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)

We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10(-1064) and IFN-gamma genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.
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PMID:Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation. 1220 38

Interleukin-12 (IL-12) is an immunoregulatory cytokine that plays an essential role in cell-mediated immunity. It is known to induce T cell apoptosis in in vivo systems such as graft-versus-host disease (GVHD) and experimental autoimmune uveitis (EAU). However, the role of IL-12 in T cell apoptosis in the absence of antigenic stimulation has not been clearly defined. This study was conducted to investigate whether IL-12, in the absence of an antigen, is able to induce T cell apoptosis, and also, which signalling pathways utilized by IL-12 are involved in this process. Our data clearly showed that IL-12 in the absence of an antigen induces apoptosis in T cells. Flow cytometry and ELISA showed FasL up-regulation and increased IFN-gamma synthesis in IL-12 treated T cells, while Fas and TNF-R1 showed little change. Semi-quantitative RT-PCR demonstrated that IL-12 was able to up-regulate TNF-alpha and FasL mRNA expression. Furthermore, IL-12 induced apoptosis was associated with caspase-3, caspase-2, caspase-7, DNA fragmentation factor 45 (DFF45) and Fas associated death domain (FADD) whereas TNF receptor associated death domain (TRADD) and receptor interacting protein (RIP) were not. Inhibition of Janus tyrosine kinase (JAK) was able to suppress IL-12 induced T cell apoptosis. Anti-FasL antibody was able to block IL-12 induced T cell apoptosis. In conclusion, our findings suggest that IL-12 is able to induce T cell apoptosis in the absence of an antigen. In addition, the present data suggest that this process is FasL mediated and caspase-3 dependent. Furthermore, JAK was shown to be involved in this process. These results may have significant implications in the understanding of IL-12 mediated T cell apoptosis.
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PMID:IL-12 plays a significant role in the apoptosis of human T cells in the absence of antigenic stimulation. 1224 79

To clarify the immune response of CD57+ T cells (most of them are CD8+) in peripheral blood (PB) against alloantigens in order to elucidate the T helper 1 (Th 1) immune response, we assessed the role of CD57+ T cells in IFN-gamma (one of the representative Th 1 cytokines) production in a one-way mixed lymphocyte reaction (MLR). In this study, we showed that CD57+ T cells in responder cells were essential for effective IFN-gamma production in allogeneic MLR due partly to the augmentation of the alloresponse of regular T cells. Furthermore, IFN-gamma production in MLR correlated with the proportions of CD57+ T cells in PB regardless of the responders' age. We also showed that the extent of the expansion of CD57+ T cells in paediatric patients after haematopoietic stem cell transplantation (HSCT) was markedly lower than that in adult patients. In addition, CD57+ T cells purified and activated with a combination of cytokines showed a greater cytotoxicity than regular T cells against human umbilical vein endothelial cells. Because IFN-gamma production in one-way MLR is a useful predictor of graft-versus-host disease (GVHD), especially in the acute phase that occurs after allogeneic HSCT, our findings suggested that CD57+ T cells play a role in the development of GVHD and thus may explain the reason as to why a higher donor age is associated with an increased risk of developing GVHD while, in addition, the incidence of severe GVHD in paediatric patients is lower than that in adult patients.
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PMID:CD57+ T cells augment IFN-gamma production in a one-way mixed lymphocyte reaction and their expansion after stem cell transplantation in paediatric patients. 1229 68

Proinflammatory cytokines released by host tissues during conditioning treatment and interferon gamma released from donor T cells play a major role in acute graft-versus-host disease (GVHD). In the past year the interaction of cytokines has been elucidated further. Host antigen-presenting cells play a key role in the induction of allogeneic recognition. Their activity is modulated by cytokines such as flt3-ligand, viruses, and donor T cells. Expansion of donor T cells is crucial for the pathogenesis of acute GVHD. Cytokines of the T helper 1 response-IFN-gamma, IL-12, and IL-18-regulate the expansion of donor and host cells via the induction of Fas and FasL and subsequent apoptosis. However TNF-alpha, FasL, and IL-1 also cause damage to target cells. Cytokine and receptor gene polymorphism has an impact on the activity of both host and donor cell activation. Genetic factors, conditioning treatment, lipopolysaccharides (LPS) from gram-negative microorganisms, viral infections, and donor T cells determine the activity level of host antigen-presenting cells and macrophages, which have an impact on acute GVHD and other complications of allogeneic stem cell transplantation.
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PMID:Cytokines, viruses, and graft-versus-host disease. 1239 68

