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)

Stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy. Some patients seem to have an imbalance of the immune response after SCT and cytokines are known to regulate this response. Recently, platelets have been shown to contain members of the chemokine family, suggesting a role of platelets as inflammatory cells. We measured and compared levels of platelet activation markers, chemokines, and soluble factors in patients undergoing SCT. IL-8 and GROalpha exhibited a significant elevation in the early phase (1 or 2 weeks) after SCT; this trend was marked after autologous SCT. Furthermore, these levels significantly and positively correlated with the change in G-CSF. In contrast, ENA-78 exhibited a significant elevation in the later phase (3 or 4 weeks) after SCT. In addition, its level negatively correlated with the change in G-CSF. Soluble CD40 ligand and platelet-derived microparticles significantly increased after both auto- and allo-SCT. In addition, ENA-78 positively correlated with the level of platelet-derived microparticles. The increase of RANTES seems to be related to platelet activation, since RANTES was in the dynamic phase similar to soluble CD40 ligand and platelet-derived microparticles. RANTES exhibited changes similar to IL-6, TNFalpha, and soluble IL-2 receptors, which are GVHD markers. Thus, the platelet-derived chemokines ENA-78 and RANTES exhibited particular changes after SCT. Our results suggest that ENA-78 play a role in hematopoietic conditions in which G-CSF is not involved, and RANTES generation after allo-SCT relates to GVHD.
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PMID:Role of platelet-derived chemokines (RANTES and ENA-78) after stem cell transplantation. 1663 46

This study was aimed to analyze the mRNA expression of cytokines (TGF-beta, IL-2, IL-6, IL-10, IFN-gamma, TNF-alpha, FAS-L) in five rhesus treated with haploidentical peripheral blood stem cell transplantation after nonmyeloablative preparative regimens and to explore the role of these cytokines in the development and pathology of acute graft-versus-host-disease (aGVHD). Five rhesus monkeys received nonmyeloablative haploidentical peripheral blood stem cells transplantation. Semi-quantitative reversed transcription polymerase chain reaction (RT-PCR) was used to analyze the kinetics of cytokine mRNA expression in the transplantation and aGVHD. The results showed that five rhesus monkeys acquired hematopoietic reconstitution successfully. The graft was rejected in one monkey which survived without disease, the other four achieved mixed chimerism and full donor chimerism. Chimerism of low centigrade in one monkey achieved high centigrade at 35 days after donor stem cell infusion. Intestinal aGVHD grade III developed in one monkey. Cytokines of Th1 and Th2 changed after transplantation. In period of aGVHD, expression of TGF-beta decreased but all others increased in various levels. When donor chimerism decreased, the cytokines decreased accordingly. It is concluded that the decrease of TGF-beta mRNA may be an indicator to predict aGVHD, and can be used as a differential diagnostic indicator for intestinal GVHD.
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PMID:[Kinetic study of various cytokine mRNA expressions in rhesus treated with haploidentical peripheral blood stem cell transplantation]. 1680 Sep 45

The molecular mechanisms governing skin fibrosis in murine sclerodermatous graft-versus-host disease (Scl GVHD) are not known. We used Affymetrix DNA microarrays representing >14,000 mouse genes to characterize global gene expression in skin during development of Scl GVHD in lethally irradiated BALB/c (H-2d) mice transplanted with B10.D2 (H-2d) bone marrow and spleen cells. These mice develop skin thickening, whereas control mice transplanted with syngeneic BALB/c (H-2d) bone marrow and spleen cells do not develop disease. We found consistent differences between mice with Scl GVHD and controls in cytokine messenger RNAs (mRNAs) for both Th1-like (IFN-gamma) and Th2-like (IL-6, Il-10, and IL-13) inflammatory patterns. mRNAs for chemokines CCL2, CCL5, CCL17, IFN-gamma inducible chemokines (CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC), and for growth factors such as platelet-derived growth factor-c, connective tissue growth factor, fibroblast growth factor 1, epidermal growth factor, nerve growth factor-beta, vascular endothelial growth factor (VEGF)-alpha, and VEGF-beta were elevated, similar to human scleroderma. mRNAs for cell adhesion molecules, such as L-selectin (selectin lymphocyte), P-selectin (selectin platelet), E-selectin (selectin endothelium), and vascular cell adhesion molecule 1, were also upregulated. In separate experiments, we confirmed the increased synthesis of IFN-gamma and IL-2, unchanged IL-10, and absence of tumor necrosis factor-alpha, and IL-4 proteins by flow cytometry of isolated skin T cells. These constellations of immunologic changes provide a "fingerprint" for fibrosing autoimmune disease. They are useful to understand the pathogenesis of Scl GVHD, to identify markers for early diagnosis of disease, and to devise more effective strategies for intervention in early scleroderma and Scl GVHD.
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PMID:Cutaneous gene expression by DNA microarray in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. 1691 93

