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)

(C57BL/6 x DBA/2)F1-hybrid mice injected with lymphoid cells from wild-type, C57BL/6 donors develop acute, lethal graft-versus-host disease (GVHD) in which the intestine is a major target. In its destructive phase intestinal GVHD is characterized by apoptosis of intestinal crypt epithelial cells and the development of endotoxaemia. Injection of as little as 10 microg endotoxin is lethal in mice with acute GVHD, and associated with the release of large amounts of tumour necrosis factor-alpha (TNF-alpha) into the serum. To explore the role of interferon-gamma (IFN-gamma) in the pathogenesis of intestinal GVHD we used IFN-gamma gene knockout (gko) mice as donors. Recipients of grafts from these donors did not develop intestinal GVHD and, unlike recipients of wild-type grafts, did not die when injected with lipopolysaccharide (LPS). We also found that injection 10 microg LPS into recipients of wild-type grafts induced apoptosis of intestinal epithelial crypt cells and was associated with a burst of nitric oxide production in the intestine. Administration of N(omega)nitro L-arginine methyl ester blocked this response. In contrast, LPS did not induce either intestinal epithelial cell apoptosis or increased nitric oxide production in recipients of IFN-gamma gko grafts. These findings indicate that donor-derived IFN-gamma is instrumental for the development of intestinal GVHD. In a previous study we showed that recipients of IFN-gamma gko grafts develop high levels of LPS-induced TNF-alpha release. When our current data are viewed in the context of this observation, they suggest that intestinal epithelial cell apoptosis in the parent-->F1-hybrid model of acute GVHD is mediated primarily by nitric oxide rather than TNF-alpha, and that this depends on donor-derived IFN-gamma.
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PMID:The role of interferon-gamma, nitric oxide and lipopolysaccharide in intestinal graft-versus-host disease developing in F1-hybrid mice. 1280 91

Graft-versus-host disease (GVHD) represents one of the major complications of allogeneic hematopoietic stem cell transplantation. Techniques to prevent GVHD have included ex vivo T-cell depletion of the graft or prolonged in vivo immunosuppression. Both reduce the frequency and severity of GVHD but also reduce T-cell-mediated graft-versus-malignancy effect, and increase the risk of infection. A major goal in transplantation is to prevent alloreactivity while preserving activity against tumors and infectious agents. We have used activation of the Notch pathway to try to generate T cells able to specifically regulate alloantigen responses. We used allogeneic Epstein-Barr virus lymphoblastoid B cells (EBV-LCLs) as stimulator cells. Such LCLs are excellent (allo) antigen-presenting cells and can be obtained in large numbers even from donors who have received extensive chemo/radiotherapy. We overexpressed a Notch ligand, Jagged-1, in these cells by adenoviral vector transduction. Stimulation of CD45RA+ naive T cells by Jagged-1 EBV-LCL reduces production of interferon-gamma, interleukin-2, and interleukin-5, but up-regulates transforming growth factor-beta 1 synthesis, consistent with induction of a regulatory T-cell phenotype. Transfer of these T cells to fresh lymphocyte cultures inhibits proliferative and cytotoxic immune responses to the priming alloantigens while sparing responses to third-party stimulator cells. Notch activation in the presence of alloantigen-presenting cells may therefore be a means of inducing specific regulatory T cells while preserving other T-cell functionality.
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PMID:Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells. 1284 95

Adoptive T-cell therapy using CD3/CD28 co-stimulation likely requires in vivo generation of antigen specificity. Because CD28 promotes TH1/TC1 (T1) or TH2/TC2 (T2) differentiation, costimulation may generate donor T1 or T2 cells capable of differentially mediating allogeneic graft-versus-tumor (GVT) effects and graft-versus-host disease (GVHD). Costimulation under T1 or T2 conditions indeed generated murine TH1/TC1 cells secreting interleukin-2/interferon-gamma (IL-2/IFN-gamma) or TH2/TC2 cells secreting IL-4/IL-5/IL-10. In vivo, allogeneic T1 cells expanded, maintained T1 secretion, and acquired allospecificity involving IFN-gamma and IL-5. In contrast, allogeneic T2 cells expanded less and maintained T2 secretion but did not develop significant allospecificity.Allogeneic, but not syngeneic, T1 cells mediated a GVT effect against host-type breast cancer cells, as median survival time (MST) increased from 25.6 +/- 2.6 (tumor controls) to 69.2 +/- 5.9 days (P < 1.2 x 10(-9)). This T1-associated GVT effect operated independently of fasL because T1 cells from gld mice mediated tumor-free survival. In contrast, allogeneic T2 cells mediated a modest, noncurative GVT effect (MST, 29 +/- 1.3 days; P <.0019). T1 recipients had moderate GVHD (histologic score, 4 of 12) that contributed to lethality after bone marrow transplantation; in contrast, T2 recipients had minimal GVHD (histologic score, 1 of 12). CD3/CD28 co-stimulation, therefore, generates T1 or T2 populations with differential in vivo capacity for expansion to alloantigen, resulting in differential GVT effects and GVHD.
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PMID:CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effects. 1285 80

