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)

Acute graft-versus-host disease (aGVHD) is the major complication of allogeneic stem cell transplantation (allo-HSCT), significantly limits the application of the therapy. Current evidence suggests that dysregulated cytokine production is responsible for many manifestations of aGVHD. The mechanisms have been most clearly delineated in mouse models, detailed analysis of human tissue is required. Monitoring serum levels of cytokine sIL-2R, TNF-alpha and IFN-gamma after transplantation or cytokine gene expression before transplantation can predict prognossis of aGVHD. GVHD have graft-versus-leukemia (GVL) effect, and GVL can be seperated from GVHD. IL-2, IL-12, IL-11, KGF and G-CSF could possess the roles of reducing GVHD while preserving GVL.
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PMID:[Roles of Cytokines in Acute Graft-Versus-Host Disease] 1257 74

We studied the effect of rHuKGF on acute, lethal graft- vs.-host disease (GVHD) in the C57BL/6-->(C57BL/6 X DBA/2)F(1)-hybrid model. rHuKGF-treated recipients did not develop intestinal GVHD despite elevated levels of intestinal NO and TNF alpha, did not develop endotoxemia, and did not die. LPS augmented serum TNF alpha release and intestinal NO production, but did not induce intestinal epithelial cell apoptosis, a phenomenon associated with acute GVHD. These data suggest that KGF prevents the development of acute lethal GVHD by protecting epithelial cell injury mediated by TNF-alpha, NO, and other potential cytotoxic factors. We noted a moderate reduction in intestinal KGFR mRNA expression in untreated GVH mice on day 8, when IFN-gamma mRNA levels were highest. This reduction in KGFR mRNA levels was not seen in recipients of IFN-gamma gene knockout grafts, suggesting that IFN-gamma may be involved in reducing KGFR mRNA expression in the intestine. A similar reduction in intestinal KGFR mRNA expression was also seen in rHuKGF-treated recipients, suggesting that rHuKGF does not mediate its protective effect by maintaining KGFR at control levels. KGF-treatment also redirected the cytokine response in acute GVH mice from Th1 to a mixed pattern of both Th1 and Th2 cytokines. This was associated with histopathologic changes resembling chronic GVHD.
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PMID:Effect of recombinant human keratinocyte growth factor (rHuKGF) on the immunopathogenesis of intestinal graft-vs.-host disease induced without a preconditioning regimen. 1502 87

Palifermin, a recombinant human keratinocyte growth factor, was tested for potential benefits on acute graft-versus-host disease (GVHD) and hematopoietic recovery in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. This randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety and tolerability of palifermin (n = 69) as compared with placebo (n = 31) in patients conditioned with cyclophosphamide and fractionated total-body irradiation (Cy/TBI) or busulfan and cyclophosphamide (Bu/Cy) and given methotrexate along with a calcineurin inhibitor (cyclosporine A, tacrolimus) for GVHD prophylaxis. All patients received 3 doses before conditioning and either 3 (cohort 1), 6 (cohort 2), or 9 (cohort 3) doses after HSCT. Palifermin doses were 40 mug/kg per day (cohort 1 only) or 60 mug/kg per day (all cohorts). Six patients (placebo = 2, palifermin = 4) experienced a total of 11 dose-limiting toxicities (most often skin, respiratory, or oral mucositis). The most common adverse events included edema, infection, skin pain, or rash. Times to neutrophil and platelet engraftment were similar. No significant differences in acute GVHD incidence or severity, survival, or day 100 relapse rates were observed between groups. Palifermin was associated with reduced incidence and mean severity of mucositis in patients conditioned with Cy/TBI but not Bu/Cy. We conclude that palifermin was generally safe in allogeneic HSCTs but had no significant effect on engraftment, acute GVHD, or survival in this trial.
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PMID:Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). 1683 78

