Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KM2210, a conjugate of estradiol and chlorambucil (CBL), which was originally developed as an anti-breast cancer agent, inhibits proliferative response of human mononuclear cells to alloantigens in mixed lymphocyte culture in a dose-dependent manner, but has no effect on their response to phytohemagglutinin. Neither estradiol benzoate nor CBL alone showed these unique actions. The suppressive effect of KM2210 on MLC was abrogated by adding of anti-transforming growth factor-beta (TGF-beta) antibody to the culture, but was not affected by the addition of interleukin-2, suggesting that KM2210, unlike CBL, displays its actions via TGF-beta. In experimental allogeneic bone marrow transplantation using mice, daily oral administration of KM2210 (2 mg/kg/day) for 30 days posttransplant significantly inhibited the alloantigen-specific immune reactions. Furthermore, the survival rate of the KM2210-treated mice was significantly higher than that of the cyclosporine-treated (2 mg/kg/day, p.o.) mice, and no adverse effect of KM2210 on hematopoietic recovery was found. These results strongly suggest possible clinical benefits of KM2210 as a new immunosuppressive agent for the prevention and treatment of graft-versus-host disease and other allospecific immune reactions.
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PMID:The alloantigen-specific immunosuppressive activity of estradiol-chlorambucil conjugate (KM2210) and its beneficial effect on allogeneic bone marrow transplantation in mice. 138 90

Although chronic graft-versus-host disease (GVHD) remains a frequent complication of bone marrow transplantation (BMT), the pathogenesis remains unclear. We examined the potential role of cytokines in mediating chronic GVHD. Skin samples from seven patients with cutaneous chronic GVHD, six post-BMT controls and six normal controls were evaluated by reverse transcription polymerase chain reaction for the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha), Th1-associated cytokines IL-2 and interferon-gamma (IFN-gamma), Th2-associated cytokines IL-4, IL-5 and IL-10, and fibrosis-associated cytokines platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). IFN-gamma transcription was significantly more frequent in cutaneous chronic GVHD (86%) vs post-BMT and normal controls (17% (P = 0.03) and 0 (P = 0.005), respectively). IL-2 transcription was more frequent in chronic GVHD (28%) and post-BMT controls (50%) vs normal controls (17%). TNF-alpha mRNA was frequent in chronic GVHD (71%) and post-BMT controls (83%), but not significantly more than in normal controls (50%). Transcription of IL-1alpha, IL-4, IL-5 and IL-10 was infrequent in all three groups. PDGF and TGF-beta mRNA were detected in the majority of all samples. The frequent transcription of IFN-gamma in cutaneous chronic GVHD supports its potential role in mediating the associated tissue injury. While the cellular sources of these cytokines are uncertain, their expression and secretion in situ may propagate the cytotoxic cascade and perpetuate the tissue injury. Better understanding of the contribution of FN-gamma and other cytokines to the pathogenesis of chronic GVHD may allow the design of more specific and more effective therapy.
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PMID:Cytokine expression in human cutaneous chronic graft-versus-host disease. 880 19

We have previously shown that allospecific murine CD8+ T cells of the Tc1 and Tc2 phenotype could be generated in vitro, and that such functionally defined T-cell subsets mediated a graft-versus-leukemia (GVL) effect with reduced graft-versus-host disease (GVHD). To evaluate whether analogous Tc1 and Tc2 subsets might be generated in humans, CD8+ T cells were allostimulated in the presence of either interleukin-12 (IL-12) and transforming growth factor-beta (TGF-beta) (Tc1 culture) or IL-4 (Tc2 culture). Tc1-type CD8 cells secreted the type I cytokines IL-2 and interferon gamma (IFN-gamma), whereas Tc2-type cells primarily secreted the type II cytokines IL-4, IL-5, and IL-10. Both cytokine-secreting populations effectively lysed tumor targets when stimulated with anti-T-cell receptor (TCR) antibody; allospecificity of Tc1- and Tc2-mediated cytolytic function was demonstrated using bone marrow-derived stimulator cells as targets. In addition, both Tc1 and Tc2 subsets were capable of mediating cytolysis through the fas pathway. We therefore conclude that allospecific human CD8+ T cells of Tc1 and Tc2 phenotype can be generated in vitro, and that these T-cell populations may be important for the mediation and regulation of allogeneic transplantation responses.
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PMID:In vitro generation of allospecific human CD8+ T cells of Tc1 and Tc2 phenotype. 929 48

