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)

Clinical and preclinical data indicate that tumor necrosis factor (TNF)-alpha is an important mediator of acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation. We completed a study using etanercept, a fusion protein capable of neutralizing TNF-alpha, for the initial treatment of aGVHD. Etanercept (25 mg subcutaneously) was administered twice weekly for 16 doses, along with methylprednisolone (2 mg/kg) and tacrolimus for biopsy-proven aGVHD. Twenty patients with a median age of 47 years (range, 8-63 years) were enrolled. Fourteen patients with grade II aGVHD (11 family donors and 3 unrelated donors) and 6 patients with grade III aGVHD (3 family donors and 3 unrelated donors) were treated. Twelve patients completed 16 doses of therapy, and 8 received 5 to 15 doses. Reasons for not completing all doses of etanercept included progression of aGVHD (n = 4), relapsed leukemia (n = 2), progression of pulmonary and central nervous system lesions (n = 1), and perforated duodenal ulcer (n = 1). Fifteen (75%) of 20 patients had complete resolution of aGVHD within 4 weeks of therapy. Increasing levels of soluble TNF receptor 1 plasma concentration during the first 4 weeks of therapy indicated progression of aGVHD in 5 patients. In contrast, for 15 responding patients, soluble TNF receptor 1 plasma concentration levels returned to baseline. These data demonstrate the feasibility of using cytokine blockade in the early treatment of aGVHD.
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PMID:Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease. 1612 38

Peripheral blood T cells were isolated from 19 allogeneic and 4 autologous stem cell transplant (SCT) recipients and assessed for tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma transcription by reverse transcription-polymerase chain reaction. Levels were compared with resting donor T-cell transcription levels. Increased production of TNF-alpha predicted for the onset of severe (grade II-IV) graft-versus-host disease (GVHD) (P = .001). Increased TNF-alpha (P = .025) and IFN-gamma (P = .001) transcription also independently predicted for the eventual onset of extensive chronic GVHD. Increased TNF-alpha or IFN-gamma transcription was not seen in either a syngeneic SCT recipient or 4 autologous SCT controls. These findings provide a means by which GVHD can be predicted before it is clinically evident, thus allowing for accurate diagnosis and monitoring of GVHD and possibly more cost-effective management of post-SCT immunosuppression.
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PMID:Prospective monitoring of tumor necrosis factor alpha and interferon gamma to predict the onset of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. 1612 41

Graft-versus-host disease (GVHD) is a multistep disease process following allogeneic bone marrow transplantation (BMT). It has been postulated that the induction of acute GVHD requires the presence of Peyer patches (PPs). A new tumor necrosis factor (TNF)-deficient strain has been developed that totally lacks PPs and displays the defects characteristic of TNF ablation but not lymphotoxin-associated defects characterized by lack of both PPs and lymph nodes. To determine the necessity of PPs in acute lethal GVHD induction, we transplanted full major histocompatibility complex (MHC)-mismatched grafts into myeloablated TNF knockout recipients. No differences in the survival or GVHD-associated histopathologic lesions were observed between the recipients. We conclude that neither PPs nor host TNF-alpha is required for the development of acute lethal GVHD in mice that undergo myeloablative conditioning and allogeneic BMT.
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PMID:Peyer patches are not required for acute graft-versus-host disease after myeloablative conditioning and murine allogeneic bone marrow transplantation. 1616 14