T helper (Th) cells and cytolytic T lymphocytes (CTL) play defined roles in the cellular immune response. This distinction wavered when Th lymphocytes were shown to kill antigen-presenting cells displaying the relevant antigen. Here we demonstrate that also the opposite can be true: CTL can exert helper functions. We noticed that certain CMV-specific CTL lines grew after antigen activation also without exogenous IL-2. These lines produced their own IL-2, which supported the expansion of other CTL and Th cell lines. High levels of helper cytokines like IL-4, IL-5 and IL-6 were detected in the culture supernatants. Thus, we set up a helper assay to study the functional interactions between T cells (or their supernatants) and B cells. Conditioned media from helper CTL lines induced secretion of antigen-specific antibodies by B cells pulsed with antigen as first signal. We conclude that it is possible to isolate CTL lines that exhibit helper functions for T cells and B cells. If this possibility is proven also in vivo, we should revise some of our views on the pathogenesis of diseases in which CD8 cells are key players, such as in viral infections, graft rejection and GVHD.
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PMID:Helper function of cytolytic lymphocytes: switching roles in the immune response. 1717 58

Mesenchymal stem cells (MSC) are of particular interest for their potential clinical use in tissue engineering as well as for their capacity to reduce the incidence and severity of graft-versus-host disease in allogeneic transplantation. We have previously shown that MSC-mediated immune suppression acts via the secretion of soluble factor(s) induced upon stimulation. The aim of this study was to identify the molecule(s) involved and the underlying mechanism(s). We show that murine MSC secrete high levels of interleukin (IL)-6 and vascular endothelial growth factor, which are directly correlated to the inhibition of T-cell proliferation. The T-cell activation is partially restored upon addition of a neutralizing anti-IL-6 antibody or the prostaglandin E2 inhibitor indomethacin. Interestingly, no indoleamine 2,3-dioxygenase activity was detected in our conditions. Instead, we show that MSC reduce the expression of major histocompatibility complex class II, CD40, and CD86 costimulatory molecules on mature dendritic cells (DC), which was responsible for a decrease in T-cell proliferation. Moreover, we show that the differentiation of bone marrow progenitors into DC cultured with conditioned supernatants from MSC was partly inhibited through the secretion of IL-6. Altogether, these data suggest that IL-6 is involved in the immunoregulatory mechanism mediated by MSC through a partial inhibition of DC differentiation but is probably not the main mechanism. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. 1751 Feb 20

Recombinase activating genes 1/2 (RAG1/2) deficiency, critical to initiate gene rearrangement encoding lymphocyte receptors, causes T-B- severe combined immunodeficiency (SCID) and Omenn syndrome (OS), characterised by erythroderma, hepatosplenomegaly, lymphadenopathy, activated, clonal T cell expansions with restricted TCRVbeta family usage, and opportunistic infection. Many features of OS resemble graft-versus-host disease (GvHD). Frequency of GvHD-associated cytokine gene polymorphisms (CGPs) with OS was investigated to explain phenotypic differences between T-B- SCID and OS. Allele frequencies of IFNgamma T874A, IFNgamma-R1, TNFalphad microsatellites, IL-10 promoter region C592A and A1082G, IL-4 C-590T, IL-6 G-174C, IL-4R Q+576R, IFNgamma-R1 T-56C, TNFalphaRII 196 M/R single-nucleotide polymorphisms and IL-1Ra intron 1 VNTR were examined in 33 OS and 23 SCID patients. No significant differences in allele frequencies were found between the groups, and no trends identified. The mechanisms determining the OS or T-B-NK+ SCID phenotype remain to be determined.
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PMID:GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes. 1757 55

