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)

The liver is a major target organ of graft-versus-host disease. We have induced graded intensities of acute GVHD to minor histocompatibility antigens in a well-characterized murine bone marrow transplant model and analyzed hepatic pathology one month after BMT. Nuclear-magnetic-resonance relaxation times and proton spectra were compared to systemic clinical disease, serum biochemistries, and histologic findings. T2 relaxation times correlated directly with the intensity of histologic abnormalities, but the hepatic histology remained mild even in animals with moderate GVHD. In contrast, NMR proton spectra of hepatic tissue showed large decreases in metabolite levels (acetate and glycogen) in animals with moderate systemic disease despite mild hepatic histology. We conclude that NMR of the liver can be used to differentiate hepatic from systemic GVHD in this model and may help to elucidate the differential effects of GVHD in various target organs.
 ...
PMID:Nuclear magnetic resonance of hepatic graft-versus-host disease in mice. 225 43

The present studies dealt with the pathogenesis of renal involvement in murine chronic graft-versus-host disease, which is a model for human systemic lupus erythematosus. The disease was induced in (C57BL10xDBA/2)F1 hybrids by injection of DBA/2 lymphocytes. The animals developed systemic disease accompanied by deposition of autoantibodies in the glomeruli and a lupus type of nephritis. Antibodies were eluted from glomeruli isolated during various stages of the disease by magnetic extraction from iron-perfused kidneys. For assessment of the specificity of the antibodies, we used indirect immunofluorescence, an enzyme-linked immunosorbent assay, and immunoblotting. In glomeruli from week 4, autoantibodies were found to be directed against several antigens, among which were the glomerular basement membrane component laminin and the glomerular enzyme dipeptidyl peptidase IV, whereas week 8 glomeruli also showed antibodies directed against nuclear antigens. Both laminin and dipeptidyl peptidase IV are known nephritogenic antigens occurring in renal tubular epithelial brush border preparations. Antibodies eluted from isolated glomeruli of diseased animals bound in a granular pattern along the glomerular capillary wall after in vivo transfer. Anti-renal tubular epithelial antibodies in the sera of diseased animals were affinity purified and injected into naive mice, which induced immune complex glomerulonephritis and proteinuria, thus confirming the nephritogenic role of these autoantibodies in this model.
 ...
PMID:Characterization and in vivo transfer of nephritogenic autoantibodies directed against dipeptidyl peptidase IV and laminin in experimental lupus nephritis. 239 30

Adoptive immunotherapy with donor leukocytes has emerged as a promising strategy for the treatment of myeloma recurrence after allogeneic transplantation. 2.9 x 10(8)/kg donor mononuclear cells containing 1.4% CD34+ and 37% CD3+ cells were administered to a 48-year-old patient with non-secretory plasmablastic myeloma relapsing 9 months after a blood stem cell transplant from his HLA-identical sibling. In view of the extensive marrow infiltration and the aggressive behaviour of the disease, the donor cells were preceded by a course of EDAP chemotherapy. There was rapid clinical improvement, and CR was achieved on day 30 post infusion. However, three subcutaneous plasmacytomas showing anaplastic features developed within a few days. These failed to respond to interferon-alpha and continued to grow for 5 weeks in the absence of marrow plasmacytosis or other evidence of systemic disease. Grade 3 acute liver GVHD developed on day 79 which was controlled with immunosuppression. Overt systemic relapse occurred on day 90 as the GVHD came under control. The course of our case suggests highly proliferative malignant cells may escape the graft-versus-tumour effect of immunocompetent allogeneic cells in extramedullary sites subsequently resulting in overt systemic relapse if left untreated. New approaches are needed to deal with the problem of extramedullary disease recurrence.
 ...
PMID:Graft-versus-myeloma after donor leukocyte infusion: maintenance of marrow remission but extramedullary relapse with plasmacytomas. 964 83

Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT), limits the application of this curative but toxic therapy. Studies of inflammatory pathways involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the "cytokine storm" characteristic of acute GVHD. Experimental approaches to the prevention of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel "cytokine shields" such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while preserving a graft-versus-leukemia effect in animal models, and they now deserve formal testing in carefully designed clinical trials. (Blood. 2000;95:2754-2759)
 ...
PMID:The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. 1077 17

The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-y) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.
 ...
PMID:Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. 1089 51

Allogeneic haematopoietic stem cell transplantation remains the treatment of choice for a number of malignancies. However, graft-versus-host disease (GVHD) has long been regarded as a serious complication of this procedure. Although GVHD may affect any organ, intestinal GVHD is particularly important because of its frequency, severity and impact on the general condition of the patient. Recent studies have led to progressive elucidation of the mechanism of GVHD. Donor T cells are critical for the induction of GVHD, because depletion of T cells from bone marrow grafts effectively prevents GVHD but also results in an increase of leukaemia relapse. It has been shown that the gastrointestinal tract plays a major role in the amplification of systemic disease because gastrointestinal damage increases the translocation of endotoxins, which promotes further inflammation and additional gastrointestinal damage. Consequently, the management of intestinal GVHD (and the intestine itself) is a subject that should be highlighted. In this article, approaches to the prevention of intestinal GVHD are discussed after being classified into three categories: regimens in common clinical use, regimens under investigation and original regimens used at our hospital. The standard regimen that is used most widely for prevention of GVHD is cyclosporin plus short-term methotrexate. Corticosteroids can be added to this regimen but careful consideration of the adverse effects of these hormones should be considered. Tacrolimus is a newer, more potent alternative to cyclosporin. T-cell depletion (TCD) after transplantation has been shown to prevent acute GVHD, however, the survival benefit of TCD has not been as great as expected. Mycophenolate mofetil can be useful for the treatment of acute GVHD as part of combination therapy. Regimens currently under investigation in animal experiments include suppression of inflammatory cytokines and inhibition of T-cell activation, and, specifically at our institution, hepatocyte growth factor gene therapy. The evidence-based therapy used at our institution includes systemic antibacterial therapy (including eradication of intestinal bacteria) to prevent the intestinal translocation of lipopolysaccharide and avoid the subsequent increase of various inflammatory cytokines. In addition, because of the similarities between intestinal GVHD and ulcerative colitis, sulfasalazine, betamethasone enemas and eicosapentaenoic acid have been used to treat intestinal GVHD in some patients.
 ...
PMID:Intestinal graft-versus-host disease: mechanisms and management. 1248 19

