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)

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning, donor T cell activation and effector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and IL-11 are cytokines that may be useful in disrupting Phase I of the GVHD cascade by blocking gastrointestinal tract damage and lowering serum levels of lipopolysaccharide and TNF-alpha. Cyclosporin, FK506 and sirolimus are some of the main agents that disrupt Phase II (donor T cell activation). Mycophenolate mofetil likely acts on this phase as well. Other novel drugs that affect Phase II are tolerance-induction agents such as cytotoxic T lymphocyte antigen (CTLA)-4 Ig and anti-CD40 ligand, and preliminary results using CTLA-4 Ig in GVHD prevention are encouraging. Two exciting agents that appear to affect only activated lymphocytes are ABX-CBL and visilizumab. Examples of agents that disrupt Phase III are the IL-2 receptor antagonist daclizumab and the anti-TNF-alpha monoclonal antibody infliximab. These anticytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.
 ...
PMID:Novel therapeutics for the treatment of graft-versus-host disease. 1222 48

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.
 ...
PMID:IL-12 plays a significant role in the apoptosis of human T cells in the absence of antigenic stimulation. 1224 79

We made the hypothesis that donor and recipient gene polymorphisms that drive the host response to microorganisms could be associated with infections after bone marrow transplantation (BMT). HLA-identical BMT was performed for patients with acute (n = 39) or chronic leukemia (n = 68). Genotyping was performed in 107 D/R DNA pairs for gene polymorphisms of cytokines (tumor necrosis factor-alpha [TNF-alpha] and TNF-beta, interleukin-1 receptor antagonist [IL-1Ra], IL-6, and IL-10), adhesion molecules (CD31 and CD54), Fcgammareceptors (FcgammaRIIa, IIIa, IIIb), mannose-binding lectin (MBL), and myeloperoxidase (MPO). First infection (overall) and first episodes of bacterial, viral, or invasive fungal infection were studied retrospectively for 180 days after BMT. Univariate and multivariate analyses, using death as a competing event, were performed to study risk factors. In multivariate analysis, first overall infections were increased in patients with the FcgammaRIIa R-131 genotype (hazard ratio [HR] = 1.92; P =.04), and severe bacterial infections were increased when the MPO donor genotype was AG or AA (HR = 2.16; P =.03). Viral and invasive fungal infections were not influenced by any genetic factor studied. Interestingly, we also found that (1) time to neutrophil recovery was shorter when donors were FcgammaRIIIb HNA-1a/HNA-1b (HR = 1.77; P =.002); (2) donor IL-1Ra (absence of IL-1RN*2) increased the risk for acute graft-versus-host disease (GVHD) (II-IV) (HR = 2.17; P =.017); and (3) recipient IL-10 (GG) and IL-1Ra genotypes increased the risk for chronic GVHD (P =.03 and P =.03, respectively). Finally, 180-day transplantation-related mortality rates were increased when donors were FcgammaRIIIb HNA-1a/HNA-1a or HNA-1b/HNA-1b (HR = 2.57; P =.05) and donor MPO genotype was AA (HR = 5.14; P =.004). In conclusion, donor and recipient gene polymorphisms are informative genetic risk factors for selecting donor/recipient pairs and could help in the understanding of mechanisms involved in host defenses of BM transplant recipients.
 ...
PMID:Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. 1239 99

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.
 ...
PMID:Cytokines, viruses, and graft-versus-host disease. 1239 68

Tumor necrosis factor-a (TNFalpha) plays an important role in the initiation and persistence of inflammation in a variety of skin disorders. The availability of selective TNFalpha blockers has provided new therapeutic opportunities. TNFa inhibitors have been employed with success in treating psoriasis in controlled trials, although further studies are warranted to better define which subgroup of patients can benefit most from this treatment and modalities of combination therapy. In addition, an increasing number of case reports indicates that anti-TNFalpha agents are of value in the treatment of other skin diseases, such as pyoderma gangrenosum and Behcet's syndrome, and in the treatment of graft-versus-host disease.
 ...
PMID:Targeting tumor necrosis factor-alpha as a potential therapy in inflammatory skin diseases. 1247 58