Irradiated (800 rads) AKR mice received intravenous (i.v.) reconstitution with a mixture of B10.BR T-depleted bone marrow cells and spleen cells. Only in groups of mice treated additionally with i.v. cyclophosphamide (Cy; 150 mg/kg), 24 hr before transplantation, was long-term (> 60% at 50 days) survival seen. In mice receiving only irradiation all animals died by 30 days post-transplantation. Histological changes consistent with graft-versus-host disease (GVHD) were seen in the liver of reconstituted mice at 30 days, along with an organ-specific increase in V beta 3 T-cell receptor-positive (TCR+) cells. No such increase in V beta 3 TCR+ cells was seen in the spleen from the same mice. These data are consistent with a tissue antigen-driven expansion of V beta 3 TCR+ cells associated with GVHD in the liver in this model. When we analysed cytokine production in vitro from CD3+ cells restimulated with 'host' (AKR) antigen-presenting cells (APC), we found a transition in cytokine production from preferential synthesis of type-1 cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] at early times (day 15) post-reconstitution to increased production of type-2 cytokines [IL-4, transforming growth factor-beta (TGF-beta) and IL-10] at later times (day 30) post-reconstitution in Cy-treated recipients. Animals not receiving Cy did not show this 'switch' in cytokine production at later time points. We have observed a similar polarization in cytokine production, along with increased graft survival, in recipients of vascularized and non-vascularized allografts after portal venous (p.v.), but not i.v., pretransplant donor-specific immunization. We next studied AKR mice receiving 800 rads and subsequently reconstituted with B10.BR stem cells via the p.v. route. Again these mice showed prolonged survival (> 50% at 50 days), with polarization to IL-4, IL-10 and TGF-beta on restimulation of CD3+ cells in vitro at 30 days post-transplant and increased V beta 3 TCR+ cells in the liver. Infusion of anti-IL-12 monoclonal antibodies into irradiated mice receiving i.v. cell reconstitution produced a similar pattern of changes to those seen after p.v. reconstitution, while a combination of anti-IL-10 and anti-TGF-beta monoclonal antibodies reversed the changes seen after p.v. reconstitution. These data are consistent with an important role for differential cytokine production in the regulation of GVHD following allogeneic bone marrow transplantation.
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PMID:Analysis of cytokine production and V beta T-cell receptor subsets in irradiated recipients receiving portal or peripheral venous reconstitution with allogeneic bone marrow cells, with or without additional anti-cytokine monoclonal antibodies. 961 72

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.
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PMID:Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease. 1070 95

The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level. Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-beta (TGF-beta) results in induction of tolerance, rendering alloreactive murine CD4(+) T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-beta-tolerant CD4(+) T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G(1) phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGFbeta + IL-10-tolerant cells were incapable of phosphorylating TCR-zeta, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27(kip1) cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle. These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-beta-tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo.
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PMID:Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T cells that do not induce graft-versus-host disease. 1115 38

Graft-versus-host disease (GVHD) and failure of engraftment limit clinical bone marrow transplantation (BMT) to patients with closely matched donors. Engraftment failure of purified allogeneic hematopoietic stem cells (HSCs) has been decreased in various BMT models by including donor BM-derived CD8(+)/alphabetagammadeltaTCR(-) facilitating cells (FCs) or CD8(+)/alphabetaTCR(+) T cells in the BM inoculum. To aggressively investigate the GVHD potential of these donor CD8(+) populations, a purified cell model of lethal GVHD was established in a murine semiallogeneic parent --> F(1) combination. Lethally irradiated recipients were reconstituted with purified donor HSCs alone or in combination with splenic T cells (T(SP)), BM-derived T cells (T(BM)), or the FC population. In marked contrast to the lethal GVHD present in recipients of HSCs plus T(SP) or CD8(+) T(BM), recipients of donor HSC+FC inocula did not exhibit significant clinical or histologic evidence of GVHD. Instead, HSC+FC recipients were characterized by increased splenocyte expression of transforming growth factor-beta (TGF-beta) and the induction of the regulatory T-cell genes CTLA4, GITR, and FoxP3. These findings suggest that the FCs, which express a unique FCp33-TCRbeta heterodimer in place of alphabetaTCR, permits HSC alloengraftment and prevents GVHD through the novel approach of regulatory T-cell induction in vivo.
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PMID:Absence of clinical GVHD and the in vivo induction of regulatory T cells after transplantation of facilitating cells. 1529 18

