Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL-2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.
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PMID:Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor. 804 47

Cytostatic chemotherapy instead of supralethal total body irradiation (TBI) has been increasingly used as an alternative myeloablative regimen before bone marrow transplantation (BMT). While irreversible azoospermia/amenorrhoea seems to occur less frequently with such conditioning, graft-versus-host disease (GVHD) remains unaffected. Five-year disease-free survival in accelerated chronic granulocytic leukemia (CGL), after BMT with matched sibling grafts has been 0.10-0.30. Mitobronitol, cytosine arabinoside, and cyclophosphamide were used for conditioning. Patients were transplanted with unmanipulated HLA/MLC identical sibling bone marrow. For recovery, a pathogen-low room was available without air filtering and laminar airflow. Seven of eight accelerated-CGL patients were engrafted: full allogeneic reconstitution was detected in four and mixed chimerism in three patients. Five out of the seven engrafted patients survived at least nine months (median = 42 months), two are considered cured (8-9 years survival). The four leukemia-free survivors displayed full allogeneic reconstitution and presented symptoms of chronic GVHD. One patient became a genetically verified father. Acute GVHD and veno-occlusive liver disease (VOLD) were absent in all patients, diffuse interstitial pneumonitis (IP) occurred in one case. Non-supralethal conditioning with mitobronitol/cytarabine/cyclophosphamide in accelerated-CGL allows allogeneic bone marrow reconstitution with survival and cure rates comparable to those achieved with other protocols using TBI or busulphan conditioning. Unlike the latter treatments, however, our protocol leads to fewer transplant-related complications including acute GVHD, IP, VOLD, and azoospermia/amenorrhoea.
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PMID:Non-supralethal mitobronitol/cytarabine/cyclophosphamide conditioning without irradiation before bone marrow transplantation for accelerated chronic granulocytic leukemia: apparent absence of acute graft-versus-host disease. 832 Oct 45

Neutrophil chemotactic and functional defects occur in beta-thalassemia and in patients after bone marrow transplantation (BMT). Interleukin-8 (IL-8) is a novel chemotactic and activating peptide for neutrophils and can be detected in the circulation. IL-8 serum concentrations were evaluated in 30 beta-thalassemic patients before and after BMT. Serial samples from 16 patients were also studied. Fourteen sera from healthy children, 43 patients with chronic viral hepatitis, 16 patients on chronic transfusion treatment for various hematologic disorders, and 28 healthy adults were studied as controls. IL-8 was evaluated by an enzyme-linked immunosorbent assay. Patients with beta-thalassemia had higher IL-8 concentrations than did normal controls, patients with liver disease, and patients on chronic transfusion. beta-Thalassemic patients with severe liver siderosis and fibrosis had the highest IL-8 concentrations. After BMT in patients with successful engraftment, IL-8 concentrations decreased significantly. In contrast, in patients with acute graft-versus-host disease (GVHD), IL-8 concentrations were not statistically different from the concentrations found before BMT and were higher than in patients with no complications and patients with graft rejection. IL-8 may play a part in the immune dysregulation that occurs in beta-thalassemia and may be involved in the immune mechanisms leading to GVHD.
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PMID:Elevated interleukin-8 serum concentrations in beta-thalassemia and graft-versus-host disease. 848 7

BALB/c mice injected at birth with (BALB/c x C57BL/6)F1 hybrid spleen cells developed host versus graft disease (HVGD) with immunological features, such as various autoantibodies, immune complex nephritis, hepatosplenomegaly, and malignant lymphomas. In addition we found that the increased IgE levels correlated strongly with the histological grades or stages of the liver disease. In the sera of mice with HVGD and liver alterations, anti-smooth muscle antibodies (ASMA) and anti-nuclear antibodies (ANA) were detected. The subclass of ASMA was IgG1, whereas the subclasses of ANA were IgG1, IgG2a, and IgG2b. When the recipient BALB/c mice were injected at birth and at Day 3 in addition also with monoclonal anti-IL-4 antibody 11B11, the increase of IgE and IgG1 was markedly reduced and the liver disease was drastically prevented. These observations suggest that IL-4 plays an important role in the initiation of the immunoregulatory function or pathogenesis of the allogeneic effects and that the monoclonal anti-IL-4 antibody 11B11 prevents the immunodysfunctions and the autoimmune hepatopathy in mice with HVGD. The increased IgE level in the serum is a good marker of HVGD.
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PMID:Increased IgE level as a marker of host-versus-graft disease: inhibition of this HVGD with a monoclonal antibody to IL-4. 851 6

