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)

Graft-versus-host disease (GVHD) and graft-versus leukemia (GVL) effects are closely related to each other after allogeneic stem cell transplantation. This association exists because of the extensive and complicated interaction between cellular donor components and recipient components concomitant with cytokine storms. It has been demonstrated that part of this interaction may be related to the induction of a variety of regulatory cells, such as regulatory T-cells and natural killer T (NKT) cells. A lower number of NKT cells may be found in patients with autoimmune diseases, cancer, viral infection, and severe GVHD. When activated, NKT cells rapidly release suppressive cytokines, such as interleukin 4 (IL-4), IL-10, and IL-13, as well as inflammatory cytokines, such as interferon gamma and tumor necrosis factor alpha. NKT cells therefore act as a double-edged sword in their progressive or suppressive effects on diseases. Such contradictory phenomena may be related to the function or types of antigen-presenting cells (APCs) in response to their ligand. A single-dose injection of a ligand for NKT cells, alpha-galactosylceramide (alpha-GalCer), can induce immunity through fully mature dendritic cells in an antigen-specific manner. By contrast, multiple injections of alpha-GalCer would induce tolerance, which may be caused by immature APCs. This response suggests that the function of NKT cells can be determined by alpha-GalCer for controlling the immune response. Furthermore, activation of NKT cells followed by activation of APCs and IL-12 production may lead to activation of NK cells and suppress GVHD in mismatched major histocompatibility complex combinations or may induce GVL effects. Control and modification of NKT cell function may play an important role in regulating GVHD/GVL effects.
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PMID:Application of natural killer T-cells to posttransplantation immunotherapy. 1571 80

Chronic graft versus host disease (cGVHD) is the result of an immune-mediated attack by transplanted donor lymphocytes, entailing inflammatory damage to host target organs. Clinically, the post-bone marrow transplantation (BMT) graft versus leukemia (GVL) effect may be associated with GVHD. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of cGVHD in a murine model. To evaluate whether amelioration of cGVHD in mice by induction of oral immune regulation in donors toward recipient pretransplant lymphocyte antigens is associated with attenuation of the GVL effect donor B10.D2 mice were fed with Balb/c splenocytes, B10.D2 splenocytes, bovine serum albumin (BSA), or regular chow, every other day for 10 days. Subsequently, transplantation of 2 x 10(7) splenocytes from donor B10.D2 mice to recipient Balb/c mice was undertaken, followed by inoculation of 3 x 10(3) BCL-1 leukemia on the day of BMT. Control groups were fed identically without leukemia inoculation. Mice were followed for survival and leukemia progression. Induction of tolerance was assessed by a mixed lymphocyte reaction (MLR). Cutaneous GVHD was assessed macroscopically. To elucidate the mechanism of any observed effect, serum interferon (IFN), interleukin (IL-2), IL-12, IL-4, and IL-10 were determined by enzyme-linked immunosorbent assay and flow cytometry analysis for CD4+, CD8+, and NK1.1+ lymphocyte subpopulations was performed. There was no significant difference in leukemia progression manifested by survival or white blood cell counts of orally immune-regulated mice compared with control animals. Cutaneous cGVHD was significantly ameliorated in Balb/c mice transplanted from tolerized B10.D2 mice. This effect was associated with a significant reduction in the mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against Balb/c target splenocytes; significantly decreased serum IFN-gamma and IL-2; increased serum IL-12 levels; increased peripheral NK1.1+ cells; and CD4+/CD8+ lymphocyte ratio. Oral tolerization of BMT donors toward recipient antigens ameliorates cGVHD without hampering the GVL effect.
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PMID:Alleviation of chronic GVHD in mice by oral immuneregulation toward recipient pretransplant splenocytes does not jeopardize the graft versus leukemia effect. 1578 61

Administration of cyclosporine (CyA) following autologous bone marrow transplantation elicits a T-lymphocyte autoaggression syndrome with remarkable similarity to acute and chronic graft-versus-host disease (GVHD). This syndrome termed syngeneic (S) GVHD is mediated by a restricted repertoire of autoreactive T cells that promiscuously recognize major histocompatibility complex (MHC) class II determinants in association with a peptide from the invariant chain (CLIP). The present studies evaluated and compared antigen-specific autoreactive T cells during acute and chronic SGVHD isolated ex vivo with a soluble MHC class II-immunoglobulin (sMHC class II-Ig) molecular construct. Two major subsets were detected that had overlapping specificity recognizing the MHC class II binding domain of CLIP but were differentially dependent on the N- and C-terminal flanking domains of this peptide. Both subsets were detected in acute and chronic SGVHD. Interestingly, the cytokine profiles of the CLIP-reactive T cells closely correlated with the onset and progression of disease. Levels of type 1 cytokines, particularly IFN-gamma mRNA production assessed by quantitative polymerase chain reaction (PCR), were dominant during acute SGVHD, whereas chronic SGVHD was associated with type 2 cytokine mRNA production. Although there was a dramatic polarization with respect to cytokine production, only subtle changes in antigen specificity were detected. Of additional interest, autoreactive T cells producing IL-10 mRNA were detected in both acute and chronic SGVHD, suggesting that this cytokine may play an important but perhaps paradoxical role in both the onset and progression of this experimental autoaggression syndrome.
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PMID:Antigen-specific T-lymphocyte responses in acute and chronic syngeneic graft-versus-host disease. 1580 45