Posttransplantation lymphoproliferative disease (PTLD) presenting as an Epstein-Barr-virus (EBV)-related nasal plasmacytoma developed in a renal-allograft recipient 13 years after transplantation. Systemic dissemination occurred despite immunosuppression withdrawal, surgery, irradiation, and chemotherapy. A nonmyeloablative hematopoietic-stem-cell-transplantation (HSCT) with peripheral blood HSC from the kidney donor was performed. With the onset of graft-versus-host disease, resolution of the systemic disease was demonstrated clinically and molecularly by serial quantification of plasma EBV-DNA. Isolated relapse occurred in the central nervous system (CNS), a known tumour sanctuary site, ultimately leading to death. Nonmyeloablative HSCT might be considered a cellular therapy for PTLD, but possible CNS relapse must be effectively tackled.
 ...
PMID:Treatment of postrenal transplantation lymphoproliferative disease manifesting as plasmacytoma with nonmyeloablative hematopoietic stem cell transplantation from the same kidney donor. 1463 12

Search for an etiology of bronchiectasis consists in identifying constitutional or acquired defense mechanisms of the respiratory mucosa. The question is timely because causes change. In developing countries, presumed sequelae of infection account for about 30% of the cases despite vaccination campaigns, control of endemic tuberculosis, and widespread use of antibiotics. Genetic diseases account for 20% of the causes when identified by high-performance prospective diagnostic tests (CFTR mutation). Computed tomography enables the identification of frequent associations between bronchiectasis and rheumatoid disease or ulcerative colitis. Recent diseases such as HIV infection or GVHD can also lead to bronchiectasis. Nevertheless, the cause remains unknown in 30-50% of patients. After a detailed analysis of the clinical presentation and diagnostic criteria specific for each etiology, we propose a two-phase diagnostic procedure. The first step, used for all patients (careful history taking, physical examination, imaging, bronchofibroscopy, limited blood tests) enables detecting localized bronchial obstacles and obvious etiologies (situs inversus of primary ciliary dyskinesia, known systemic disease, HIV...). If the first step is negative, the second phase is oriented by the clinical context. Sequelae of infection (tuberculosis...) in older subjects or migrants, a genetic cause in younger subjects, particularly if there is a familial history and/or infertility, a systemic disease or allergic bronchopulmonary aspergillosis if there is an extra-respiratory context. This etiological search should help improve patient management and provide a better prognosis and prevention of bronchiectasis.
 ...
PMID:[Etiological work-up for bronchectasia in adults]. 1568 8

Recent reports suggest that bone marrow might serve as a source of skin progenitor cells. Graft-versus-host disease (GVHD) is a systemic disease that involves the skin, the liver, and the gastrointestinal tract, and contributes to transplant-related morbidity and mortality. To evaluate whether donor-derived bone marrow cells participated in its pathophysiology, we correlated the severity of GVHD in skin from sex-mismatched recipients with the percentage of donor-derived keratinocytes using fluorescence in situ hybridization (FISH) for detecting the Y chromosome. Y-positive signals were observed in female epidermis in both keratinocytes and lymphocytes. These results support the notion that donor-derived hematopoietic stem cells may contain pluripotent stem cells. Furthermore, there was a strong correlation between the frequency of Y-positive keratinocytes and the histopathologic grade of GVHD (p = 0.004), as well as with the number of Y-positive lymphocytes infiltrating the epidermis (p = 0.005), suggesting a role for donor-derived keratinocytes in the pathophysiology of GVHD. However, no clusters of Y-positive keratinocytes were found in the epidermis, and no correlation was observed between the number of Y-positive keratinocytes and time course of GVHD after transplantation. We hypothesize that donor-derived stem cells may play a role in the regeneration of damaged keratinocytes in GVHD.
 ...
PMID:Correlation of donor-derived keratinocytes and severity of graft-versus-host disease (GVHD) in epidermis. 1579 20

To explore the interactions between regulatory T cells and pathogenic effector cytokines, we have developed a model of a T cell-mediated systemic autoimmune disorder resembling graft-versus-host disease. The cytokine responsible for tissue inflammation in this disorder is interleukin (IL)-17, whereas interferon (IFN)-gamma produced by Th1 cells has a protective effect in this setting. Because of the interest in potential therapeutic approaches utilizing transfer of regulatory T cells and inhibition of the IL-2 pathway, we have explored the roles of these in the systemic disease. We demonstrate that the production of IL-17 and tissue infiltration by IL-17-producing cells occur and are even enhanced in the absence of IL-2. Regulatory T cells favor IL-17 production but prevent the disease when administered early in the course by suppressing expansion of T cells. Thus, the pathogenic or protective effects of cytokines and the therapeutic capacity of regulatory T cells are crucially dependent on the timing and the nature of the disease.
 ...
PMID:Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. 1713 Mar


1 2 Next >>