Palifermin (recombinant human keratinocyte growth factor) prevents the development of acute, lethal graft-versus-host disease (GVHD). It does so, at least in part, by protecting cells from injury. Another property of Palifermin is immune regulation. How the latter influences the evolution of GVHD remains uncertain. We explored the effect of Palifermin on GVHD in the DBA/2 --> ((DBA/2)x(C57BL/6))F(1)-hybrid strain combination, a model associated with autoantibody production and glomerulonephritis. Untreated recipients survived until at least day 150 post-induction. Palifermin-treated recipients succumbed between days 50 and 90 with levels of proteinuria of up to 20 g/L, ascites, and rapidly progressive, crescentic glomerulonephritis that was most severe in mice with the greatest levels of proteinuria. Kidney sections from both Palifermin-treated and untreated recipients showed the presence of granular deposits of IgG, IgM, IgA, and C3 in the mesangium and the glomerular basement membrane. Electron microscopy confirmed the extensive glomerular immune complex deposition. Antinuclear and anti-dsDNA antibodies were present in sera from both treated and untreated recipients; however, those in the latter were only detectable if the serum was kept at 37 degrees C, indicating that they were cryoglobulins. IL-4 was detectable only in cultures from Palifermin-treated recipients and the levels of IL-5 and IL-13 were significantly higher in the Palifermin-treated group than in untreated GVHD mice. IFN-gamma was only detectable in untreated GVHD mice. These data suggest that although Palifermin can protect mice with acute GVHD, it exacerbates GVHD in a model associated with autoantibody production and a preponderance of Th2 cytokines.
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PMID:Effect of palifermin in a murine model of graft-versus-host disease (GVHD) associated with Th2 cytokine production, autoantibody production, and glomerulonephritis. 1695 10

Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and economic outcomes. Palifermin (Kepivancetrade mark), an N-truncated recombinant human keratinocyte growth factor-1, is the first agent to be approved for prevention of oral mucositis. Keratinocyte growth factor, a potent epithelial mitogen, appears to play a major role in the healing process. Palifermin has multiple biological activities that appear to protect the mucosal epithelium and promote its early regeneration after irradiation- and chemotherapy-induced injury. These include inhibition of epithelial cell apoptosis and DNA damage, up-regulation of detoxifying enzymes and down-regulation of pro-inflammatory cytokines, as well as enhanced migration, proliferation and differentiation of epithelial cells. Palifermin reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem-cell transplantation. Clinical sequelae, including febrile neutropenia and resource use (opioid analgesia and parenteral feeding), are concomitantly reduced. Other potential applications being explored include use in the solid tumour setting, reduction of intestinal mucositis and reduction of GVHD in allogenic transplantation. Thus, the development of palifermin and other potential new agents for preventing chemotherapy- and radiotherapy-induced mucositis represents an important breakthrough in oncological supportive care.
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PMID:Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis. 1703 May 44

Mucositis occurs in < or = 98% of patients undergoing stem cell transplant for haematological malignancies and is associated with significant morbidity and mortality. Patients with severe mucositis have more pain, more difficulty with daily activities such as talking and eating, and are more likely to have bacteraemia. Palifermin is a keratinocyte growth factor that has been shown to decrease severity and duration of mucositis with a concurrent decrease in patient-reported symptoms and use of narcotics and total parenteral nutrition. Research is ongoing into palifermin's potential ability to decrease graft-versus-host disease and improve reconstitution of functional T lymphocytes after allogeneic stem cell transplant, to hasten wound healing and to reduce mucositis following external beam radiation therapy in solid tumour patients.
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PMID:Palifermin: a keratinocyte growth factor that reduces oral mucositis after stem cell transplant for haematological malignancies. 1705 84