Recombinant human granulocyte-colony-stimulating factor (rhG-CSF) can widely regulate human immunologic response. In the protocol of peripheral blood stem/progenitor cell mobilization, rhG-CSF can change the numbers and functions of T cells. Then the results can impact the incidence of graft-versus-host disease after allogeneic peripheral blood stem/progenitor cell transplantation. The regulation of rhG-CSF on T cell is an indirect action which is based on the direct action to monocytes and dendritic cells. The numerous IL-10 secreted by monocytes plays a key role in cytokines production, proliferative response and cytotoxicity of T cells. Endogenous IL-10 can induce high expression of SOCS3 and the SOCS3 is very important for regulating the signal transduction of the activities of T cells. In this review influences of rhG-CSF on T-cells in mobilization process and related mechanisms were elaborated with emphasis.
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PMID:[Effects of rhG-CSF on T cell during peripheral blood stem/progenitor cell mobilization and its mechanisms--review]. 1585 6

Several clinical trials evaluating the induction of autoimmune graft-versus-host disease (GVHD) after autologous bone marrow transplantation (BMT) as antitumor immunotherapy have shown that autologous GVHD is associated with increased production of interleukin (IL)-10. The induction of autologous GVHD also segregated with single nucleotide polymorphisms in the IL-10 promoter region (IL-10 -592 and IL-10 -1082 ) and with CA repeats in the first intron of the interferon (IFN)-gamma gene. Polymorphisms within these promoter regions can significantly modify the cytokine response because of differential transcription factor efficiency. This study evaluated the relationship between inheritance of polymorphisms within the IL-10 promoter and in the IFN-gamma gene and the overall survival of patients who received autologous BMT for metastatic breast cancer. Peripheral mononuclear cells from 87 women enrolled in 3 autologous BMT (plus induction of autologous GVHD) clinical trials were examined. By using a Cox proportional hazard model, trends in survival after autologous BMT were analyzed. The model included inheritance polymorphisms of IL-10 -592 , IL-10 -1082 , CA repeats within the first intron of the IFN-gamma gene, estrogen and progesterone receptor status, and stage of disease. Increased survival was significantly associated with patients having the IL-10 -592 promoter allele associated with high IL-10 production (hazard ratio, 0.23; 95% confidence interval, 0.09-0.55; P = .001). The effect of the strong IL-10 promoter allele on survival seems to be independent of the development of clinical autologous GVHD. However, decreased survival was significantly associated with patients having CA repeats associated with higher IFN-gamma transcription (hazard ratio, 2.34; 95% confidence interval, 1.21-4.54; P = .011). Inheritance of specific alleles that modify IL-10 and IFN-gamma production may have unexpected effects on the efficacy of immune-based strategies after autologous BMT. Additional studies are necessary to further define the influence of IL-10 and IFN-gamma on the immune response after BMT.
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PMID:The effects of interleukin 10 and interferon gamma cytokine gene polymorphisms on survival after autologous bone marrow transplantation for patients with breast cancer. 1593 34

Inducible costimulator (ICOS) is expressed on activated and memory T cells and is involved in the regulation of cytokine production. We studied the role of ICOS on alloreactive T cells in graft versus host disease (GVHD) and determined that ICOS expression was up-regulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells with wild-type (WT) T cells in 2 GVHD models. In both models, recipients of ICOS-/- T cells demonstrated significantly less GVHD morbidity and mortality, which was associated with less intestinal and hepatic GVHD but increased cutaneous GVHD. In addition, recipients of ICOS-/- donor T cells displayed a slight decrease in graft versus leukemia (GVL) activity. Further analysis of alloreactive ICOS-/- T cells showed no defect in activation, proliferation, cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T cells had decreased serum levels of interferon-gamma (IFN-gamma), while interleukin-4 (IL-4) and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed toward T helper-2 (Th2) differentiation. These data suggest a novel role for ICOS in the regulation of Th1/Th2 development of activated T cells. In conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to a Th2 immune deviation while GVL activity is slightly diminished.
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PMID:Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation. 1595 89

