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)

The macrolide lactone, tacrolimus (FK506), is utilized in bone marrow transplantation (BMT) to prevent graft-versus-host disease (GVHD). In the current study, we evaluated the ability of FK506 to modify the function of dendritic cells (DCs) derived from CD34+ hematopoietic progenitor cells (HPCs). Comparable to DCs obtained in the absence of FK506, DCs cultured in the presence of FK506 (FK-DCs) had higher expression of CD1a+ and formed a greater number of DC colonies. Despite the same expression of costimulatory molecules, FK-DCs displayed a reduced capacity to stimulate an allogeneic T cell response, and showed significantly lower interleukin (IL)-12 production. While normal DCs pulsed with the exogenous antigen, keyhole limpet hemocyanin (KLH) induced specific Th1-like interferon-gamma(IFN-gamma) producing CD4+ T cell line, FK-DCs induced Th2-like interleukin-4 (IL-4) producing CD4+ T cell line. These data demonstrate the ability of FK506 to induce Th2-promoting function in developing DCs.
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PMID:Tacrolimus (FK506) treatment of CD34+ hematopoietic progenitor cells promote the development of dendritic cells that drive CD4+ T cells toward Th2 responses. 1107 1

We experienced a case of demyelinating, inflammatory cervical myelopathy after bone marrow transplantation for chronic myelocytic leukemia (CML). A 28 years-old man who had been having skin and liver graft versus host disease (GVHD), developed paresthesia in the legs, and then, difficulty in walking. At the time of admission, weakness of the hands also appeared. There was no evidence of CML recurrence after bone marrow transplantation. The myelopathy was characterized by multiple abnormal spotty signal intensities in the cervical spinal cord on MRI and these were in part Gd-enhanced. A course of pulse-dose methylprednisolone was given, followed by prednisolone. The neurological deficits were improved to the degree of full recovery. The inflammatory myelopathy together with a plaque in the cerebral hemisphere, moderately delayed p-100 latency of VEP and elevation of myelin basic protein of the spinal fluid, is difficult to distinguish from that of multiple sclerosis. Although the precise mechanism of GVHD-myelopathy is not known, it is likely that the donor myelin-reactive T-lymphocytes were non-specifically activated with GVHD reaction and directed to a central nervous system. Tacrolimus might have precipitated the focal immune reaction by way of cytotoxic effects on brain capillaries. The "GVHD-myelopathy" presented here may thus be akin to multiple sclerosis in its immune mechanism.
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PMID:[A case of inflammatory demyelinative myelopathy after bone marrow transplantation]. 1108 92

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.
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PMID:Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities. 1110 Feb 78

We report a case of cerebral hemorrhage associated with cyclosporin A (CsA)/FK506-related encephalopathy that developed in a 16-year-old woman after allogeneic bone marrow transplantation. Hematopoietic engraftment occurred on day 15, and the patient developed systemic convulsions after CsA was replaced by FK506 for the treatment of acute graft-versus-host disease (GVHD). Based on magnetic resonance imaging, laboratory findings and cerebrospinal fluid studies, she was diagnosed as having CsA/FK506-related encephalopathy with cerebral hemorrhagic infarction. Although she recovered completely after discontinuation of FK506, she developed convulsions again 15 days after re-administration of FK506. A computed tomography scan showed cerebral hemorrhage. She died of respiratory failure. Vascular damage induced by immunosuppressive drugs and enhanced by acute GVHD seemed to be the cause of the cerebral hemorrhage. Since hypertension, which was present during both of the central nervous system events, seemed to have contributed to the development of the cerebral hemorrhage, it is proposed that CsA and FK506 should be reduced or discontinued when patients who have risk factors of hypertension become hypertensive even if they have no symptoms of neurotoxicity.
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PMID:Fatal cerebral hemorrhage associated with cyclosporin-A/FK506-related encephalopathy after allogeneic bone marrow transplantation. 1110 Jul 53