Both inflammatory and anti-inflammatory cytokines have been reported to be associated with acute graft-versus-host disease (aGVHD). However, their role and possible mutual interactions during aGVHD are not well understood. Eight patients with aGVHD and eight without who had undergone allogeneic HLA-identical peripheral blood stem cell transplantation were studied. The patients had no other complications known to affect serum concentration of cytokines, including infection. Serum concentrations of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma were concurrently measured by a new technique, the cytometric bead array (CBA). We found that serum concentrations of IL-5, IL-6 and IL-10 were significantly higher in patients with aGVHD than in patients without it. By ratiometric analysis, the ratios of IL-5/IL-2, IL-5/IL-4, IL-6/IL-4 in patients with aGVHD were increased compared to the patients with no evidence of aGVHD. ROC analysis demonstrated that the ratio of IL-5/IL-4 was the most sensitive parameter associated with aGVHD. The second best marker of aGVHD was increased IL-5 concentration. Thus, our results indicate that the ratio of a particular cytokine/cytokine could be a potential diagnostic marker for aGVHD, more sensitive that the serum level of a given cytokine. This observation is consistent with a cross-talk among some cytokines and their possible interactions via respective receptors on cytokine-producing cells; these interactions may play an important role in pathogenesis of aGVHD. Further studies including a large number of patients and concurrent measurement of a variety of cytokines are needed to fully assess the diagnostic value of the cytokine ratiometric analysis. The CBA methodology provides a convenient and useful tool in such studies.
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PMID:Serum cytokine concentrations and acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: concurrent measurement of ten cytokines and their respective ratios using cytometric bead array. 1659 75

This study was aimed to analyze the mRNA expression of cytokines (TGF-beta, IL-2, IL-6, IL-10, IFN-gamma, TNF-alpha, FAS-L) in five rhesus treated with haploidentical peripheral blood stem cell transplantation after nonmyeloablative preparative regimens and to explore the role of these cytokines in the development and pathology of acute graft-versus-host-disease (aGVHD). Five rhesus monkeys received nonmyeloablative haploidentical peripheral blood stem cells transplantation. Semi-quantitative reversed transcription polymerase chain reaction (RT-PCR) was used to analyze the kinetics of cytokine mRNA expression in the transplantation and aGVHD. The results showed that five rhesus monkeys acquired hematopoietic reconstitution successfully. The graft was rejected in one monkey which survived without disease, the other four achieved mixed chimerism and full donor chimerism. Chimerism of low centigrade in one monkey achieved high centigrade at 35 days after donor stem cell infusion. Intestinal aGVHD grade III developed in one monkey. Cytokines of Th1 and Th2 changed after transplantation. In period of aGVHD, expression of TGF-beta decreased but all others increased in various levels. When donor chimerism decreased, the cytokines decreased accordingly. It is concluded that the decrease of TGF-beta mRNA may be an indicator to predict aGVHD, and can be used as a differential diagnostic indicator for intestinal GVHD.
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PMID:[Kinetic study of various cytokine mRNA expressions in rhesus treated with haploidentical peripheral blood stem cell transplantation]. 1680 Sep 45

Interleukin(IL)-15 is a promising immunotherapeutic agent for immune reconstitution following stem cell transplantation. To investigate whether IL-15 would aggravate graft-versus-host disease (GVHD) in the setting of unrelated umbilical cord blood (CB) transplantation, we examined the effect of IL-15 on activation marker expression, proliferation and cytokine production of CB in a one-way mixed lymphocyte culture (MLC) assay. We found that IL-15 differentially enhanced CD69 and CD25 expression on CB T cells following allo-stimulation. The maximum degree of allo-specific CB proliferation was achieved on Day 6. IL-15 down-regulated the CB alloreactive proliferative response on Days 4, 6, and 8, with preferentially enhanced autologous proliferation. Exogenous IL-15 further enhanced CB TNF-alpha and IL-10 production in both autologous and allogeneic MLC 6 days after allopriming. Thus, IL-15 was effective in enhancing activation marker expression and cytokine production during CB alloreactivity, but failed to enhance allospecific proliferation. Further studies would be needed to study the role of IL-15 on GVHD in the setting of CB transplantation.
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PMID:Effect of interleukin-15 on alloreactivity in umbilical cord blood. 1686 Jul 14

