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)

A 5-year-old girl with Ph-positive chronic myelogenous leukemia, who underwent umbilical cord blood transplantation, developed two episodes of electrical status epilepticus while receiving tacrolimus (FK506) then cyclosporin A (CsA), as treatment against graft-versus-host disease. MRI including diffusion weighted MR imaging of the brain revealed abnormalities in the hippocampus and posterior white matter following FK506 and CsA treatment, respectively. While posterior white matter injury has been described with both FK506 and CsA, no previous report describes hippocampal injury from either drug. The MRI changes in the hippocampus in our case suggest possible increased susceptibility to hippocampal injury with FK506.
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PMID:FK506-associated limbic injury following umbilical cord blood transplantation. 1294

Successful clinical small-bowel transplantation is still difficult to achieve. Two features render the small intestine unique among vascularised solid organ grafts. First, the bowel contains a large amount of lymphoid tissue within the Peyer's patches, mesenteric lymph nodes, and intraepithelial lymphocytes, which are thought to mediate graft-versus-host disease and provide a major stimulus for the recipient's immune system. Unfortunately, mere surgical reduction of these tissues, by using segmental allografts, does not furnish any immunological advantage. Second, the small bowel lacks specific serum markers such as blood urea nitrogen (BUN) in the kidney or bilirubin in liver transplantation. Clinical signs such as fever, pain, or tenderness of the abdomen may indicate an already advanced destruction of the graft. Therefore, very potent immunosuppressive regimens are necessary to avoid small-bowel allograft rejection or even to reverse an ongoing rejection process. Cyclosporin was shown in small and large animal models to control rejection reactions sufficiently. However, there are two even more promising immunosuppressive agents currently under investigation. FK506, a macrolide lactone isolated from Streptomyces tsukubaensis, leads to long-term survival of small-bowel allografts in a rodent model and has already been used in a few clinical small-bowel transplantations. RS61443, a mycophenolic acid morpholinoethylester, selectively inhibits T- and B-cell proliferation. We have investigated the use of FK506 and RS61443 for the reversal of small-bowel allograft rejection in a small animal model.
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PMID:The use of FK506 and RS61443 for reversal of small-bowel rejection. 1462

Reduced intensity (RI) allogeneic stem cell transplantation (AlloSCT) was initially demonstrated in adults following HLA-matched family and unrelated adult donor AlloSCT. There is little information about RI AlloSCT in children. We report results of a pilot study of RI AlloSCT in 21 recipients (< or =21 years). Age: median 13 (0.5-21) years, 8F:13M, 14 unrelated cord blood units (UCB) (10 4/6, 4 5/6), two related BM (6/6, 5/6), four related PBSC (2 6/6, 2 5/6), and one related BM+PBSC (6/6). RI: fludarabine, busulfan (n=14); fludarabine, cyclophosphamide (n=4); fludarabine, melphalan (n=1); total body irradiation, fludarabine, cyclophosphamide (n=1); or fludarabine, cyclophosphamide, and etoposide (n=1). Graft-versus-host disease prophylaxis: FK506 0.03 mg/kg/day and mycophenolate mofetil 15 mg/kg/q 12 h. UCB median nuc/kg and CD34/kg was 4.3 x 10(7)/kg (0.9-10.8) and 1.9 x 10(5)/kg (0.3-6.9), and related BM/PBSC median nuc/kg and CD34/kg was 8.3 x 10(8) (4.7-18.9) and 5.0 x 10(6)/kg (4.6-6.4). Maximal chimerism following unrelated cord blood transplantation, 100% x 7, 98% x 1, 95% x 2, 55% x 1, and 0% x 3; related PBSC/BM, 100% x 5, 65% x 1, and 55% x 1. Graft failure occurred in 5/21 (24%). In summary, RI AlloSCT in children is feasible and tolerable (< or =25% GF) and results in > or =85% of recipients initially achieving > or =50% donor chimerism.
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PMID:A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. 1473 Mar 37

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.
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PMID:A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. 1507 23

We report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center and the risk factors associated with survival. Median age: 9 years (0.5-20); diagnosis: ALL (9), AML (4), CML (1), HD (3), HLH (1), NHL (3), NBL (2); B-thal (1), FA (1), FEL (1), Krabbe (1), WAS (1), SAA (1); median follow-up: 11 months; conditioning: total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9); GVHD prophylaxis: MMF/FK506 (18), cyclosporin A (CsA)+steroids+/-MMF (7) or CsA+methotrexate (MTX) (4); median total nucleated cells (TNC): 3.8 x 10(7)/kg (1.1-11); median CD34+: 2.3 x 10(5)/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). Neutrophil engraftment by cumulative incidence curves 63% (median 28 (95% confidence interval (CI) 18-32)). Probability of >/=grade II acute graft-versus-host disease (aGVHD) by day +60 27%, >/=grade III aGVHD 20% and chronic graft-versus-host disease 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and standard risk 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048). These results suggest that CD34/kg cell dose and non-TBI-ablative conditioning may be important variables influencing OS following UCBT in pediatric recipients. Given the small number of patients, these results should be viewed cautiously.
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PMID:Outcomes of unrelated cord blood transplantation in pediatric recipients. 1510 15