Acute and chronic graft-versus-host disease (GvHD) remain major obstacles to successful allogeneic hematopoietic stem cell transplantation, contributing substantially to morbidity and non-relapse mortality. Better understanding of the immunopathophysiology of GvHD has identified a number of targets for intervention. Among newly developed agents suitable for the prevention and treatment of GvHD, monoclonal antibodies hold much promise. Monoclonal antibodies currently available, such as infliximab and anti-interferon-gamma (anti-IFN-gamma), are capable of blocking of the action of initiating and effector cytokines. Antibodies directed against activated T cells, including daclizumab, visilizumab and ABX-CBL, may offer more specificity than the more broadly acting pan-T-cell-depleting agents. Finally, the clinical investigation of antibodies to adhesion molecules (such as LFA-1), or distal effector mechanisms (such as FasL) may offer another level of specificity. Many of these monoclonal antibodies have already undergone clinical testing. Campath-1H has been used for the prevention of acute GvHD with success. Daclizumab, infliximab, visilizumab, and ABX-CBL have shown promising activity in steroid-resistant acute GvHD in early clinical testing. This review summarizes current experience with monoclonal antibodies in the management of acute and chronic GvHD. Over the next decade, however, the challenge will be to define the relative place of these antibodies in the therapeutic armamentarium for GvHD and their impact on long-term survival.
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PMID:Monoclonal antibodies for the prevention and treatment of graft-versus-host disease. 1293 20

The cellular and molecular mechanisms underlying the blunted allo-responsiveness of umbilical cord blood (UCB) T cells have not been fully elucidated. Protein expression of NFATc2 (nuclear factor of activated T cells c2), a critical transcription factor necessary for up-regulation of multiple cytokines known to amplify T-cell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purified CD4+ UCB T cells to adult peripheral blood CD4+ T cells (AB) at baseline, 6, and 16 hours of primary stimulation. NFAT-regulated genes exhibited lower expression in UCB CD4+ T cells including the following: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor alpha (IL-2Ralpha; CD25), CD40L, and macrophage inflammatory protein 1 alpha (MIP-1alpha). Transcription factors involved in the NFAT pathway including C/EBPbeta, JunB, and Fosl1 (Fra-1), as well as Th1- and Th2-related transcription factors STAT4 (signal transducers and activators of transcription 4), T-bet, and c-maf showed reduced expression in UCB compared with AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data were confirmed using RNase protection assays, flow cytometry, and quantitative multiplexed cytokine measurements. Reduced global expression of NFAT-associated genes, as well as cytokines and chemokines, in UCB CD4+ T cells may contribute to the decreased graft-versus-host disease (GVHD) observed after UCB transplantation.
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PMID:Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation. 1294 96

Murine mixed hematopoietic chimerism can be achieved following nonmyeloablative conditioning with cyclophosphamide, T cell-depleting monoclonal antibodies, and thymic irradiation. Donor lymphocyte infusions (DLIs) 35 days after bone marrow transplantation (BMT) convert mixed to full donor chimerism and mediate graft-versus-lymphoma effects without graft-versus-host disease. We evaluated the role of T-cell subsets in DLIs in converting mixed to full donor chimerism in a fully major histocompatibility complex-mismatched strain combination. Whereas DLIs administered on day 35 converted 100% of mixed chimeras to full donor chimerism, conversion was less frequent when either CD4 or CD8 cells were depleted, indicating that both subsets contribute to the conversion. Surprisingly, administration of CD8-depleted DLIs led to complete loss of donor chimerism in a high proportion (54%) of recipients compared with CD4-plus CD8-depleted DLIs (15%) or CD4-depleted DLIs (0%) (P <.05). DLIs administered at early time points after BMT (eg, day 21) also precipitated rejection of donor marrow by recipient alphabeta T cells, in association with donor CD4 cell expansion and high production of interleukin 2 (IL-2), IL-4, and interferon-gamma. Thus, DLIs can paradoxically induce marrow rejection by residual host alphabeta T cells. These results have implications for the timing of and use of subset depletion of DLIs in recipients of nonmyeloablative transplants.
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PMID:Graft-versus-host-reactive donor CD4 cells can induce T cell-mediated rejection of the donor marrow in mixed allogeneic chimeras prepared with nonmyeloablative conditioning. 1451 13