Previous studies in murine bone marrow transplantation (BMT) models using neutralizing anti-tumor necrosis factor (TNF) antibodies or TNF receptor (TNFR)-deficient recipients have demonstrated that TNF can be involved in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). TNF in these GVHD and GVL models was thought to be primarily produced by activated monocytes and macrophages, and the role of T cell-derived TNF was not determined. We used TNF(-/-) mice to study the specific role of TNF produced by donor T cells in a well-established parent-into-F1 hybrid model (C57BL/6J-->C3FeB6F1/J). Recipients of TNF(-/-) T cells developed significantly less morbidity and mortality from GVHD than recipients of wild-type (wt) T cells. Histology of GVHD target organs revealed significantly less damage in thymus, small bowel, and large bowel, but not in liver or skin tissues from recipients of TNF(-/-) T cells. Recipients of TNF(-/-) T cells which were also inoculated with leukemia cells at the time of BMT showed increased mortality from leukemia when compared with recipients of wt cells. We found that TNF(-/-) T cells do not have intrinsic defects in vitro or in vivo in proliferation, IFN-gamma production, or alloactivation. We could not detect TNF in the serum of our transplant recipients, suggesting that T cells contribute to GVHD and GVL via membrane-bound or locally released TNF.
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PMID:Donor T cell-derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation. 1242 95

Alfa-Galactosyl Ceramide was isolated from Ocean sponge which has antitumor effect against several tumors in in vivo animal model with no cytotoxicity. KRN7000(KRN) is the most potent alpha-Galactosyl Ceramide modified from the one isolated from Ocean sponge. KRN is also active against metastatic tumors through the activation ofanimal immune system. Research efforts in learning the mechanism of action, we found the important role of dendritic cells(DC) and NKT cells. NKT cells was first characterized in 1988 which is overlap some part with NK cells and T-Cells and majority is different from NK and T. KRN is active through the activation of DC and NKT in giving antigen specific immune stimulation in animal. This antigen specific stimulation is memorized by immune system and can reject second tumor challenge. KRN is not active in nude mice and NKT deficient animal. NKT cells level in blood is lower in patients with autoimmune disease, cancer, HIV positive or aplastic anemia. NKT rapidly releases IL-4 and IFN-gamma at high level when activated. NKT is CD1d and TCR restricted. NKT plays important role in autoimmune disease such as Type 1 Diabetes, Scleroderma and Systemic Lupus Erythematosus, infections such as Mycobacteria, Listeria and Malaria, GVHD control and tumor rejection. NKT acts as double edge sword, aggressive and suppressive ways. KRN can prevent the onset of Type 1 Diabetes, inhibit replication of hepatitis virus B in liver and suppress malaria replication in activating NKT cells. KRN can activate NKT through DC and activated NKT activates NK, T and macrophage. KRN also expands NKT cells and expanded NKT has full function. Although the exact role of DC and NKT is not clear, KRN clinical study results in conjunction with DC and NKT cell activation are expected.
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PMID:Role of NKT cells and alpha-galactosyl ceramide. 1243 Aug 64

Transferring DBA/2 spleen cells into (C57BL/10xDBA/2) F1 (referred to as BDF1) mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th(2) cytokines, hypergammaglobulinemia, and immune complex-mediated glomerulonephritis that resembles systemic lupus erythematosus. DNA motif consisting of an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines (CpG ODN) induces Th(1) cytokine production in mice. This study examines the effect of administering CpG ODN to mice undergoing chronic GVHD, based on the premise that altering Th(1)/Th(2) activity might beneficially impact on disease progression.GVHD BDF1 mice injected with DBA/2 spleen cells were treated with weekly intraperitoneal injection of 50 microg CpG ODN. This treatment significantly suppressed the production of IgG anti-DNA autoantibody and reduced the development of glomerulonephritis. Serum IgG2a titers were higher in the CpG ODN than in non-CpG control group, whereas IgG1 titers were unchanged. As predicted, IFN-gamma levels were significantly higher in the CpG ODN-treated group, while IL-4 levels were lower, resulting in a shift in the Th(1)/Th(2) cytokine ratio. Results suggest that CpG ODN administration may be of therapeutic benefit in chronic GVHD.
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PMID:Therapeutic effect of CpG motifs on the development of chronic graft-versus-host disease in mice. 1244 Nov 43

