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)

Tumor necrosis factor is one of the recently cloned cytokines with pleiotropic effects on normal and malignant cells. Our knowledge about the scope of cells producing or responding to this cytokine has enormously expanded. In critically ill patients with acute hepatic failure, acute graft-versus-host disease, or septic shock, circulating tumor necrosis factor can be measured and useful prognostic correlations do exist. Despite promising in vitro results, early clinical trials with tumor necrosis factor for the treatment of cancer have failed thus far to reveal major antineoplastic activity in cancer patients. However, more clinical trials are necessary, since different routes of administration and combinations with other cytokines may lead to favorable results.
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PMID:Tumor necrosis factor: an update on basic research and clinical applications. 221 7

Because keratinocytes (KCs) express HLA-DR in a wide variety of skin diseases in which mononuclear leukocytes are observed in close apposition to KCs (i.e., graft-versus-host disease), and since gamma interferon (IFN-gamma) induces HLA-DR expression on KCs, we asked whether IFN-gamma treatment of KCs would influence the adherence of mononuclear leukocytes. When allogeneic peripheral blood mononuclear leukocytes (PBML) and a Leu-3+ T cell clone were coincubated with IFN-gamma-treated KCs (300 U/ml, 3 days), there was a marked increase in binding compared with nontreated KCs. Similar binding results were obtained using a cutaneous squamous carcinoma cell line (SCL-1) after IFN-gamma treatment. The IFN effect was relatively specific for IFN-gamma, as neither IFN-alpha nor -beta had any effect. Tumor necrosis factor exposure (500 U/ml, 3 days) increased the binding of the Leu-3+ T cell clone to both KCs and SCL-1 cells. Neutrophils displayed a less marked (but statistically significant) increase in binding to IFN-gamma-treated KCs. Using the Leu-3+ cell clone and SCL-1 cells, detailed kinetic analysis of the effect of IFN-gamma on binding was performed. The increased adherence between the cells began to appear after only 7 hours of treatment with r-IFN-gamma (300 U/ml) and reached a plateau at 48 hours, with significantly enhanced binding continuing for at least 48 hours after removal of IFN-gamma. The mechanism of binding was explored by preincubation of the PBML/Leu-3+ T cells with anti-LFA-1 (lymphocyte function-associated antigen) antibody (0.6-6.0 micrograms/ml), which totally inhibited the binding with no effect by anti-LFA-2 or -3 or class I or II antibodies despite documented binding of these antibodies to the cells. These results suggest that, after exposure to IFN-gamma, the ability of KCs to bind mononuclear leukocytes is strongly enhanced, and this adherence may be important in leukocyte trafficking in the skin as well as contributing to altered KC-leukocyte interaction, which may be of fundamental importance in a variety of skin disease.
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PMID:Recombinant gamma interferon increases the binding of peripheral blood mononuclear leukocytes and a Leu-3+ T lymphocyte clone to cultured keratinocytes and to a malignant cutaneous squamous carcinoma cell line that is blocked by antibody against the LFA-1 molecule. 244 90

Tumor necrosis factor (TNF) is a cytokine produced mainly by activated monocytes/macrophages. We review here data obtained in four experimental models analyzed in our laboratory: cerebral malaria, graft-versus-host disease, BCG infection, and bleomycin-induced pulmonary fibrosis. We have shown that the triggering of these pathological conditions requires activation of T lymphocytes and overproduction of TNF, since these syndromes are associated with increased production of TNF mRNA and can be prevented either by T-cell depletion or by in vivo administration of neutralizing anti-TNF antibodies. These observations suggest that TNF is a central mediator in various immunopathological conditions and thus widen the field of T-cell mediated pathology.
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PMID:[Tumor necrosis factor (TNF) and pathology; its relationships with other cytokines]. 248 41

