma LCAT activity is an effective and practical method for assessing early allograft function following OLTx.

Humans↗

PubMed1989

[Long-term results of orthotopic liver transplantation during the cyclosporin era. 393 orthotopic liver transplantations accomplished in 313 consecutive patients at the Pittsburgh Transplantation Center].

During the cyclosporine era 1980-1984, 393 consecutive orthotopic liver transplantations (OLT) were performed in 313 patients at the University of Pittsburgh. This paper analyses the long-term results in this group of patients who have been followed-up for a minimum of three years. The results of OLT for different indications are discussed. The five-year survival rates after OLT for metabolic diseases, biliary atresia, primary biliary cirrhosis, posthepatic cirrhosis and primary hepatobiliary cancer are 75%, 68%, 60%, 58.9%, 53.2% and 23.8%, respectively. Recurrence of the primary disease after OLT is rare for benign diseases but rather frequent for malignant ones. The incidence of retransplantation for delayed rejection and for extrahepatic complications is discussed. The quality of life for most of the long-term survivors is good. Because of its good long-term results, OLT should become the therapy of choice in a lot of acute and chronic hepatopathies.

Cyclosporins↗

PubMed1988

Aplastic anemia complicating orthotopic liver transplantation for non-A, non-B hepatitis.

Aplastic anemia developed in 9 of 32 patients (28 percent) undergoing orthotopic liver transplantation for acute non-A, non-B hepatitis, at one to seven weeks after the procedure. No patient previously had evidence of hematologic dysfunction or conditions known to be associated with aplastic anemia. No other cases of aplastic anemia were identified among 1463 patients undergoing liver transplantation for all other indications at the four centers participating in the study (chi-square = 415, P less than 0.001; 95 percent confidence interval for the incidence of aplastic anemia after transplantation for non-A, non-B hepatitis, 13 to 44 percent, vs. 0.00 to 0.13 percent for all other indications). The operative and postoperative treatment of these patients was not otherwise different, indicating that the aplastic anemia was a complication of the hepatitis, not of the transplantation procedure. Four of the nine patients died of complications due to infections. Three of the surviving patients have been followed for less than six months, one for one year, and one for two years. The two patients followed the longest have recovered marrow function to an appreciable degree, and two of the others have evidence of early recovery. We conclude that patients undergoing orthotopic liver transplantation for non-A, non-B hepatitis are at a high risk for the development of aplastic anemia.

Adolescent↗

PubMed1988

Occurrence of cytomegalovirus hepatitis in liver transplant patients.

The differential diagnosis of liver dysfunction after orthotopic liver transplantation can be difficult. Cytomegalovirus (CMV) hepatitis is one possibility. This report reviews our experience with 17 cases of pathologically proven CMV hepatitis following liver transplantation and demonstrates the need for percutaneous liver biopsies to establish the diagnosis. There were seven pediatric patients (ages 2-11 years, five males, two females) and ten adult patients (ages 17-53 years, eight males, two females). The most common symptoms were prolonged fever (15 patients, with a mean duration of 22 +/- 5.5 days), elevation in total bilirubin (14 patients), and elevation in liver enzymes (15 patients); all symptoms were also found in rejection. Leukopenia and thrombocytopenia, reported to frequently occur with CMV infection, were found in only three and five patients, respectively. Twelve patients with the above symptoms underwent percutaneous biopsy on one or more occasions to differentiate CMV hepatitis from rejection. The diagnosis was made at retransplantation in five patients. CMV hepatitis followed treatment for acute rejection in 14 patients and occurred without additional immunosuppression in three patients. All patients were maintained on cyclosporine and prednisone. Acute rejection episodes were treated with a 5-day tapering dose of steroids (17 courses in 12 patients), OKT3 monoclonal antibody [Ortho (4 patients)] antithymocyte globulin [Upjohn (2 patients)], and azathioprine (1 patient). CMV was isolated from urine (nine patients), blood (nine patients), throat (seven patients), lungs (two patients), and other organs (two patients). CMV was cultured from the liver biopsy specimens in five of the seven attempts in pediatric patients. When the diagnosis was confirmed in the absence of rejection, immunosuppression was routinely lowered. When rejection occurred concomitantly with CMV hepatitis, therapy had to be individualized. Retrospectively, three patients treated for rejection were noted at retransplantation to have only CMV hepatitis, and all three patients died. A high index of suspicion and the judicious use of liver biopsies is essential in order to differentiate CMV hepatitis from other causes of posttransplant liver dysfunction.

Adolescent↗

PubMed1988

Renal artery reconstruction for harvesting injuries in kidney transplantation with particular reference to the use of vascular allografts.

At the University of Pittsburgh during the calendar year 1986, an arterial injury occurred during harvesting in 20 (7.5%) of the 270 grafts used to perform kidney transplantation (KTx). Four cases required reconstruction, using extension iliac arterial allografts from cadaveric donors of the same blood type; 6 patients, remodelling of the aortic patch in multiple arteries; 4 cases, repairs for injuries to the smaller segmental/polar arteries; 6 cases, a combination of the above techniques. These ex vivo arterial reconstructions are described and the use of donor arterial homografts is emphasized. No deaths have occurred at an average follow-up of 19 months. The postoperative acute tubular necrosis (ATN) rate was significantly higher (90%) compared with non-reconstructed kidneys during the same year (30%). The 1-year graft survival of kidneys undergoing arterial reconstruction (75%) was statistically no different than the overall kidney-transplant survival. Whenever extension iliac allografts were utilized, the cyclosporin-steroid immunosuppression required to control the kidney rejection contributed to the long-term patency rate of the graft. Since the number of organs available for grafting is limited, reconstruction of injured renal vessels has become justified, allowing valuable kidneys to be used that would otherwise be lost.

