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 interleukin 1 (IL-1) gene family includes three members (IL-1-alpha, IL-1-beta and IL-1Ra) that mediate immune and inflammatory responses through two specific cell surface receptors. Cytosine to thymine transitions at codons -889 and -511 in the IL-1-alpha and IL-1-beta genes, respectively, and an 86-base pair repeat in the IL-1Ra are believed to influence gene transcription. We have genotyped these three polymorphisms in 90 donor/recipient pairs undergoing unrelated donor bone marrow transplantation (BMT) at the University of Minnesota. We found no association between the occurrence of acute GVHD and donor and/or recipient polymorphisms of any of the three IL-1 genes. The presence of at least one IL-1alpha- 889 T allele in the donor was associated with significantly improved survival in univariate analysis (survival at 1 year 40% C/C donor, 68% T/C donor, 75% T/T donor, P < 0.01). Multiple regression analysis showed that if the donor and recipient each possessed the IL-1alpha T allele there was significantly improved survival [relative risk (RR) 0.2, P < 0.01] and decreased treatment-related mortality (TRM; RR 0.2, P = 0.01). The presence of the IL-1beta T allele in donor and recipient was also associated with improved survival (RR 0.2, P < 0.01) and decreased TRM (RR 0.1, P < 0.01). These data suggest that donor polymorphism in IL-1alpha and IL-1beta might influence survival after unrelated donor BMT, but does not alter risk of GVHD.
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PMID:Interleukin-1 genotype and outcome of unrelated donor bone marrow transplantation. 1275 1

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The immunobiology of acute GVHD is complex and can be conceptualized to be a three-step process. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines TNF-alpha and IL-1. As a consequence expression of MHC antigens and adhesion molecules is increased, thus enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T-cell interaction with host APCs and subsequent proliferation, differentiation, and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses, and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host.
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PMID:Immunobiology of acute graft-versus-host disease. 1455 73

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

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The pathophysiology of acute GVHD is complex and can be conceptualized to be a three-step process based on murine studies. In step 1, the conditioning regimen leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines. As a consequence, the expression of MHC antigens and adhesion molecules is increased enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T cell interaction with host APCs and subsequent proliferation, differentiation and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host. The following review discusses the three-step process of the pathophysiology of experimental acute GVHD.
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PMID:Pathophysiology of acute graft-versus-host disease. 1473 53

Analysis of non-histocompatibility leucocyte antigen (HLA) functional genomics, together with conventional risk factors in haematopoietic stem cell transplantation (HSCT) can lead to predicting outcome in HLA-matched sibling transplant recipients. Polymorphisms of cytokine genes including tumour necrosis factor alpha, interleukin-10, interferon gamma and interleukin (IL)-6, associate with more severe acute graft-versus-host disease (aGvHD). Donor genotype for IL-1 receptor antagonist (IL-1Ra) has been associated with reduced aGvHD severity. Other genotypes (patient IL-1Ra, IL-6 and donor IL-1 alpha) have been associated with chronic GvHD, or overall survival (Vitamin D receptor and oestrogen receptor). Polymorphisms within genes associated with host defence/inflammatory responses (mannose binding lectin genes, myeloperoxidase genes and the FC gamma receptors) have been associated with infections. Polymorphisms of pharmacogenes, such as methylenetetrahydrofolate-reductase, have been associated with aGvHD and other post-transplant complications. The NOD2 gene polymorphism, associated with Crohn's disease, has been shown to be associated with risk of gut GvHD. The majority of the studies have been carried out in single centre HLA-matched sibling cohorts and in relatively few matched unrelated donor transplants. This review gives an overall perspective of the current field of non-HLA genetics with regard to HSCT outcome, clinical relevance and potential application of the results to clinical management of HSCT.
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PMID:Genetic polymorphisms predicting the outcome of bone marrow transplants. 1556 51

Blood uric acid levels and purine metabolism are affected in many ways after bone marrow transplantation (BMT). Although BMT is usually performed when patients have a low residual disease burden, a proportion of them are still at risk of tumor lysis syndrome, even with limited disease or after nonmyeloablative conditioning regimens; moreover, an alteration in uric acid turnover can also be observed in patients with persistently normal uric acid blood levels. Apart from this obvious complication, multiple physiopathological events occurring after transplantation may derange uric acid homeostasis. Although there is only indirect evidence (derived from obstetric eclampsia and experimental gout arthritis), a transplant-related increase in cytokine production (particularly TNF, IL-1 and IL-6) may activate xanthine oxidase which, in turn, may be responsible for a further cytokine bout: deranged cytokine homeostasis is involved in the pathogenesis of some of the main acute post-BMT complications, such as hepatic veno-occlusive disease (VOD) and acute graft-versus-host disease (aGVHD). Hyperuricemia is also a well-known side effect of cyclosporine A, the reference drug for the prevention of post-BMT GVHD, which may affect uric acid turnover by reducing glomerular filtration and/or affecting tubular handling; the available evidence favors the former explanation. Hyperuricemia is found in long-term transplanted patients as part of a metabolic pattern reminiscent of the so-called 'X' or 'metabolic'syndrome related to insulin resistance: there is still no precise interpretation of this post-transplant complication nor any definite data concerning its real incidence and outcome. Hyperuricemia is frequently regarded as a marginal finding in the context of X syndrome, but it is pathogenetically linked to the other component of the syndrome and has proved to be autonomously responsible for tissue and vessel damage. Finally, BMT is a possible therapeutic strategy for some inherited forms of hyperuricemia, particularly Lesch- Nyhan disease, although there is still some perplexity concerning the possibility of preventing the development of neurological impairment.
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PMID:Hyperuricemia and bone marrow transplantation. 1560 10

