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B Nashan

Publications and source records attributed to B Nashan.

At least 73 records · Page 4Linked to original sources
PubMed1996

Chronic rejection in lung allografts: immunohistological analysis of fibrogenesis.

In ongoing chronic rejection after lung transplantation, alveolar interstitial fibrosis develops. However, little is known about the mechanisms involved. In order to investigate these mechanisms, expression of extracellular matrix molecules (ECM) (undulin, decorin, tenascin, laminin, and fibronectin) and cytokines [transforming growth factor (TGF)-beta 1, TGF-beta 3, platelet-derived growth factor (PDGF), and PDGF receptor] were semiquantitatively evaluated in chronically rejected lung allografts, using standard immunohistochemical techniques. Additionally, the presence of macrophages was analysed. The present study demonstrates an increased infiltration of macrophages with a concomitant upregulation of cytokines (TGF-beta 1, TGF-beta 3, and PDGF) and an increased deposition of ECM in chronic lung rejection. These cytokines have an important role in the stimulation of fibroblasts which are a major source of ECM. Upregulated expression of ECM in the alveolar interstitial space leads to alveolar malfunction by thickening of the wall and, thus, is one of the causative factors of respiratory dysfunction in chronic lung graft rejection.

Adult↗
PubMed1996

Endoscopic management of biliary tract strictures in primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: In a subgroup of patients, primary sclerosing cholangitis (PSC) is complicated by high-grade focal strictures of the bile ducts, and this can have an unfavorable influence on the natural course of the disease. The aim of this study was to evaluate the efficacy and safety of endoscopic treatment in this selected patient group. PATIENTS AND METHODS: Twelve symptomatic patients with primary sclerosing cholangitis and major ductal strictures were included in a prospective study of endoscopic treatment. All patients were managed by repeated angioplasty-type balloon dilation and nasobiliary catheter perfusion. A minimum of two treatment sessions was used, and therapy was continued until satisfactory reopening of the strictures was obtained. Routine endoscopic follow-up was performed after three, six, 12, 18, and 24 months, and then at yearly intervals. The efficacy of therapy was assessed by evaluating clinical symptoms, laboratory data, and cholangiograms. RESULTS: The long-term follow-up averaged 23 months (range: 12-50 months). Two to nine (mean: three) treatment sessions were required to obtain satisfactory reopening of major biliary strictures. Eight patients showed considerable and sustained improvement. The mean serum bilirubin, alkaline phosphatase, gamma-glutamyl-transpeptidase, and alanine aminotransferase levels felt significantly by 73% (P = 0.0164), 46% (P = 0.0022), 55% (P = 0.0022), and 58% (P = 0.0022), respectively. The average radiographic stricture score before treatment was 3.2 +/- 0.8 (P = 0.0033). Three patients required liver transplantation seven, 12, and 40 months after the initiation of endoscopic treatment, due to a deterioration in hepatic function or an inability to exclude complex biliary malignancy. No major procedure-related side effects were observed. CONCLUSIONS: Our results suggest that the endoscopic treatment of PSC patients with dominant bile duct strictures is effective, safe, and well-tolerated. However, it is important not to overlook the potential development of cholangiocarcinoma.

Adolescent↗
PubMed1996

[Liver transplantation in patients with primary sclerosing cholangitis. Determining timing with reference to risk of malignancy].

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease associated with hepatobiliary malignancies which are in the majority of cases not known prior to transplantation. Applying the Mayo PSC natural history model, patients can be classified in low, medium and high risk groups; particularly patients at medium and high risk are in danger of developing malignancies in a PSC setting. Therefore, regular scoring of patients using the above-mentioned model is suggested, and transplantation should be performed at scores above 4.

Adult↗
PubMed1995

Backgrounds of early intragraft immune activation and rejection in liver transplant recipients. Impact of graft reperfusion quality.