Adult↗

PubMed1988

Primary lymphoma of the liver showing immunohistochemical evidence of T-cell origin. Successful management by right trisegmentectomy.

Primary malignant lymphomas of the liver are extremely rare. Thus far, 28 cases (1-13) of this entity have been described, but after careful clinical and histological staging, no other sites of extrahepatic involvement were demonstrated in 17 of these cases (2,3,5-13). We recently had the opportunity to investigate and manage a case of true primary malignant peripheral T-cell lymphoma of the liver in a 22-year-old man. To our knowledge this is the first reported case of a primary T-cell lymphoma of the liver. The patient was successfully treated with a right trisegmentectomy and no tumor recurrence has appeared after five years.

Adult↗

PubMed1988

Isolation and primary cultures of human intrahepatic bile ductular epithelium.

A technique for the isolation of human intrahepatic bile ductular epithelium, and the establishment of primary cultures using a serum- and growth-factor-supplemented medium combined with a connective tissue substrata is described. Initial cell isolates and monolayer cultures display phenotypic characteristics of biliary epithelial cells (low molecular weight prekeratin positive; albumin, alphafetoprotein, and Factor VIII-related antigen negative). Ultrastructural features of the cultured cells show cell polarization with surface microvilli, numerous interepithelial junctional complexes and cytoplasmic intermediate prekeratin filaments.

Antigens↗

PubMed1988

The diagnosis and treatment of posttransplant lymphoproliferative disorders.

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Adolescent↗

PubMed1988

Transplantation for primary biliary cirrhosis.

Primary biliary cirrhosis is a frequent indication for liver transplantation. The purpose of this report is to present our experience with liver transplantation for primary biliary cirrhosis. Attention is given to the causes of hepatic dysfunction seen in allografts. In addition, we review the postoperative problems encountered and the quality of life at time of last follow-up in patients with transplants for primary biliary cirrhosis. A total of 97 orthotopic liver transplant procedures were performed in 76 patients with advanced primary biliary cirrhosis at the University of Pittsburgh from March 1980 through September 1985. The transplant operation was relatively easy to perform. The most common technical complications experienced were fragmentation and intramural dissection of the recipient hepatic artery, which required an arterial graft in 20% of the cases. Most of the postoperative mortality occurred in the first 6 mo after transplantation, with an essentially flat actuarial life survival curve from that time point to a projected 5-yr survival of 66%. Common causes of death included rejection and primary graft nonfunction. Thirteen of the 76 patients had some hepatic dysfunction at the time of the last follow-up, although none were jaundiced. Recurrence of primary biliary cirrhosis could not be demonstrated in any of the patients. Antimitochondrial antibody was detected in the serum of almost all of the patients studied postoperatively for it. Most important, almost all of the 52 surviving patients have been rehabilitated socially and vocationally.

Activities of Daily Living↗

PubMed1988

Sensitivity of activated human lymphocytes to cyclosporine and its metabolites.

Alloreactive T cells generated as clones from mixed lymphocyte cultures, or propagated from heart or liver transplant biopsies, were tested for secondary proliferation measured in the primed lymphocyte test in the presence of Cyclosporine A and metabolites fractionated from human bile. Significant differences were observed in Cyclosporine A sensitivity between various cell cultures ranging as high as 100-fold. The liver is the primary site of Cyclosporine A metabolism, which yields a number of hydroxylated and N-dimethylated derivatives that are eventually secreted into the bile. Bile was collected from adult liver transplant patients on Cyclosporine A therapy and following extraction with diethyl ether, separated by high pressure liquid chromatography. Thirteen fractions were tested for their effect on lymphocyte proliferation in concanavalin A activation, mixed lymphocyte cultures and primed lymphocyte test assays. The strongest immunosuppressive effect was found with fraction 8, which contained metabolite M17, which has a single hydroxylation in position 1. Only three other fractions 9, 10, and 13, which contained metabolites M1, M18, and M21, respectively, exhibited immunosuppressive activity, albeit much lower than that of Cyclosporine A. Differences in Cyclosporine A sensitivity among alloreactive T cells followed similar patterns with Cyclosporine A metabolites. Thus, the assessment of the Cyclosporine A effect must consider differences in drug sensitivity of lymphocytes involved in transplant immunity and the generation of metabolites with immunosuppressive activity.

Bile↗

PubMed1988

Improved hepatic function in the 24-hour preserved rat liver with UW-lactobionate solution and SRI 63-441.

The present study compares rat liver preservation for 9, 12, and 24 h in the standard Eurocollins solution with preservation for the same time periods in the new UW-lactobionate solution. Pharmacologic manipulation with a potent platelet-activating factor antagonist, SRI 63-441, was also evaluated. After cold storage in each of the test solutions, the livers underwent 90 min of warm, oxygenated, sanguinous perfusion. A significant increase in liver weight was noted in Eurocollins-stored versus UW-lactobionate-stored livers. After 90 min of perfusion, livers preserved in UW-lactobionate produced significantly more bile and liberated significantly less glucose and transaminases when compared with Eurocollins-stored livers. Significant augmentation of bile production was observed when donor animals were pretreated with SRI 63-441 and the livers were then stored in UW-lactobionate for 24 h. Eurocollins-stored livers demonstrated increased hepatocyte vacuolization and endothelial disruption when compared with UW-lactobionate-stored livers after 12 and 24 h of preservation. This study demonstrates the superiority of UW-lactobionate solution in liver preservation and suggests that SRI 63-441 may be beneficial in the further reduction of cold ischemic injury.

Adenosine↗