Gamma-radiation of blood products is considered the mainstay of transfusion-associated graft-versus-host disease prevention. Previous studies have detected lymphocyte inhibition rate in blood components just one time after irradiation but there is evidence of cellular variability with production of cytokines at different storage time which could be related with irradiation activity and cellular damage repair. IFN-gamma, a Th1 cytokine, and TNF-alpha, a pro-inflammatory one, had a central role in the stimulation of cellular and inflammatory reactions. In this study whole blood was collected from five volunteer healthy donors and each donor bag was divided into two satellite bags: one of them was exposed to 137Cs-irradiation with a 2500 cGy dose. Samples for cytokine production, detected by ELISA methods, and proliferative response, evaluated by incorporation of H3 thymidine, were taken at the following storage time: 0, 24, 48, 72 and 96 h. The time-response curve of irradiated mononuclear cells from blood bags (BBMC) in mitogenic activation showed a time-related inhibition of cell proliferation with an enhanced response only after 24 h of storage and about 84% inhibition at 96 h. A similar pattern is follow by IFN-gamma production after OKT3 stimulation. TNF-alpha levels both in lipopolysaccharide stimulated or unstimulated cells were always high. This data suggest that BBMC cells maintain the ability to produce cytokines after gamma-radiation. On the ground of this study seems to be necessary to evaluate hypothetical risk associated with the administration of cytokine via irradiated blood components.
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PMID:IFN-gamma and TNF-alpha production in gamma-irradiated blood units by mononuclear cells and GVHD prevention. 1250 17

To investigate the mechanisms underlying the issue that bone marrow mesenchymal stem cells (MSC) could trigger low responsiveness of allogeneic T lymphocytes against alloantigens, phenotypes of T cells were analysed with flow cytometry before and after coculture of allogeneic T lymphocytes with MSC. Further, expression of cytokines including IL-4, IFN-gamma and TGF-beta1 was evaluated by RT-PCR and ELISA as well. The results showed that CD8(+) subpopulation was increased and CD25(+) subset was decreased in proportion after coculture of allogeneic T lymphocytes with MSC for 2 weeks. RT-PCR assay showed that MSC expressed TGF-beta1 but not IL-4 and IFN-gamma, and the result was further proved by ELISA assay showing that the secretion of TGF-beta1 reached to 1 ng/ml in 72 hours. It was concluded that allogeneic MSC suppressed T cells activation by alteration of T cell subpopulations. The suppressive effect was at least in part due to the secretion of TGF-beta1. The results indicate that MSC pretreatment might be useful in the prevention of GVHD in HLA-mismatched bone marrow transplantation and further donors for hematopoietic stem cells could be selected from greater potentials.
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PMID:[Mesenchymal stem cells suppress allogeneic T cell responses by secretion of TGF-beta1]. 1251 58

To investigate the value of apoptosis of the allo-antigen specific T cells induced by Fas/FasL pathway in order to prevent GVHD in allo-transplant, the CD34(+) cells were transfected with FasL or not, used as effector cells, mixed with allo-antigen specific T lymphocytes with presence or absence of IFN-gamma or IL-2. After 5 days, apoptosis of T cells was detected by TdT nick end mediated dUTP labeling (TUNEL) and flow cytometry. The effects of IFN-gamma or IL-2 on apoptosis of CD34(+) cells of graft induced by Fas/FasL pathway observed as controls. The apoptosis incidence of T cells was (12.1 +/- 1.5)% when CD34(+) cells transfected with FasL were used as effector cells, that was much higher than that T cells with CD34(+) cells non-transfected (p < 0.01). In the presence of IFN-gamma or IL-2, apoptosis incidence reached to (20.1 +/- 2.3)% or (17.6 +/- 1.3)% respectively (p < 0.01). When sFasL was added to CD34(+) cells freshly isolated or induced with IFN-gamma or IL-2, the incidence or apoptosis of CD34(+) cells was (7.8 +/- 0.8)%, (18.7 +/- 1.6)% (p < 0.01) or (7.9 +/- 1.0)% (P > 0.05) respectively. The results suggest that it is possible to induce apoptosis of the allo-antigen specific T cells in grafts activated by allo-antigen by exogenous Fas ligand expressed on receptor cells and that may hopefully provide a new method to prevent GVHD
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PMID:[Apoptosis of the allo-antigen specific T cells induced by CD34(+) cells transfected with exogenous gene FasL]. 1251 39


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