The role of hepatitis C virus (HCV) infection in severe liver failure (LF) following bone marrow transplantation is still uncertain. We therefore decided to determine the presence of HCV-RNA in 31 patients who died of severe LF after BMT and in 26 matched BMT controls who did not develop LF. HCV-RNA was identified by polymerase chain reaction and anti-HCV by second generation enzyme-linked immunoassay and by 4-band recombinant immunoblotting assay in serum samples obtained before and after BMT. Biochemical and clinical parameters of liver disease were obtained by reviewing clinical records. LF developed at a median interval of 80 days (20-570) from transplantation and was clinically assessed as VOD (n = 7), liver GVHD (n = 5) or hepatitis (n = 19). HCV-RNA was detected, respectively, in 15/31 (48%) and in 12/26 (46%) of LF patients and controls (P = 0.9). Conversely, the risk of dying of LF was 62% and 53% (P = 0.5) respectively, for HCV-RNA positive and negative patients. Anti-HCV profile did not correlate with viremia, nor with type of liver disease. These findings indicate that, despite a 47% prevalence of HCV infection in our series, HCV-RNA positivity was neither a predictor of VOD nor a marker for life-threatening liver disease.
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PMID:Hepatitis C virus infection and liver failure in patients undergoing allogeneic bone marrow transplantation. 853 14

Bile acids are natural detergents and the end-products of cholesterol metabolism. Their functions are mostly digestive: induction of bile flow and solubilization of biliary and alimentary lipids. They circulate along the enterohepatic cycle, and probably also along a shorter route, the cholehepatic shunt. They are relatively hydrophobic and perpetuate or worsen the hepatic lesions when their excretion is impaired in cholestasis, because of their affinity for biological membranes. Their functions depend on their relative hydrophilicity and ionization, ie on their structure and state of conjugation. They have an immunosuppressive effect in vivo and in vitro. Ursodeoxycholic acid (UDC) is a hydrophilic bile acid used in chronic cholestatic diseases. Biological improvement has been proven in autoimmune cholangiopathies in adults, and cystic fibrosis-associated liver disease in children. Clinical studies are on the way for other indications. It is still too early to evaluate the long-term clinical benefits, eg the reduction in needs for liver transplantation. UDC acid may induce a bicarbonate-rich hypercholeresis through the cholehepatic shunt, that would explain its efficacy in cystic fibrosis. In disorders of bile acid synthesis or transport, it could shunt the enzymatic block, or reestablish the bile flow through its osmotic effect. Like other bile acids it interacts with membranes, and is thought to stabilize them. In chronic cholestasis it would protect the membranes against the adverse effect of non-excreted endogenous bile acids. This interaction can also explain its immunosuppressive effect, through non-specific inhibition of transmission at the cell surface. That would explain the preferential clinical efficacy of UDC in autoimmune cholestasis, and stimulate its evaluation in "immunological" indications, such as liver transplantation and hepatic graft versus host disease.
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PMID:[Bile acids and their therapeutic use in children]. 854 2