In patients with acute graft-versus-host disease (GVHD), IL-6 gradually increased > 14 days before clinical onset of acute GVHD and decreased when acute GVHD disappeared. Interferon-gamma (IFN gamma) levels increased < 14 days before clinical acute GVHD and decreased at the disappearance of acute GVHD. Tumor necrosis factor-alpha (TNF alpha) levels increased almost simultaneously with the onset of acute GVHD and also decreased when it disappeared. However, these results do not necessarily mean that the increased levels of IL-6, IFN gamma and TNF alpha induced acute GVHD; they merely show that acute GVHD is observed more frequently in patients with increased IL-6, IFN gamma and TNF alpha levels than in those with normal levels. Although increased IL-6 levels were also observed in patients without acute GVHD, concomitant increase of IFN gamma and TNF alpha was not detected in such cases, showing that IL-6 can be increased by even graft-versus-host reaction (GVHR) which may not develop into clinical acute GVHD. Taken together, acute GVHD appeared to be induced by synergistic interaction of IL-6, IFN gamma and TNF alpha, consistent with a cytokine cascade. A similar interaction of IL-6 and TNF alpha was also observed in chronic GVHD. Although IFN gamma levels were slightly increased in chronic GVHD and sometimes aggravated the disease status, IL-6 and TNF alpha appeared to be more closely involved in the induction of chronic GVHD. In autologous BMT, increased cytokine levels were not observed unless IL-2 was administered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. 792 Mar 9

Tumor necrosis factor-alpha (TNF) has been implicated in the pathogenesis of a variety of human diseases including septic shock, cachexia, graft-versus-host disease and several autoimmune diseases. Monoclonal antibodies directed against TNF provide an attractive mode of therapeutic intervention in these diseases. We have generated a murine monoclonal antibody (A2) with high affinity and specificity for recombinant and natural human TNF. To increase its therapeutic usefulness, we used genetic engineering techniques to replace the murine constant regions with human counterparts while retaining the murine antigen binding regions. The resulting mouse-human chimeric antibody should have reduced immunogenicity and improved pharmacokinetics in humans. Molecular analysis of light chain genomic clones derived from the murine hybridoma suggests that two different alleles of the same variable region gene have rearranged independently and coexist in the same hybridoma cell. The chimeric A2 antibody (cA2) exhibits better binding and neutralizing characteristics than the murine A2 which was shown to contain a mixture of two kappa light chains. The properties of cA2 suggest that it will have advantages over existing murine anti-TNF antibodies for clinical use.
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PMID:Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. 823 30

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We examined here the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c x C57BL/6) F1 that received C57BL/6 spleen cells markedly reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.
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PMID:A metalloproteinase inhibitor prevents lethal acute graft-versus-host disease in mice. 922 53

Tumor necrosis factor-alpha (TNF-alpha) is a highly pleiotropic cytokine produced mainly by activated macrophages. This cytokine has been found to mediate the growth of certain tumors, the replication of HIV-1, septic shock, cachexia, graft-versus-host disease, and autoimmune diseases. The binding of TNF-alpha to the p55 tumor necrosis factor receptor type I (TNFRI) is considered one of the initial steps responsible for the multiple physiologic effects mediated by TNF-alpha. The role of TNF-alpha as an inflammatory mediator through TNFRI makes both of these genes attractive targets for intervention in both acute and chronic inflammatory diseases. We have designed antisense oligodeoxynucleotides (ODNs) containing chemically modified purine and pyrimidine bases that specifically inhibit TNFRI expression and functions. These ODNs were designed to hybridize to the 3'-polyadenylation signal region of the TNFRI gene. In cell-based assays, gene-specific antisense inhibition occurred in a dose-dependent fashion at submicromolar concentrations in the presence of cellular uptake enhancing agents. Within ODN sets with a common pattern of stabilizing backbone substitution, the inhibition of the gene expression is found to be correlated with the affinity of the ODNs for their cognate mRNA target sites, providing direct evidence for an antisense mechanism of action. In addition, events triggered by the binding of TNF-alpha to TNFRI, such as the production of IL-6 and IL-8, were significantly reduced by treatment of cells with the anti-TNFRI ODN. Therefore, antisense ODNs can be used to control biologic processes mediated by TNF-alpha and may be useful as therapeutic agents to treat conditions resulting from overproduction of TNF-alpha.
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PMID:Sequence-specific inhibition of the tumor necrosis factor-alpha receptor I gene by oligodeoxynucleotides containing N7 modified 2'-deoxyguanosine. 936 4