In this multicenter study, 30 patients undergoing matched related or unrelated allogeneic stem-cell transplantation for leukemia were treated with palifermin, and retrospectively compared to a matched control group. Palifermin recipients transplanted with an unrelated donor showed a significant reduction of severity, incidence and duration of oral mucositis WHO grades 2-4. In addition, in the palifermin group the use of opioid analgesics and the duration of total parenteral nutrition decreased, whether stem cells were used from matched related or unrelated donors. No beneficial influence of palifermin on the incidence and severity of acute GVHD (aGVHD) was apparent. The incidence and duration of febrile neutropenia, documented infections, hematopoietic recovery or overall survival remained unchanged. The most common adverse effects included rash or erythema, generally mild and transient in appearance. Thus, the administration of palifermin was generally well tolerated and safe, and significantly reduced oral mucositis whereas--regardless of donor status--no effect on the incidence and severity of aGVHD was seen.
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PMID:Palifermin reduces incidence and severity of oral mucositis in allogeneic stem-cell transplant recipients. 1850 Mar 68

Conditioning therapy in connection with haematopoietic SCT (HSCT) induces a disruption of the intestinal barrier function facilitating the permeation of bacteria and endotoxin through the bowel wall with subsequent increased risk of septicaemia and a worsening of GVHD in the allogeneic setting. Palifermin (recombinant human keratinocyte growth factor) reduces the severity of oral mucositis with HSCT. The present trial investigates its effect on intestinal barrier function. Seventeen lymphoma patients undergoing autologous HSCT received palifermin. Intestinal permeability was assessed before the conditioning therapy and on days +4 and +14. Clinical oral and gastrointestinal toxicity was prospectively assessed in parallel. A comparison was made with matched historical study patients (n=21). Patients treated with palifermin had a significantly better preserved intestinal barrier function (P=0.01 on day +4) and were in less need of total parenteral nutrition (P=0.005) as compared with controls. No significant reduction of clinical gastrointestinal or oral toxicity was observed. The intestinal barrier function, normally disrupted by the conditioning therapy, is preserved by palifermin. Whether intestinal barrier preservation protects from invasive infections, and in the allogeneic setting diminishes GVHD severity, remains to be investigated in randomized controlled trials.
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PMID:Gut protection by palifermin during autologous haematopoietic SCT. 1904 60

In the last decade there has been increasing awareness of the importance of thymus gland function in the reconstitution of host immunity following hematopoietic transplantation. A functional thymus contributes to foster T compartment reconstitution, with an increased diversity of T receptor rearrangement, and a more physiological distribution of the functional subpopulations. Palifermin, a keratinocyte growth factor (KGF) approved for reducing the incidence and severity of oral mucositis, has been proposed as a possible strategy for improving thymus function and immune reconstitution after hematopoietic transplantation. In vitro and animal models show palifermin to protect the thymus from chemo-/radiotherapy induced damage, increasing thymic production, accelerating immune reconstitution, improving response to vaccines, and reducing the incidence of graft-versus-host disease in animal models. To date, no studies have analyzed this possible application in humans. This study reports preliminary data on immune reconstitution in 50 autologous transplant recipients (30 treated with palifermin and 20 controls). The results suggest that palifermin at the doses and involving the regimens indicated for the prevention of oral mucositis has no effect upon thymus gland function in adult patients, and induces no changes in T immune recovery (either CD4 or CD8) or in the percentage of functional T subpopulations or T helper lymphocytes.
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PMID:[Immune reconstitution and regulation following autologous hematopoietic transplantation using palifermin]. 2138 Dec 83

Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We conducted a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16 days, P=0.006) and patient-controlled analgesia (PCA, 6 vs 10 days, P=0.023), as well as the length of initial hospital stay (LOS, 32 vs 37 days, P=0.014). However, the effect of palifermin was only significant in patients who received a TBI- but not BU-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17 days, P<0.001) and PCA (7 vs 12 days, P=0.033), and the length of stay (32 vs 38 days, P=0.001). Palifermin did not affect GVHD, graft failure or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT.
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PMID:Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants. 2275 Sep 97


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