Extracorporeal photopheresis (ECP) has been successfully used to treat some inflammatory conditions. Following ECP, lymphocytes become apoptotic and untreated monocytes, exposed to post-ECP lymphocytes, reduce proinflammatory cytokine secretion. This study attempted to establish if this monocyte immunosuppression was linked to phosphatidylserine externalization (detected using Annexin V) on the apoptotic lymphocytes. Using density gradient and magnetic separation, lymphocytes were isolated from three cutaneous T-cell lymphoma and nine chronic graft versus host disease (cGvHD) patients pre-ECP and prior to re-infusion (post-ECP). The collected lymphocytes were cultured overnight and Annexin V levels determined. Peripheral blood was taken from the same patient 20 h later and the monocytes were isolated. The 'fresh' monocytes were introduced to each 20 h pre- and post-ECP lymphocyte culture, stimulated with lipopolysaccharide (LPS) and Brefeldin A and subsequently tested for intracellular tumour necrosis factor alpha, interleukin 1 alpha (IL1alpha), IL1beta, IL6 and IL8. For cGvHD patients, the relative levels of IL1alpha and IL6 were reduced in the untreated, LPS-stimulated monocytes exposed to post-ECP lymphocytes. However, the down-regulation of IL1alpha and IL6 did not correlate to levels of Annexin V-positive lymphocytes. ECP-treated lymphocytes can reduce the ability of LPS-stimulated monocytes to produce some proinflammatory cytokines; however, this effect is not dependent on phosphatidylserine externalization.
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PMID:The down-regulation of IL1alpha and IL6, in monocytes exposed to extracorporeal photopheresis (ECP)-treated lymphocytes, is not dependent on lymphocyte phosphatidylserine externalization. 1657 48

Several autoimmune diseases are thought to be mediated in part by interleukin (IL)-18. Many are those with associated increased interferon-gamma (IFNgamma) levels such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, and graft-versus-host disease. In addition, ischemia, including acute renal failure in human beings, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft-versus-host disease, and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. IL-18 is a member of the IL-1 family; IL-1beta and IL-18 are related closely, and both require the intracellular cysteine protease caspase-1 for biological activity. The IL-18 binding protein, a naturally occurring and specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of caspase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors, and anti-IL-18 receptor monoclonal antibodies.
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PMID:Interleukin-18 and the pathogenesis of inflammatory diseases. 1733 92

The wider use of allogeneic stem cell transplantation (allo-SCT) is still limited by the immunologic recognition and destruction of host tissues, termed graft-versus-host disease (GVHD). The role of inflammatory cytokines such as TNF-alpha and IL-1, and their impact on immune effectors (mainly CD4+ and CD8+ T) cells has been extensively studied in the context of GVHD occurring after standard myeloablative allo-SCT. However, recent data suggested that GVHD pathophysiology is likely to involve more complex interactions where antigen-presenting cells, especially dendritic cells (DCs), may play a major role at time of initiation of acute GVHD. In addition, the wider use of reduced intensity and less toxic conditioning (RIC) regimens prior to allo-SCT would allow better visualization of the fine functions of immune effectors, thereby offering a window of opportunities to better decipher the intimate pathophysiological mechanisms underlying GVHD. The aim of this work is to review the available research evidence on the role of DCs as in vivo regulators of alloimmune reactivity, and their interactions with other immune effectors.
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PMID:Inflammatory cytokines and dendritic cells in acute graft-versus-host disease after allogeneic stem cell transplantation. 1808 60

A murine model for acute lethal graft vs. host disease (GVHD) was used to study the role that a number of cytokines play in the development of lethal GVHD. In this study we focused on the role of IL-1, IL-2, IL-4, IL-6, IFN-gamma and TNF-alpha. Lethally irradiated (C57BL x CBA)F1 mice were reconstituted either with 10(7) allogeneic BALB/c spleen cells or with a similar number of syngeneic cells, as a control. A significant rise in serum levels of IL-6, TNF-alpha and IFN-gamma levels was found in allogeneically reconstituted mice. This is in contrast to the syngeneic control group in which no rise was seen. Serum IL-2 and IL-4 levels were below the detection limit. In the supernatant of Con A stimulated spleen cells from allogeneically reconstituted mice IL-6, IFN-gamma and TNF-alpha concentrations were increased. The expression of mRNA for cytokines as detected by reverse transcription PCR was studied in spleen cells. In the allogeneic reconstituted mice the mRNA expression of IL-1alpha, IL-2, IL-6, IFN-gamma and TNF-alpha displayed faster kinetics compared with that in syngeneic reconstituted mice. The effect of treatment with recombinant cytokines, antibodies to cytokines and to cytokine receptors on the development of GVHD was investigated. Administration of recombinant IL-2 to allogeneically reconstituted mice strongly increased the morbidity and mortality whereas injection of IL-1alpha and TNF-alpha did not influence survival. Administration of antibodies against IL-2 or the IL-2 receptor decreased the morbidity and mortality. Anti-IL-6, anti-IFN-gamma, and anti-TNF-alpha mAB, on the other hand, did not affect the morbidity and mortality of GVHD. The results of this study suggest successive waves of cytokine-secreting cell populations consistent with the induction of an inflammatory response in the development of acute GVH disease.
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PMID:Cytokine Detection and Modulation in Acute Graft vs. Host Disease in Mice. 1847 21


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