In solid organ transplantation, acute rejections are most frequent during the first weeks. The aim of this study was to investigate the relationship between graft reperfusion injury and later immune responses against the graft. Intragraft immune activation was routinely monitored by transplant aspiration cytology in 47 recipients of hepatic allografts. As a parameter of reperfusion quality, oxygen saturation of hemoglobin (SO2) in hepatic tissue was determined intraoperatively by a near-infrared spectroscopy. Grafts that presented aspiration cytology scores of 2 or more (i.e., more than 10% of lymphocytes activated) at 1 week after operation (group I, n = 14) were associated with a higher heterogeneity of hepatic tissue SO2 at the end of operation (coefficient of variation in 12 points 18.3 +/- 18.3%, mean +/- SD) than grafts with no or very mild intragraft immune activation (group II, n = 33, 9.2 +/- 4.2%; P < 0.01). Group I was also accompanied by higher postoperative peak glutamic oxalacetic transaminase level (corrected by graft size, P < 0.05) and higher donor age (43.9 +/- 12.9 vs. 32.6 +/- 13.9 years, P < 0.02). Heterogenous reperfusion (P < 0.01), higher peak glutamic oxalacetic transaminase level (P < 0.01), and higher donor age (P < 0.05) were also associated with clinical rejection at 1 week (n = 10), but not with later-onset rejection (n = 11). These data suggest that intragraft immune activation and clinical rejection in the early phase after hepatic engraftment are strongly influenced by graft injury, which can be recognized early after reperfusion.

Adult↗
PubMed1995

Extramedullary erythropoiesis in human liver grafts.

Extramedullary erythropoiesis in the adult is very rare and is generally confined to situations of severe bone marrow irritation or replacement. In this study, we describe the occurrence of intrahepatic erythropoiesis in patients who have received a liver allograft and who have no evidence of bone marrow dysfunction. By routinely performed transplant aspiration cytology (TAC), marked intrahepatic erythropoiesis could be detected in 39 of 312 patients (12.5%) with liver allograft. In 19 patients, including 5 of 8 (63%) after combined liver and kidney transplantation, intrahepatic erythropoiesis occurred within the first 3 weeks after surgery. Twenty patients showed intrahepatic erythropoiesis between 3 weeks and 4 months after transplantation. Erythropoiesis was usually transient, lasting between 1 and 3 weeks. Cytologically, mature as well as immature erythroblasts of GlyA+ CD36+ CD45- phenotype could be detected in the grafts, whereas they were absent in blood; histologically, the cells could be localized to the sinusoids of the liver. There was no clear correlation of preoperative or postoperative hemoglobin levels, graft function, kidney function, and immunosuppressive medication with the presence or absence of erythropoiesis. Moreover, serum levels of erythropoietin (EPO) and stem cell factor (SCF) in patients with and without intrahepatic erythropoiesis in the early postoperative phase did not show significant differences. These findings show that intrahepatic erythropoiesis can occur transiently in human liver allografts and suggest that systemic stimuli as well as local factors may contribute to it.

Biopsy↗
PubMed1995

Early intragraft inflammatory events of liver allografts leading to chronic rejection.

In this retrospective study, we have investigated the early intragraft inflammatory events of 12 liver allografts leading to chronic rejection. The cytological findings and clinical follow-up were analyzed in detail. Nine patients underwent at least one typical lymphoid activation of acute rejection, and three of them were treated more than once. Diagnosis of rejection was based on biopsy histology, cytology and liver dysfunction. In addition to the acute rejections, cytological analysis demonstrated in 11 of 12 grafts an unidentified lymphoid episode that differed from that of rejection. These lymphoid responses were associated with viral infections; cytomegalovirus (CMV) infection in 10 of 12 patients, hepatitis C virus (HCV) infection in 2 of 12 patients, 1 combined with CMV, and hepatitis B virus (HBV) infection in 1 patient. Graft dysfunction was still seen at the end of the follow-up. Thus, intragraft inflammation caused either by acute rejection or by viral infections may be involved in the induction of chronic rejection.