Graft-versus-host disease (GvHD) complicates many allogeneic stem cell transplants (alloSCT), and several factors are known to be associated with the development of GvHD besides human leucocyte antigen (HLA) incompatibility. We investigated whether changes in serum levels of soluble IL-2 receptor (sIL-2Ralpha), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF) and soluble Fas (sFas) correlated with the development of GvHD in patients undergoing SCT, and might thus be potentially of use to anticipate the development of GvHD, allowing early modification of immunosuppressive therapy.sIL2Ralpha and sFas levels were significantly raised in allograft, autograft (allo and auto) and non-graft groups compared to the normal controls (HC), but there was no statistical difference between the three patient groups. TNF-alpha was raised in the auto and allo groups and the non-graft patients compared to the HC group (median 4.37 pg/ml), but only reached significance in the allo group (median 6.02 pg/ml; p = 0.008) when this was compared with the non-graft patients. There was no significant difference in TGF-ss levels between any of the groups. The median serum VEGF levels were decreased in allo and auto patients compared to HC, (31 and 62 pg/ml versus 90 pg/ml, respectively), with a significant difference in the auto group (p = 0.007). VEGF levels were significantly lower in the auto versus the allo group (p = 0.008) and also in the auto versus the non-graft group (median 104 pg/ml; p = 0.011). When the allo group was divided into patients who developed GvHD and those who did not, serum VEGF levels were significantly higher in those with GvHD (p = 0.028).
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PMID:Cytokine profiles in stem cell transplantation: possible use as a predictor of graft-versus-host disease. 1601 56

Halofuginone, a low molecular weight plant alkaloid, inhibits collagen alpha1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graft-versus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-beta (TGF-beta), an important immunomodulator. The present study was undertaken to explore the effects of halofuginone on activated T cells. Peripheral blood T cells were activated by anti-CD3 monoclonal antibodies in the absence and presence of halofuginone and assessed for nuclear factor (NF)-kappaB activity, production of tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma), T cell apoptosis, chemotaxis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). A delayed-type hypersensitivity (DTH) model was applied to investigate the effect of halofuginone on T cells in vivo. Preincubation of activated peripheral blood T cells with 10-40 ng/ml halofuginone resulted in a significant dose-dependent decrease in NF-kappaB activity (80% inhibition following incubation with 40 ng halofuginone, P = 0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-alpha, IFN-gamma, interleukin (IL)-4, IL-13, and TGF-beta (P < 0.005). Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P = 0.0001 and 0.005, respectively). In contrast, T cell chemotaxis was not affected. Halofuginone inhibited DTH response in mice, indicating suppression of T cell-mediated inflammation in vivo. Halofuginone inhibits activated peripheral blood T cell functions and proinflammatory cytokine production through inhibition of NF-kappaB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.
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PMID:Halofuginone inhibits NF-kappaB and p38 MAPK in activated T cells. 1676 68

Finding effective treatments for patients with systemic sclerosis (SSc) remains one of the final frontiers in therapeutic discovery. Although remarkable progress has been made in the symptomatic treatment of various organ system manifestations, little is available that treats the underlying disease process. SSc patients do not respond to many of the medications that provide benefit in related diseases, such as systemic lupus erythematosus, polymyositis and chronic graft-versus-host disease. Current research has not even clarified whether the complex pathogenesis starts primarily in vascular, immunological or connective tissues. Herein are discussed selected emerging therapeutics and therapeutic approaches designed to target the underlying immunological and fibrotic disease processes. Distinctive fibrotic features and data from translational research consistently place transforming growth factor-beta (TGFbeta) as a central mediator in SSc. The discovery of agents targeting TGFbeta, its activation or its intracellular signaling suggest that TGFbeta pathway inhibitors efficacious for the treatment of SSc may soon be identified. IL-4 and IL-13 are other fibrotic mediators produced during immune activation that might be targeted for SSc therapy, and therapeutics targeting these interleukins are also being developed. Immune dysregulation, leading to overproduction of these or other fibrotic mediators might respond to currently available immunosuppressives: mycophenolate, cyclosporine, tacrolimus or sirolimus, alone or in combination. Nucleic acid-containing immune complexes may also contribute to toll-like receptor mediated immune dysregulation in SSc, suggesting that agents targeting the innate immune system may ameliorate SSc. Thus, the complexity of SSc pathogenesis provides a plethora of targets for urgently needed new therapies.
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PMID:Targeting fibrosis in systemic sclerosis. 1721 85


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