We studied whether the induction of autologous graft-versus-host disease (GVHD) has an antileukemic effect and consequently increases the survival of patients undergoing autologous peripheral blood stem cell transplantation (PBSCT). In all, 22 acute myeloid leukemia patients with favorable and intermediate cytogenetic risk, in their first complete remission, were administered cyclosporine c.i.v. from day 0 to day +28 at a dose of 3.0 mg/kg per day and interferon-gamma (IFN-gamma) at 0.025 mg/m(2) s.c. every other day from day +14 to day +42 following autologous PBSCT. Natural-killer (NK)-cell activity assays and skin biopsies were performed. Successful engraftment was achieved in all patients at a median of 13 days without significant additional toxicity. Histologically confirmed cutaneous GVHD developed in 12 patients, and NK-cell activity was significantly augmented after autologous PBSCT in those patients (P=0.03). After a median follow-up duration of 37.7 months (range, 7.3-72.8), the 3-year disease-free survival (DFS) and overall survival (OS) rates were 64.4 and 73.1%, respectively, without significant correlation with GVHD status or augmentation of NK-cell activity. These data suggest that the administration of cyclosporine and IFN-gamma following autologous PBSCT improves OS and DFS, which may be attributable to the antileukemic effect, although no difference in survival could be demonstrated between cutaneous GVHD-positive and -negative groups.
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PMID:Autologous peripheral blood stem cell transplantation with induction of autologous graft-versus-host disease in acute myeloid leukemia. 1456 89

Graft versus host disease is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Galectin-1, a mammalian lectin that modulates T cell function and apoptosis, has been shown to be immunomodulatory in animal models of autoimmune disease. We investigated the efficacy of galectin-1 in a murine model of graft versus host disease and found that 68% of galectin-1-treated mice survived, compared to 3% of vehicle-treated mice. Galectin-1-treated animals also had reduced inflammatory infiltrates in tissues compared to animals treated with vehicle alone. Galectin-1 did not affect engraftment of donor hematopoietic cells. However, galectin-1-treated animals demonstrated increased cellularity in bone marrow and spleen with increased numbers of splenic B cells and CD4 T cells compared to those animals treated with vehicle alone. Galectin-1 treatment also significantly improved reconstitution of normal splenic architecture following transplant. Production of type I cytokines interleukin-2 (IL-2) and interferon-gamma was reduced in splenocytes derived from galectin-1-treated transplanted mice when compared to animals treated with vehicle alone, while production of the type II cytokines, IL-4 and IL-10, was similar between the two groups of animals. Although splenocytes from galectin-1-treated transplanted animals responded to both third party antigens and leukemic challenge, host alloreactivity was significantly reduced when compared to cells from vehicle-treated animals. These results demonstrate that galectin-1 therapy is capable of increasing survival and suppressing the graft versus host immune response without compromising engraftment or immune reconstitution following allogeneic hematopoietic stem cell transplant.
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PMID:Amelioration of graft versus host disease by galectin-1. 1469 44

CD40 signaling has been implicated in various pathogenic processes such as chronic inflammatory disease, graft-versus-host disease, autoimmune disease and cancer. We previously demonstrated in an in vitro system that the CD40/CD40L pathway mediates late interleukin (IL) 12 production in response to Cryptococcus neoformans. The purpose of this study was to examine the course of C. neoformans infection in the absence of CD40/CD40L costimulation. We compared infection in mice genetically lacking CD40L (CD40L(-/-)) and in the wild-type counterpart. The animals were injected intratracheally with C. neoformans and monitored for clearance of the organism and the development of cellular immune response. CD40L(-/-) mice exhibited an exacerbation of infection, evaluated as scarce inflammatory response in the lung, that mirrored an increase of fungal burden. This correlated with impairment of nitrite production and antimicrobial activity by macrophages against C. neoformans and unrelated microorganisms such as Candida albicans. Moreover, IL-12 production by splenic macrophages was diminished in CD40L(-/-) mice and interferon-gamma production by CD4 and CD8 T cells was decreased. CD4 T cells retained the ability to express a costimulatory molecule, CTLA-4, but showed a decrease in CD28 expression. This latter molecule is implicated in a positive effect on proliferation, cytokine production and survival of T cells. Collectively these data demonstrate that absence of CD40L correlates with (i) reduced antimicrobial activity of natural effector cells; (ii) reduction of the magnitude of T cell response; and (iii) increase of fungal growth in the brain. These findings suggest that disruption of CD40/CD40L may be deleterious for development of an efficient immune response to C. neoformans and may identify potential molecular targets for novel immunotherapeutic approaches
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PMID:Disruption of CD40/CD40L interaction influences the course of Cryptococcus neoformans infection. 1473 88

Umbilical cord blood transplants are associated with a lower incidence of graft-versus-host disease (GVHD) than adult marrow or peripheral blood stem cell transplants, and this could be related to a difference in cytokine production between fetal and adult mononuclear cells after allogeneic stimulation. Mixed lymphocyte reactions (MLRs) involving adult cells were associated with greater interferon-gamma (IFNgamma) secretion than MLRs between cord blood cells, although IL-2 secretion was similar. Experiments in which T cells were separated from accessory cells then recombined in artificial combinations indicated that differences in T cells were primarily responsible for the greater [IFNgamma]:[IL-2] ratios generally found after MLRs involving adult cells compared to fetal cells, but accessory cells also influenced this ratio. The cellular basis for the observed difference was not established, but mononuclear cell preparations from cord blood contained significantly higher proportions of CD16(+)56(-) NK-type cells and a CD19(+)1c(+) B cell subset, as well as more CD45 RA-expressing nai;ve T cells.
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PMID:Comparison of adult and fetal cytokine secretion during mixed lymphocyte reactions. 1475 70


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