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)

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.
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PMID:Thalidomide for erythema nodosum leprosum and other applications. 1268 Apr 78

Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0-5 post-BMT (IL-6 and IL-8, P<0.05) and days 6-10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0-5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2-4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.
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PMID:Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation. 1276 83

LIGHT is a tumor necrosis factor (TNF) superfamily ligand that regulates T cell immune responses by signaling through the herpes virus entry mediator (HVEM) and the lymphotoxin beta receptor (LTbetaR). This review will present a summary of recent advances made regarding the immunobiology of the LIGHT-HVEM and LTbetaR systems. LIGHT has emerged as a potent initiator of T cell co-stimulation signals effecting CTL-mediated tumor rejection, allograft rejection and graft versus host disease. Constitutive expression of LIGHT leads to tissue destruction and autoimmune-like disease syndromes. In contrast to LTalphabeta, LIGHT plays a minimal role in lymphoid tissue development, yet some evidence indicates a role in negative selection in the thymus. These results provide an encouraging profile for the LIGHT-HVEM-LTbetaR axis as a potential target for controlling cellular immune reactions.
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PMID:LIGHT-HVEM signaling and the regulation of T cell-mediated immunity. 1278 66

The gastrointestinal (GI) tract is a major target in graft-versus-host disease (GvHD). In rodents both tumor necrosis factor (TNF) and Fas-dependent apoptosis have been shown to play a major role in GvHD lesions, but data in humans on TNF and Fas in situ expression are scarce. More recently, the role of non-T cells as GvHD effectors has also been suggested in experimental models. Here we report a detailed quantitative pathologic analysis in 95 patients who underwent gastroduodenal biopsy. This analysis included characterization and quantification of the cellular infiltrate, TNF, TNF receptors, and Fas in situ expression analyses and quantification of apoptotic cell numbers. TNF was expressed in all biopsies and it was highly specific for acute GvHD. In multivariate analysis, including pathologic factors only, increased early transplant-related mortality (TRM) was associated with the presence of more than 20 neutrophils per field. Factors affecting early and late TRM were then assessed by multivariate analyses including both pathologic and clinical factors. Increased day-90 TRM was associated with the presence of more than 5 apoptotic bodies per field within the cellular infiltrate, and with stage II or higher acute liver GvHD. One-year TRM associated with the same 2 factors and with chronic GvHD.
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PMID:Prognostic value of apoptotic cells and infiltrating neutrophils in graft-versus-host disease of the gastrointestinal tract in humans: TNF and Fas expression. 1288 13

Antithymocyte globulins (ATGs), the immunoglobulin G (IgG) fraction of sera from rabbits or horses immunized with human thymocytes or T-cell lines, are used in conditioning regimens for bone marrow transplantation, in the treatment of acute graft-versus-host disease, in the prevention or treatment of acute rejection in organ transplantation, and in severe bone marrow aplasia. In nonhuman primates, ATGs induce rapid, dose-dependent, T-cell depletion in peripheral lymphoid tissues, where apoptotic cells can be demonstrated in T-cell zones. We show here that increasing ATG concentrations in vitro resulted in reduced lymphocyte proliferative responses, associated with a rapid increase in the percentage of apoptotic cells. Apoptosis did not require prior exposure to interleukin-2, nor did it result in CD178/CD95 or tumor necrosis factor/tumor necrosis factor receptor (TNF/TNF-R) interactions; it was therefore clearly different from activation-induced cell death. Cytochrome c release, caspase-9, and caspase-3 activation were not implicated, excluding a direct involvement of the intrinsic mitochondrial pathway. The cysteine protease inhibitor E64d and cathepsin-B-specific inhibitors conferred significant protection, whereas apoptosis was associated with the release of active cathepsin B into the cytosol. These data demonstrate a role for cathepsin B in T-cell apoptosis induced by ATGs at concentrations achieved during clinical use.
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PMID:Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion. 1289 46