Biopsy, Needle↗
PubMed1995

Immunological effects of the anti-IL-2 receptor monoclonal antibody BT 563 in liver allografted patients.

The immunological effects of therapeutic monoclonal antibodies (mAbs) depend upon their interaction with the target structure as well as the isotype of the mAb which is responsible for the binding to Fc receptors of accessory cells. The aim of the presented analysis was the evaluation of the in vivo immunosuppressive effect of BT 563, a mAb directed to the alpha-chain of the interleukin-2 receptor (IL-2R). Thirty-eight patients following liver transplantation were treated prophylactically for 12 days with 10 mg/day BT 563 (clinical phase II and III study). As baseline immunosuppression cyclosporin (CyA) and low dose steroids were administered. BT 563 levels, lymphocyte subpopulations, levels of soluble CD25 and Fc receptor polymorphism were evaluated and compared to the clinical outcome. Preoperatively in all patients a small subset of CD45R0+ cells expressed CD25 with detectable density. These cells were coated by BT 563. There was no evidence for depletion of IL-2R+ cells or modulation of the IL-2R. During therapy stable levels of the soluble IL-2R were measured in patient sera. Throughout the therapy high levels of unbound BT 563 were found in sera, suggesting that IL-2R newly expressed on cells activated by the allograft could also be inhibited by BT 563. No acute rejections were observed in these patients and no side effects of BT 563 were noted. There were only minor bacterial infections, while mycotic or viral infections did not appear. Administration of BT 563 together with CyA and low dose steroids to liver allografted patients represents a safe and effective protocol. Its action is likely to be mediated by turning off the pathway of signal transduction of the IL-2R in T-cells by the antibody while IL-2 gene transcription is simultaneously modified by CyA and steroids. The addition of all three immunosuppressive mechanisms is suggested to lead to a state of anergy during mAb application that is reversible at the end of antibody therapy but does not lead to rebound rejections. Analysis of the phenotype of CD25+ cells showed that they preferentially belonged to the CD45R0+ cell type. Thus we assume that BT 563 specifically turns off preactivated cells enabling rather selective and effective immunoprophylaxis in liver allografted patients.

Antibodies, Monoclonal↗
PubMed1994

Different cellular patterns associated with hepatitis C virus reactivation, cytomegalovirus infection, and acute rejection in liver transplant patients monitored with transplant aspiration cytology.

Fine-needle aspiration biopsy (FNAB) is a routine diagnostic tool used for the monitoring of the graft during the first postoperative weeks after liver transplantation. The cellular pattern of acute liver rejection is typical in transplant aspiration cytology (TAC), documented and published by several authors. The lymphoid response associated with various viral infections may, however, provide differential diagnostic problems in the cytological monitoring. In this study, we have investigated in detail the cellular pattern of lymphoid response associated with hepatitis C virus (HCV) reactivation, and compared it with the pattern of cytomegalovirus (CMV) infection and with the typical diagnostic findings of acute cellular rejection. HCV reactivation was associated with rather mild total inflammation in the graft (4.5 +/- 1.5 CIU at the peak). The inflammatory infiltrate consisted mainly of small lymphocytes (3.1 +/- 0.2 CIU at the peak), with only occasional activated cells and without lymphoid blast response. No lymphoid activation was seen in the blood. CMV infection was associated with a mild immune response (3.9 +/- 0.4 CIU at the peak) recorded as a slight lymphoid activation and occasional blast cells both in blood and in the graft together with lymphocytosis in the graft (2.4 +/- 0.7 CIU at the peak). The typical findings of acute rejection were easily distinguished from the cellular pictures of both viral infections. The rejections were lymphoid blast (3.6 +/- 3.4 CIU at the peak) and activated lymphocyte (3.5 +/- 2.6 at the peak), dominated by a high peak of total inflammation (9.3 +/- 7.0 CIU). No blast cells and only a few activated cells were seen in the blood during rejection episodes. Thus, the cellular patterns of HCV reactivation and CMV infection differed slightly from each other, but significantly from that of acute liver allograft rejection monitored with the FNAB cytology.