The present study aimed to determine existing associations between single nucleotide polymorphisms within the promoters of interleukin (IL)-6 (-174 G/C) and IL-10 (-1082 G/A, -819 C/T, -592 C/A) genes and the outcome of allogeneic sibling hematopoietic stem cell transplantation. Ninety-three recipients and 74 donors were typed for IL-6 and IL-10 alleles by polymerase chain reaction-sequence specific primer. Then, IL-6 activity in patient serum and the concentration of C-reactive protein were analyzed at various times after transplantation in relation to transplant complications and IL-6 genotype. IL-6 activity in serum was significantly higher in patients who died as a result of toxic complications and after the 6 weeks after transplantation in patients with severe acute graft-versus-host disease (aGVHD). Recipient IL-6 G genotype was associated with increased IL-6 activity and C-reactive protein production. In univariate analyses, recipient IL-6 G and donor IL-6 GG associated or tended to associate with increased risk for aGVHD. In contrast, recipient IL-10 GCC/GCC and donor IL-10 ACC decreased the risk of aGVHD. IL-6 and IL-10 polymorphic features, together with other factors known to affect the risk of aGVHD, were also subjected to multivariate analyses. These analyses confirmed the independent contribution of recipient IL-10 GCC/GCC (odds ratio = 0.085, p = 0.046) and donor IL-6 GG (odds ratio = 3.934, p = 0.034) genotypes to the risk of aGVHD.
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PMID:IL-6 and IL-10 promoter gene polymorphisms of patients and donors of allogeneic sibling hematopoietic stem cell transplants associate with the risk of acute graft-versus-host disease. 1599 15

In order to explore what role relative cytokines play in acute GVHD (aGVHD) of mice transplanted with H-2 haploidentical nonmyeloablative bone marrow, a murine model was established by using C57BL/6J mouse as donor and (C57BL/6J x BALB/C) F1 mouse as the recipient. The recipient mice were given CsA and mycophenolate mofetile (MMF) for prophylaxis of aGVHD. The expression levels of IL-2, INFgamma, IL-4 and IL-10 in the spleen were detected by semi-quantitative RT-PCR at different time points after transplantation. The results showed that the expression levels of these cytokines increased slightly in the group only received nonmyeloablative conditioning. The expression levels of IL-2 and INF-gamma elevated significantly after transplantation in group 2 (without aGVHD prophylaxis), peaked at day 21 and day 14 respectively, then dropped rapidly, returned to the basal levels at day 35. The study on kinetic pattern of expression of IL-2 and INF-gamma in group 3 (with aGVHD prophylaxis) gave a similar result to group 2, but the peak value of cytokine expression in group 3 was much lower than that in group 2. The expression of IL-4 in Group 2 and group 3 all peaked at day 14, but the peak value in group 3 was higher than that in group 2, and decreased slowly in group 3. The expression of IL-10 increased gradually after transplantation, peaked at day 14, decreased after day 21, elevated again until day 35. It is concluded that the expression levels of these cytokines in the spleen all increase after H-2 haploidentical nonmyeloablative bone marrow transplantation. CsA and MMF can reduce the incidence and severity of aGVHD by down-regulating the expression levels of IL-2 and INF-gamma.
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PMID:[Kinetic patterns of cytokine expressions in H-2 haploidentical nonmyeloablative bone marrow transplantation in mice]. 1612 62

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (HSCT), and cytokines are recognized as important mediators of GVHD. Polymorphisms in the regulatory regions of several cytokine genes have been associated with a number of immune diseases as well as organ transplant complications. In this study we have investigated the role of tumor necrosis factor-alpha(-308), interleukin (IL)-6(-174), IL-10(-1082, -819, -592), Interferon-gamma(-874), and transforming growth factor-beta1(+869, +915) polymorphisms on HSCT outcome. Donor/recipient genotypes were analyzed by polymerase chain reaction with sequence specific primers (PCR-SSP). Although we have found a small number of low IL-6, a polymorphism at position -174 of the recipient and donor IL-6 gene was associated with the increased incidence of chronic GVHD. Therefore, this study emphasizes the probable potential role of genetic variability of donor and recipient in determining outcome after transplantation.
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PMID:Relationship between cytokine gene polymorphisms and graft-versus-host disease after allogeneic stem cell transplantation in a Brazilian population. 1624 34

The current study attempted to evaluate the association between the IL-10 promoter gene single nucleotide polymorphism (SNP) and invasive pulmonary aspergillosis (IPA) after allogeneic stem cell transplantation (SCT) in 105 patients. Three single-nucleotide polymorphisms were investigated in the proximal region of the IL-10 promoter gene (-1082/-819/-592). Two haplotypes (1082*A/819*T/592*A [ATA] and 1082*A/819*C/592*C [ACC]) were found in the current study. The overall incidence of IPA was estimated as 14.1+/-4.5% with a median onset at 186 days post-transplant (62 approximately 405 days). An increased occurrence of IPA was noted dependent on the IL-10 haplotype (0% vs 11.5+/-6.4% vs 19.7+/-7.7% for ACC/ACC vs ATA/ACC vs ATA/ATA haplotype, P=0.0307 when comparing ACC with non-ACC haplotype). In a multivariate survival analysis using Cox's proportional hazard model, the IL-10 promoter gene SNPs were identified as an independent predictive factor for the development of IPA (P=0.012, hazard ratio (HR) 9.3), along with an histocompatibility leukocyte antigen (HLA)-identical donor (P=0.005, HR 16.3), the CD34+ cell dose transplanted (P=0.004, HR 26.5), and time-dependent chronic graft-versus-host disease (GVHD; P=0.049, HR 16.0). The IL-10 ACC haplotype was found to have an apparent protective role in the development of IPA after allogeneic transplantation, regardless of HLA-disparity or chronic GVHD.
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PMID:Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation. 1624 33


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