The purpose of this study was to explore the roles of cytokines IL-2, TNF-alpha, IL-10 and IL-8 in the pathogenesis of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. The incidence of aGVHD was observed in 33 patients undergoing allogeneic hematopoietic stem cell transplantation. The aGVHD was clinically diagnosed. Sera from the 33 patients were taken before and after allogeneic hematopoietic stem cell transplantation. The IL-2, TNF-alpha, IL-8, IL-10 levels in serum of 33 patients were measured serially by using radioimmuno-assay (RIA). aGVHD occurred in 13 patients including 8 patients with aGVHD I and 5 patients with aGVHD II-IV. The results showed that the circulating levels of IL-2 and TNF-alpha were markedly elevated during aGVHD and strongly correlated with the severity of aGVHD as compared with patients without aGVHD. However, the level of the IL-10 in patients with aGVHD was significantly lower than that in patients without aGVHD. The change of IL-8 level was not significant statistically. It is concluded that IL-2 and TNF-alpha may play important roles in the pathogenesis of aGVHD, and measurement of serum IL-2 and TNF-alpha levels after allo-HSCT can provide predictive indicator for acute GVHD.
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PMID:[Changes of IL-2, IL-8, IL-10 and TNF-alpha levels in sera of patients with acute graft-versus-host disease]. 1692 15

Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.
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PMID:Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. 1693 91

This study was aimed to eveluate the role of CCR5 on donor cells in recipient models received intensive conditioning, so as provide the scientific evidence for clinical application of allo-HSCT. Lethally irradiated BALB/c mice received allogeneic bone marrow transplants from C57BL/6 mice. Mice divided into 4 groups according to receiving variant donor cells: B6 CCR5 KO group, receiving C57BL/6 CCR5(-/-) mice bone marrow cells and splenocytes; B6 WT BMC group, receiving C57BL/6 mice bone marrow cells and splenocytes; B6 CCR5 KO BMC group, receiving C57BL/6 CCR5(-/-) bone marrow cells alone; B6 WT BMC group, receiving C57BL/6 mice bone marrow cells alone. The result showed that compared to B6 WT BMC group, B6 CCR5 KO group succumbed to acute GVHD at an accelerated rate. Donor CD8(+) T cells expanded to a significantly greater extent in recipients of CCR5 KO, compared with B6 WT control cells. T cells recovered from recipients of CCR5 KO cells produced more IFN-gamma and TNF-alpha and proliferated to a T-cell at a significantly higher level than T cells from recipients of WT cells, indicating that CCR5 plays a role in downregualting donor alloreative CD8(+) T-cells expansion. Histological assessment of the mice indicated pathological lesions in the kidneys and a greater degree of liver pathological changes in mice that received CCR5 KO donor grafts. It is concluded that the knock-out of CCR5 on donor cells results in increase of GVHD and donor CD8(+) T cell expansion, as well as hepatic and renal lesions in allo-HSCT, which indicates that CCR5 is very important in allo-BMT.
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PMID:[Relationship between CCR5 and acute graft-versus-host disease in murine bone marrow transplantation]. 1709 92

Graft-versus-host disease (GVHD) is a serious complication of hematopoietic stem cell transplantation. The main clinical targets of GVHD are the skin, liver, gastrointestinal tract, and possibly the lung. The standard initial therapy for GVHD includes the use of high-dose steroids, which result in an unsatisfactory complete response (CR) rate of about 40% and the need to develop more effective therapies. The Clinical Trial Network is conducting a four-arm randomized phase II study evaluating prednisone in combination with one of the following four agents: etanercept, mycophenolate mofetil, denileukin diftitox, and pentostatin. Etanercept, an anti-TNF-alpha antibody, is also being evaluated in combination with steroids in a single-center phase II trial at the University of Michigan because of the role of TNF-alpha in the pathogenesis of GVHD. TNF-alpha and a surrogate marker, soluble TNF receptor, are elevated in patients with GVHD as early as 7 days after transplantation and maybe used in the future as a prognostic tool to identify transplant recipients at risk for developing GVHD.
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PMID:Novel strategies for the treatment and diagnosis of graft-versus-host-disease. 1733 59


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