Antibodies, Viral↗
PubMed1994

Expression of cell-matrix molecules and integrin receptors in human liver grafts during chronic rejection.

The inflammatory response of immune cells to target cells and cell-matrix molecules is regulated by several receptor-ligand molecules. As fibrosis develops in ongoing chronic rejection after liver transplantation, it is of interest to analyze patterns of integrin receptors and cell-matrix molecules in order to study the relation between immune cells and the stromal and parenchymal cells. In the present study, we demonstrated the expression of these molecules in chronic rejected human liver grafts using immunohistochemical techniques. The results showed a differential expression and induction of integrin receptors and cell-matrix molecules on resident liver cells, especially on sinusoids, reflecting a state of chronic inflammation and a specific interaction between integrin receptors and cell-matrix molecules. The patterns of induced integrin receptors on graft-infiltrating cells was closely related to the local production of cell-matrix molecules and reflected the final sequence of a stepwise progress of the inflammatory reaction.

Bile Ducts↗
PubMed1994

Spontaneous proliferation of peripheral blood lymphocytes as an indicator of intragraft immune activation in liver transplant patients.

The presence of activated lymphocytes in the blood of transplant recipients is considered to be a marker of an ongoing immune process. In this study, the clinical utility of spontaneous proliferation (SP) of peripheral blood mononuclear cells (PBMC) as a marker of in vivo activation was evaluated by in vitro [3H]thymidine incorporation in 22 patients in the 1st month after liver transplantation. Also immune activation in the graft was monitored by transplant aspiration cytology (TAC-A). In the study period, there were only 2 mild episodes of clinical acute rejection, where SP of PBMC was 1290 and 1541 cpm (vs. 99 cpm averaged in healthy controls). Though SP of PBMC was also increased in systemic infections, a significant positive correlation was observed between SP of PBMC and TAC-A score. In all episodes where TAC-A score was elevated to above 2, SP of PBMC was simultaneously increased to more than 1000 cpm. In 8 patients prophylactically treated with the anti-interleukin-2-receptor antibody, BT563, SP of PBMC was significantly lower compared to 7 patients treated with antithymocyte globulin. It is suggested that SP can be a reliable parameter of the in vivo activation of lymphocytes, which accompanies immune activation in liver graft, and is potentially useful as a sensitive, although rather non-specific, and non-invasive monitoring of intragraft alloresponse.

Adult↗
PubMed1993

Persistence of donor lymphocytes in liver allograft recipients.

Occasional cases of graft-versus-host disease after liver transplantation indicate a transfer of donor lymphocytes by human liver grafts. However, little is known about the usual fate and potential function of passenger lymphocytes in clinical liver transplantation. In this study, we have analyzed liver graft recipients for the presence of donor lymphocytes in the early course after transplantation. The presence of such cells in blood, the graft, and, occasionally, the skin was studied by the use of mAb to polymorphic HLA class I determinants and double-staining techniques in flow cytometry and immunocytology. The findings were compared with the clinical courses and with the results of routine graft biopsies. Within the first week after transplantation, in all 16 patients, between 1% and 24% donor lymphocytes (T, NK, and B cells) were detectable in blood, and in 14 of 22 patients (64%), between 2% and 23% donor T cells were found in the graft. After more than 2 weeks, donor cells were still present in blood in 2 of 14 patients at very low numbers. The presence of donor lymphocytes in the graft was associated with intragraft immune activation in 5 of 15 patients, but no clinical rejection occurred in these cases; mild graft-versus-host disease was observed in one patient. These findings demonstrate that donor lymphocytes regularly persist in liver-grafted patients for some time; this transient mixed lymphoid chimerism is only rarely associated with clinical graft-versus-host disease and some evidence even suggests that these donor-derived lymphocytes may exert beneficial immunomodulatory properties.

Adult↗