Patients who require a bone marrow transplant (BMT) for leukaemia, lymphoma or other haematological disorders receive large quantities of blood products, including red cell concentrates, during the transplant period. Many receive red cell transfusions as part of treatment prior to BMT, adding to the potential iron load. However, organ dysfunction as a consequence of the transfused iron load would be surprising given the amounts of iron transfused. We studied 76 survivors of allogeneic and autologous BMT who were at least 1 year post-transplant and found that the majority (88%) had raised ferritins. Impaired liver function was common in these patients and in half was unexplained by viral hepatitis, veno-occlusive disease or graft-versus-host disease (GVHD), suggesting that iron overload may be an important contributing factor to liver disease in the stable post-transplant setting. This view is supported by the observation of improving liver function tests in 10 patients after a trial of venesection therapy.
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PMID:Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. 867 57

A 22-year-old female with diffuse mixed T cell lymphoma in second complete remission underwent allogeneic BMT from her HLA-compatible brother. Transplantation was complicated by acute graft-versus-host disease (GVHD), cytomegalovirus (CMV) infection, and combined hepatotoxic/cholestatic liver disease 45 days post-BMT. Cholesterol levels reached 65 mmol/l, and high density lipoprotein (HDL) cholesterol decreased to 0.23 mmol/l. She developed skin xanthelasmas, lipemia retinalis, and a solitary lung lesion, which was clinically diagnosed as pulmonary cholesteroloma. All these complications resolved following plasmapheresis and hypolipidemic treatment with lovastatin and cholesterol levels normalized.
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PMID:Solitary pulmonary cholesteroloma, multiple xanthelasmas and lipemia retinalis complicating hypercholesterolemia after bone marrow transplantation. 886 64

Long-term effects after blood or bone marrow transplantation (BMT) are emerging as an important issue, as more patients are included in BMT programmes and as this procedure becomes more successful. Long-term liver dysfunction, mainly due to chronic graft-versus-host disease or hepatitis C virus infection, is a well-known complication. Nevertheless, the diagnosis of liver disease in this patient group is sometimes difficult and, despite adequate studies, it may remain undetected. A novel hepatitis-associated virus, hepatitis G virus (HGV), has recently been identified. The virus belongs to the Flaviviridae family and is known to be parenterally transmitted, although there is no clear evidence to implicate this agent in causing acute or chronic hepatitis. We report a patient who developed mild, but persistent, abnormalities in transaminases for 2 years after an autologous BMT. HGV RNA was detected in both serum and liver. HGV RNA persisted in serum for at least 8 months. No other known hepatitis virus was found. This report provides the first direct evidence of a patient with long-term liver abnormalities after a BMT in whom the only known hepatitis virus isolated was the HGV.
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PMID:Detection of hepatitis G virus from serum and liver of a patient with long-term liver dysfunction after autologous bone marrow transplantation. 916 54

We investigated the cytokine profile and peak levels of interleukin (IL) -6, IL-8, IL-10 and tumour necrosis factor (TNF) -alpha levels in 42 patients after allogeneic bone marrow transplantation (BMT). Eleven of them developed veno-occlusive disease (VOD) of the liver. Fourteen patients had moderate-to-severe acute graft-versus-host disease (aGvHD), 10 isolated bacteraemia and 7 had no major complication. Those who developed severe VOD (n=6) showed a short, very high IL-8 peak (median: 6632 pg/ml, range: 5546-10,000 vs. 280 pg/ml, 0-2042 in controls, p<0.01) 1-4 d after diagnosis of the liver disease. Five of these patients had high peak levels of IL-6. Five patients with mild VOD showed a lower increase in the cytokines tested. Bilirubin levels, at day of IL-8 peak, did not differ statistically between mild and severe VOD. The highest levels of IL-10 were found in those with aGvHD. IL-8 levels were also increased, but not to the same extent as in patients with severe VOD (p=0.01 vs. VOD). In patients with bacteraemia, very high levels of IL-6 were seen. In patients without major complications, the levels of cytokines were low. In conclusion, high levels of IL-8 occurred in severe VOD of the liver, which may be of value to determine prognosis.
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PMID:Serum levels of cytokines after bone marrow transplantation: increased IL-8 levels during severe veno-occlusive disease of the liver. 933 24


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