TNF-alpha (Tumor necrosis factor-alpha) is involved in many immunological and inflammatory processes, and might be expected to play an important role in the development of BMT-related complications. Triple therapy (pentoxifylline, ciprofloxacin and prednisone) with known anti-TNF activity was tested in 37 patients undergoing a hematopoietic progenitor transplant (HPT). A control group of 16 patients with similar characteristics was selected among consecutive patients receiving a HTP in a neighboring center who did not receive anti-TNF prophylaxis. Major transplant-related complications were registered (VOD, acute GVHD, infectious episodes, renal failure and mucositis) and survival status. TNF plasma concentrations were determined by ELISA, and pentoxifylline plasma concentrations were determined by HPLC. Among patients treated with pentoxifylline (PTX), ciprofloxacin and steroids, no difference in the mean survival time was observed compared with the control group. The incidence of procedure-related death up to day +35 was 11% in the study group and 6% in the control group. In spite of a tendency to a lower incidence of mucositis there was a higher incidence of infections (positive blood cultures) in the study group (49%) than in the control group (16.7%) (P = 0.16). This difference achieved statistical significance in patients receiving an allogeneic HPT (P = 0.05). It is likely that the use of steroids in the early period after transplant increases infectious episodes and makes control of GVHD difficult. The combined administration of steroids with pentoxifylline and ciprofloxacin has not proved beneficial in preventing mucositis, renal failure, VOD or GVHD, or in improving patient survival.
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PMID:Pentoxifylline, ciprofloxacin and prednisone failed to prevent transplant-related toxicities in bone marrow transplant recipients and were associated with an increased incidence of infectious complications. 946 81

It is now well known that the initial phase of graft-versus-host disease (GVHD) involves cytokine release during preconditioning of the recipient of an allogeneic bone marrow transplant (BMT). Tumor necrosis factor (TNF), in particular, has been implicated in pathological damage and is released pretransplant due to irradiation and cytotoxic preconditioning regimens. Interleukin-10 (IL-10), a natural immunosuppressant of TNF, may be involved in downregulation of these responses, which may be an individual patient-specific effect. In this study, we determined the genotype for polymorphisms associated with TNF and IL-10 in 80 potential allo-BMT recipients and correlated the genotype with the severity of GVHD in 49 patients for whom clinical data relating to GVHD was available. The widely studied TNF -308 polymorphism does not show any significant associations, but the d3 homozygous allele of the TNFd microsatellite is preferentially associated with grade III/IV GVHD (7 of 11 patients) compared with its occurrence in 8 of 38 patients with grade 0/II GVHD (P =.006). Alleles of the IL-10 (-)1064 promoter region microsatellite polymorphism that possess greater numbers of dinucleotide (CA) repeats also significantly associate with more severe GVHD. This region has been demonstrated to be important in the regulation of the IL-10 promoter. Eighteen of 38 patients with grade 0-II GVHD possessed alleles with greater numbers (12 or more) of dinucleotide repeats, compared with 9 of 11 cases with grade III-IV GVHD (P <.02). Of the 38 patients with grade 0-II GVHD, 3 of 38 had a both TNFd3/d3 and IL-10 (12-15) genotype, compared with 6 of 11 patients with grade III-IV GVHD (P <.001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P =.43 and.51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokine activation during the pretransplant conditioning regimens, and these results are the first to suggest a genetic predisposition to this important transplant-related complication.
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PMID:Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. 980 88

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We have examined the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a murine acute GVHD model after bone marrow transplantation. Administration of KB-R7785 to irradiated (BALB/c x C57BL/6) F1 mice that received C57BL/6 bone marrow cells and spleen cells reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The KB-R7785 treatment did not affect hematopoietic reconstitution by donor cells. Therefore, KB-R7785 could be a potent therapeutic agent for GVHD after bone marrow transplantation.
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PMID:A metalloproteinase inhibitor prevents acute graft-versus-host disease in mice after bone marrow transplantation. 1041 17


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