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

The identity of cells within squamous epithelia that represent primary targets in acute graft-versus-host disease (GVHD) has been an enigma. Murine effector T cells implicated in the alloresponse by Vbeta complementarity-determining region-3 spectratype analysis were detected with a Vbeta-specific monoclonal antibody within discrete microdomains of tongue (lingual) squamous epithelium. These microdomains, termed rete-like prominences (RLPs), are similar to the rete ridges of human skin. Cells forming the basal layer of RLPs and of human skin rete ridges were shown to express a distinctive pattern of keratin expression defined by antibodies to cytokeratin 15 (K15). In experimental murine GVHD elicited across minor histocompatibility antigen barriers (miHA), early lesions involved selective apoptosis and loss of K15(+) staining within lingual RLPs. An in vitro organ culture model designed to investigate target cell injury by short-term exposure to tumor necrosis factor-alpha and interleukin-1beta, mediators relevant to GVHD, showed a similar pattern of apoptosis and loss of K15(+) reactivity within RLPs. In aggregate, these findings establish a novel cytoskeletal marker for target epithelial subpopulations that should facilitate evaluation of mechanisms of host cell injury in GVHD. These data may also enable the development of therapeutic approaches to abrogate disease at the level of target cell blockade.
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PMID:An epithelial target site in experimental graft-versus-host disease and cytokine-mediated cytotoxicity is defined by cytokeratin 15 expression. 1450 58

Almost two decades ago, tumor necrosis factor (TNF) was identified as a protein produced by the immune system that played a major role in suppression of tumor cell proliferation. Extensive research since then has revealed that TNF is a major mediator of inflammation, viral replication, tumor metastasis, transplant rejection, rheumatoid arthritis, and septic shock. As of today, 18 different members of the TNF superfamily have been identified, and most of them have been found to mediate a wide variety of diseases including cancer, arthritis, bone resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft versus host disease, and acquired immune deficiency disease. All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-kappaB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. In this review, we have elucidated the signal transduction pathways used by the members of the TNF family and the effects of deletion of genes that mediate the pathways. Our current understanding of the signaling pathways for TNF and other family members could serve as a target for the development of therapeutics.
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PMID:The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. 1456 Nov 80

The pathophysiology of acute graft-versus-host disease (GVHD) is a complex process that can be conceptualized in three phases. In the first phase, high-dose chemoradiotherapy causes damage to host tissues, including a self-limited burst of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin 1. These cytokines activate host antigen-presenting cells (APCs). In the second phase, donor T-cells recognize alloantigens on host APCs. These activated T-cells then proliferate, differentiate into effector cells, and secrete cytokines, particularly interferon (IFN)-gamma. In the third phase, target cells undergo apoptosis mediated by cellular effectors (eg, donor cytotoxic T-lymphocytes) and inflammatory cytokines such as TNF-alpha. TNF-alpha secretion is amplified by stimuli such as endotoxin that leaks across damaged gastrointestinal mucosa injured by the chemoradiotherapy in the first phase. TNF-alpha and IFN-gamma cause further injury to gastrointestinal epithelium, causing more endotoxin leakage and establishing a positive inflammatory feedback loop. These events are examined in detail in the following review.
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PMID:The pathophysiology of acute graft-versus-host disease. 1460 75

The pathogenesis of acute graft-versus-host disease (aGVHD) includes tumor necrosis factor-alpha (TNFalpha) expression by macrophages and T cells. However, the temporal comparison of donor vs host cells to TNFalpha expression in response to irradiation conditioning and alloreactivity has not been reported. This study compared intracellular TNFalpha expression in donor vs host spleen T cells and macrophages using a murine model of aGVHD. Total body irradiation conditioning alone resulted in increased frequency of F4/80+/TNFalpha+ cells, but no increase in CD3+/TNFalpha+ cells. Syngeneic transplantation resulted in an increased frequency of F4/80+/TNFalpha+ cells, while CD3+/TNFalpha+ cells increased on days 1 and 3 but declined on day 5. Allogeneic transplantation resulted in an increased frequency of donor CD3+/TNFalpha+ cells, while the frequency of host CD3+/TNFalpha+ cells declined. Similarly, donor F4/80+/TNFalpha+ cells also increased in frequency after allotransplantation, while the frequency of host F4/80+/TNFalpha+ cells was increased on day 1 and declined through days 3 and 5. In absolute cell numbers, CD3+/TNFalpha+ cells were greater than F4/80+/TNFalpha+ cells post allotransplantation. We conclude that (1) both donor and host CD3+ and F4/80+cells are present in the post transplant period and contribute to TNFalpha production and (2) in terms of frequency, the majority of TNFalpha producing cells in the spleen after allogeneic BMT are CD3+.
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PMID:Expression of TNFalpha by CD3+ and F4/80+ cells following irradiation preconditioning and allogeneic spleen cell transplantation. 1467 80


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