We describe a patient with chronic myelogenous leukemia who developing severe intestinal bleeding after allogeneic peripheral blood stem cells transplantation (allo-PBSCT). PBSC were obtained from an HLA one-locus mismatch sibling donor. On day 26 after PBSCT, although there was no sign of graft-versus-host disease (GVHD) in either the skin or the liver, diarrhea and severe intestinal bleeding occurred. The histopathological examination of the colon revealed complete denudation of the epithelial cells of the mucosa and no obvious apoptosis. Neither red cell fragments nor hemorrhagic diathesis was seen during this episode and the patient was diagnosed as having GVHD. Methylpredonisolone followed by FK506 may be effective in controlling intestinal bleeding and was used in our patient. Acute GVHD involving only the intestine has rarely been described but when using HLA-mismatched PBSCs, acute GVHD may occur severely and atypically.
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PMID:Graft-versus-host disease confined solely to intestine after allogeneic peripheral blood stem cells transplantation in a patient with chronic myelogenous leukemia. 1520 68

Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60-3.04, P<0.0001 for grade II-IV acute GVHD; HR: 1.81, 95% CI: 1.32-2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23-2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.
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PMID:Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. 1522 Sep 58

Acute graft-versus-host disease (GVHD) is a primary T-cell-mediated complication of allogeneic hematopoietic stem cell transplantation (HSCT), occurring when donor-derived T cells are stimulated by host antigen-presenting cells (APCs), enhanced by proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha. Recent data indicate that besides differences in major histocompatibility and minor histocompatibility antigens, cytokine gene polymorphisms have a predictive value for the complication of GVHD. Patients with a high anti-inflammatory IL-10 production have been demonstrated to be protected from GVHD while patients with high TNF-alpha serum levels were more at risk for GVHD. Pharmacological immunosuppression for GVHD prophylaxis and therapy, including unspecific approaches with corticosteroids or methotrexate (MTX), as well as more specific therapy with cyclosporin A (CsA), tacrolimus (FK506), sirolimus, mycophenolate mofetil (MMF), antithymocyte globulin (ATG), and monoclonal antibodies (MAbs) directed against CD3, CD25, CD52, cytotoxic T-lymphocyte antigen (CTLA)-4, CD40 ligand, or TNF-alpha, have been proven to be effective. Recent data on novel techniques to selectively deplete alloreactive T cells by removal, destruction, or anergy induction while preserving leukemia-specific T-cell clones suggest a clinical benefit from these approaches. Gene-modified T cells that can selectively be depleted and CD4(+)CD25(+) regulatory T cells are under investigation for their ability to modulate alloreactivity after HSCT. With a better understanding of the immunopathogenesis of acute GVHD and the technical improvement of recently described therapeutic approaches, such as removal of naive T cells, selection of Th2 cells, suicide gene transduced T cells, and adoptive transfer of regulatory T cells, the use of alloreactivity as a treatment modality may be expanded to nonhematological disease entities such as solid tumors or autoimmune disorders.
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PMID:Immunopathogenesis of acute graft-versus-host disease: implications for novel preventive and therapeutic strategies. 1544 32

A 46-year-old woman with Hodgkin's disease who underwent nonmyeloablative allogeneic stem cell transplantation developed cortical blindness, seizures, and left hemiparesis on day 100 while receiving tacrolimus (FK506) and prednisone for the treatment of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed multiple changes, mainly in the bilateral occipital lobes, suggesting FK506-related leukoencephalopathy. These abnormalities improved after discontinuation of FK506. However, 3 days after the episode, cerebral hemorrhage in the left occipital lobe with perforation to the left subdural space occurred. Although FK506-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the patient's neurological symptoms almost completely resolved and radiographic findings improved after discontinuation of FK506, tapering of methylprednisolone, and initiation of mycophenolate mofetil. FK506-related leukoencephalopathy is a rare complication after allogeneic stem cell transplantation. Although the symptoms usually subside after discontinuation of FK506, therapeutic intervention in many cases may result in severe complications, including GVHD and vascular disease. We consider it important to use immunosuppressive agents without vascular endothelial toxicity for preventing the development of fatal GVHD after discontinuation of FK506.
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PMID:Successful treatment of tacrolimus (FK506)-related leukoencephalopathy with cerebral hemorrhage in a patient who underwent nonmyeloablative stem cell transplantation. 1554 Sep 7

The immunomodulator glatiramer acetate (GA, copolymer 1, Copaxone, GLAT), currently used for the treatment of multiple sclerosis, is a well-tolerated drug with a high safety profile. We have previously demonstrated that GA suppresses the immune rejection manifested in graft versus host disease, as well as in graft rejection. In an attempt to reduce the dosage and toxicity of the current immunosuppressive regimens, we have now tested the ability of GA, combined with low doses of cyclosporin (CyA) or tacrolimus (FK506), to suppress the rejection of mismatched allografts across major histocompatibility barriers. We report herewith that such combination therapy was effective in several animal models: (1) it led to a significant delay of the vigorous process of skin rejection in mice, manifested by evidential prolongation in skin graft survival (higher than that obtained with at least double dose of the immunosuppressive drug alone). (2) The combined treatment led to efficient inhibition of the functional deterioration of thyroid grafts in mice, manifested by 2.2- to 20.1-fold increase in iodine absorbance of the transplanted thyroids, as compared to each drug alone. (3) Combination therapy inhibited significantly the rejection of vascularized heart transplants in rats. Thus, cardiac allograft survival following the combined treatment with GA and low dose of CyA was longer than the survival obtained by fourfold higher dose of CyA alone. In all transplantation systems, combination therapy of GA with either CyA or FK506 significantly suppressed graft rejection and was more effective than treatment with either GA or the immunosuppressive drug alone, suggesting that such treatment may be beneficial for human transplantation.
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PMID:Combined treatment of glatiramer acetate and low doses of immunosuppressive drugs is effective in the prevention of graft rejection. 1558 56


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