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.
 ...
PMID:IFN-gamma and TNF-alpha production in gamma-irradiated blood units by mononuclear cells and GVHD prevention. 1250 17

To study the effect of donor TNF-alpha gene polymorphism on severe acute and extensive chronic graft versus host disease (GVHD), TNF-alpha gene polymorphism was analyzed by denaturing high performance liquid chromatography (DHPLC) and DNA sequencing in twenty-one patients with III/IV degree acute GVHD and twenty-seven patients with extensive chronic GVHD. The results showed that the frequency of TNF-alpha-308 (G/A) significantly increased in patients with III/IV degree acute GVHD compared to 0/I degree aGVHD patients (8/21 vs 1/28) (P < 0.01) and the frequency of TNF-alpha-308 (G/A) is significantly higher in patients with extensive chronic GVHD than in patients without chronic GVHD (7/23 vs 1/17) (P < 0.05). However, the frequency of TNF-alpha-238 (G/A) does not significantly changed in patients with III/IV degree acute GVHD and extensive chronic GVHD. In conclusion, the TNF-alpha-308 (G/A) is likely to contribute to high risk for III/IV degree acute GVHD and extensive chronic GVHD.
 ...
PMID:[Frequency of donor TNF-alpha gene polymorphism in patients with graft versus host disease following hematopoietic stem cell transplantation]. 1251 16

This review summarizes recent results investigating the role of certain cytokine gene polymorphisms, including those of TNF-alpha, IFN-gamma, IL-6, IL-10 and IL-1 receptor antagonist (IL-1Ra), in allogeneic stem cell transplantation. It discusses their role in predicting outcome and the development of a genetic risk index for graft versus host disease (GvHD) in HLA-matched sibling transplants. By the comparative use of an in vitro human skin explant model, initial results suggest that certain cytokine gene polymorphisms may be associated with more severe disease.
 ...
PMID:Predicting outcome in hematological stem cell transplantation. 1254 63

Acute graft-versus-host disease (aGVHD) is the major complication of allogeneic stem cell transplantation (allo-HSCT), significantly limits the application of the therapy. Current evidence suggests that dysregulated cytokine production is responsible for many manifestations of aGVHD. The mechanisms have been most clearly delineated in mouse models, detailed analysis of human tissue is required. Monitoring serum levels of cytokine sIL-2R, TNF-alpha and IFN-gamma after transplantation or cytokine gene expression before transplantation can predict prognossis of aGVHD. GVHD have graft-versus-leukemia (GVL) effect, and GVL can be seperated from GVHD. IL-2, IL-12, IL-11, KGF and G-CSF could possess the roles of reducing GVHD while preserving GVL.
 ...
PMID:[Roles of Cytokines in Acute Graft-Versus-Host Disease] 1257 74

A coordinated effort combining bioinformatic tools with high-throughput cell-based screening assays was implemented to identify novel factors involved in T-cell biology. We generated a unique library of cDNAs encoding predicted secreted and transmembrane domain-containing proteins generated by analyzing the Human Genome Sciences cDNA database with a combination of two algorithms that predict signal peptides. Supernatants from mammalian cells transiently transfected with this library were incubated with primary T cells and T-cell lines in several high-throughput assays. Here we describe the discovery of a T cell factor, TIP (T cell immunomodulatory protein), which does not show any homology to proteins with known function. Treatment of primary human and murine T cells with TIP in vitro resulted in the secretion of IFN-gamma, TNF-alpha, and IL-10, whereas in vivo TIP had a protective effect in a mouse acute graft-versus-host disease (GVHD) model. Therefore, combining functional genomics with high-throughput cell-based screening is a valuable and efficient approach to identifying immunomodulatory activities for novel proteins.
 ...
PMID:TIP, a T-cell factor identified using high-throughput screening increases survival in a graft-versus-host disease model. 1283 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>