The increasing number of allogeneic stem cell transplants, particularly those involving donors other than HLA-identical siblings, has made the management of acute and chronic graft-versus-host disease (GVHD) a continuing problem for transplant experts. There have been improvements in the prevention of acute GVHD with cyclosporine- and FK506-based combination therapies, as well as lymphocyte depletion. However, fewer than 50% of patients have durable improvement after initial treatment. FK506 and mycophenolate mofetil (MMF) are promising salvage therapies in steroid-resistant GVHD, as are the anti-cytokine antibodies and the purine nucleoside analog, pentostatin. The incidence of chronic GVHD has unfortunately not decreased, despite advances in treatment of acute GVHD. Treatment of chronic GVHD involves treatment of the underlying immunologic process and supportive therapies. Initial therapy has tended to be cyclosporine and prednisone. Refractory patients have hope with combination MMF and FK506, etretinate, plaquenil, and nonpharmacologic approaches, such as PUVA. Supportive care is an integral part of chronic GVHD management with emphasis on infection control and symptom control. Death in chronic GVHD is still largely attributable to infection. The progress in therapies for GVHD has been encouraging, but the future of GVHD management lies in a better understanding of its pathogenesis.
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PMID:Management of graft-versus-host disease. 1112 7

We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD.
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PMID:Stem cell transplantation for the treatment of Fanconi anaemia using a fludarabine-based cytoreductive regimen and T-cell-depleted related HLA-mismatched peripheral blood stem cell grafts. 1116 55

Thrombotic microangiopathy is a severe microvascular disorder which may occur in up to 70% of patients undergoing bone marrow transplant. Clinically the term thrombotic microangiopathy encompasses a wide spectrum of syndromes, most importantly the thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Thrombotic microangiopathy is characterized by the presence of thrombocytopenia, microangiopathic hemolytic anemia, renal impairment, neurological disturbances and multiorgan failure. Several causative agents have been advocated as triggering factors for bone marrow transplant associated thrombotic microangiopathy, including cyclosporine, FK506, the use of total body irradiation, infections and the presence of severe graft-versus-host disease. Plasma exchange represents the standard treatment for patients who develop TTP/HUS after bone marrow transplant, however, the mortality rate still remains high despite aggressive therapy.
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PMID:BMT: Bone Marrow Transplant Associated Thrombotic Microangiopathy. 1139 2

Liver disease associated with chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity. Steroids and cyclosporin (CSA), which are the standard therapy, give rather disappointing results, and toxicity is high. Tacrolimus (FK506) is a potent macrolide lactone immunosuppressant that is used in the prevention of solid organ rejection. This study evaluated the therapeutic role of FK506 in the treatment of severe cGVHD-mediated liver disease that did not respond to combined steroids and CSA therapy. Fifteen patients with various hematological disorders who underwent allogeneic stem cell transplantation were enrolled in the study. All patients had severe cholestatic liver disease disturbances and underwent liver biopsy, which was compatible with cGVHD-mediated liver disease. All the patients were negative for markers of chronic liver disease, including viral serology. They received FK506 orally (4-20 mg/day according to serum levels), and were evaluated biweekly by physical examination and liver function tests. Patients were followed for a median of 12 months (range 3-24 months). FK506 treatment ameliorated liver functions in 9 of 15 patients (60%), 5 of whom demonstrated complete normalization of liver enzymes (33%). In 5 patients, no major effect was observed, and 1 patient showed deterioration of his liver functions. Mean GGT levels decreased from 171.5 to 55.6 within 6 months of treatment. Median time to response was 3 months (range 1-11). Side effects were generally transient. Treatment with FK506 was found to be effective in the majority of patients with steroid and CSA-resistant cGVHD-associated liver disease, with manageable side effects. In view of these findings, FK506 may yet evolve into first line therapy for cGVHD induced liver toxicity.
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PMID:Amelioration of steroid-resistant chronic graft-versus-host-mediated liver disease via tacrolimus treatment. 1145 16

We report a case of a 5-year-old girl with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) who underwent cord blood (CB) stem cell transplantation (CBSCT) from an unrelated donor. The patient presented with persistent high-grade fever and hepatosplenomegaly. Because the disease was refractory to immunochemotherapy according to the HLH94 protocol, she received 2.0 x 10(7) CB nucleated cells/kg body weight (BW) after conditioning with BU/CY/etoposide. No acute GVHD developed, using FK506 for prophylaxis. The neutrophil count reached >0.5 x 10(9)/l by day 21 and the platelet count reached >50 x 10(9)/l by day 84. The patient recovered well with sequelae of neurological deficits more than 10 months after receiving CBSCT, without showing evidence of HLH or chronic GVHD. Real-time PCR proved applicable for estimation of the EBV load in PBMC of the patient. We conclude that CBSCT may be indicated for some cases of refractory EBV-HLH, who have no HLA-matched siblings and are therefore dependent on unrelated marrow donors.
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PMID:Successful umbilical cord blood transplantation from an unrelated donor for a patient with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. 1147 48

We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days post-transplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P < 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P= 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLA-matched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors.
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PMID:Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. 1150 36


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