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)

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

Graft-versus-host disease (GVHD) is a serious complication following allogeneic bone marrow transplantation (BMT). Initial immunologic events that are thought to lead to clinical GVHD include allogeneic antigen presentation, CD4+ T cell proliferation and eventually generation of specific cytotoxic lymphocytes. Interleukin-10 (IL-10) has been shown to inhibit the function of antigen presenting cells (APC) and to reduce lymphocyte proliferation. In this study we investigated the possible role of recombinant murine IL-10 (rmIL-10) as prophylactic treatment of GVHD in a murine BMT model involving B10.BR donor mice (H-2k) and AKR recipients (H-2k). In particular, we wished to determine whether early post-BMT administration of IL-10 would suppress GVHD by interfering with macrophage function and inflammatory cytokine production during the proposed "afferent' phase of GVHD. In MLR assays, rmIL-10 significantly inhibited the proliferation of donor spleen cells when stimulated by irradiated recipient spleen cells in a dose-dependent manner. In murine BMT, rmIL-10 was administered exogenously by intraperitoneal injection of 100 U daily in two different dosage schedules, on days-1, 0, 1, 2, 3, 6 to target the early post-BMT phase, and days-1, 0, 3, 5, 7, 10 after BMT, to administer the same total dose throughout the engraftment period. IL-10 injected mice had lower plasma IL-1 alpha levels on day 3 (12 pg/ml vs 64 pg/ml in controls, P < 0.05), suggesting that both macrophage function and inflammatory cytokine production were inhibited. In contrast to the MLR data, no significant improvement in morbidity and mortality from GVHD was observed. Therefore, IL-10 does not appear to be useful in GVHD prophylaxis.
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PMID:Murine IL-10 fails to reduce GVHD despite inhibition of alloreactivity in vitro. 886 48

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

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

Interleukin-1 alpha (IL-1alpha) is a pro-inflammatory cytokine that is implicated in the initiation/maintenance of graft-versus-host disease (GVHD) and the immune response to infection. A cytosine (C) to thymine (T) transition at position -889 is believed to influence gene transcription. A previous single institution study showed that the presence of at least one IL1A T allele in the donor was associated with improved survival after unrelated donor haematopoietic stem cell transplant and lower transplant-related mortality if the donor and recipient each possessed the IL1A T allele. The present study sought to confirm these results in a larger homogeneous population. Thus the study population included 426 patients older than 18 years with chronic myeloid leukaemia (CML), transplanted in first chronic phase and receiving a total body irradiation and cyclophosphamide preparative regimen. Donor recipient pairs were categorised into four groups according to the presence or absence of an IL1A T allele in the donor and recipient. There were no significant differences in patient, donor and transplant characteristics between the groups. We did not observe an association with IL-1alpha genotype in donor and/or recipient and transplant-outcome. These data suggest that the outcome of unrelated donor transplant for CML is not influenced by IL-1alpha genotype.
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PMID:Interleukin-1 alpha genotype and outcome of unrelated donor haematopoietic stem cell transplantation for chronic myeloid leukaemia. 1739 95


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