The induction of transplantation tolerance and the improvement of immune reconstitution after allogeneic bone marrow transplantation are the main research fields in the clinic organ transplantation and transplantation immunology. Over the past 5 years serial studies have been performed in our lab to induce robust transplantation tolerance by using combined strategies and improve the immune reconstitution of mice following allogeneic bone marrow transplantation by using gene-engineered bone marrow stromal cells. The results are encouraging. (1) The long-term survival of allografts was received by blockade of both CD28/B7 and CD40/CD40L or CD28/B7 and OX40/OX40L costimulation signals. In the case of blockade of both CD28/B7 and OX40/OX40L, the islet allograft survival was over 150 days compared to the control 14 days. (2) The CTLA4Ig-FasL fusion molecule expressed by adenoviral vector containing CTLA4Ig-FasL gene can prevent the autoimmune diabetes of mice and significantly prolong the survival time of cardiac allografts in rats, indicating that Fas-FasL-mediated apoptosis is able to enhance CTLA4Ig-induced transplantation tolerance. (3) In the time-window of peripheral tolerance induced by various methods, the systemic infusion of donor bone marrow cells and spleen cells obtained stable allogeneic mixed chimerism and robust transplantation tolerance. In the case of CTLA4Ig-FasL treatment combined with donor bone marrow cells more than 20% donor-origin blood cells chimerism, and more than 200 days prolonged skin allograft survival were obtained or received. (4) The murine bone marrow stromal cell line QXMSC1 transfected with IL-6 gene or IL-2+IL-3 genes significantly improved the immune reconstitution of mice following allogeneic bone marrow transplantation. Furthermore, It was observed that the mesenchymal stem cells transfected with IL-7 gene suppressed 90% of GVHD and expressed antileukemic effect, while accelerating immune reconstitution in mice following allogeneic bone marrow transplantation, which might be valuable in the clinic setting.
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PMID:[Studies on the induction of transplantation tolerance and immune reconstitution through combined strategies]. 1794 May 78

Bone marrow transplantation (BMT) is currently the treatment of choice for patients with globoid cell leukodystrophy (GLD), particularly in the early phases of the disease. Elevated interleukin (IL)-6 levels in the central nervous system of the twitcher mouse, an animal model for GLD, have been held responsible for severe graft versus host disease (GVHD), and IL-6 knock-out mice have shown lower incidence of GVHD after BMT. Here we report an eight-year-old girl with late-onset advanced stage of GLD who developed severe GVHD and died following unrelated 5/6 matched cord blood transplantation. Serum IL-6 levels pre-BMT and at day +38 were elevated (20 pg/ml and 15 pg/ml, respectively). This observation may support the findings in twitcher mice suggesting a possible role for IL-6 in the pathogenesis of GVHD in transplanted patients with GLD.
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PMID:Severe graft versus host disease in a patient with globoid cell leukodystrophy following umbilical cord blood transplantation: resemblance to the twitcher mouse model. 1799 May 86

Although stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy, it involves certain serious transplant-related complications such as graft-versus-host disease (GVHD). Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) plays important roles in regulating cell death, immune response, and inflammation. However, the role of soluble TRAIL (sTRAIL) after SCT is poorly understood. In this study, 42 patients underwent SCT; 22 patients received allogeneic SCT, while the remaining 20 received autologous SCT. In these patients, levels of sTRAIL, cytokines, and soluble factors were measured by enzyme-linked immunosorbent assay (ELISA). In addition, a basic study of the generation of endothelial cell-derived microparticle (EDMP) by TNF-alpha and soluble Fas ligand (sFasL) was conducted. sFasL and EDMP exhibited significant elevation in the early phase (2-3 weeks) after SCT. In addition, the elevation of IL-6, TNF-alpha, and sIL-2R after allogeneic SCT was observed. EDMP also exhibited changes similar to sFasL. The patients with high sTRAIL exhibited significant decrease of sFasL and EDMP as compared with those without high sTRAIL. TNF-alpha and sFasL induced an increase in procoagulant and apoptotic markers in endothelial cells, and EDMP shedding was observed. Furthermore, sTRAIL inhibited the EDMP elevation caused by TNF-alpha and sFasL. The apoptotic markers such as sFasL and sTRAIL exhibited particular changes after SCT. Our results suggest that sTRAIL generation after allogeneic SCT relates to the prevention of GVHD.
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PMID:Role of soluble tumor necrosis factor-related apoptosis-inducing ligand concentrations after stem cell transplantation. 1800 54

Despite many studies on non-HLA genetic polymorphism its role in transplantation is still not well understood. The NK cell receptor gene, MICA gene and Minor histocompatibility (mHag) system makes the puzzle still more intriguingly complex. Studies on cytokine gene polymorphism have enlightened some interesting associations such as the effect of donor IL-6 genotype on acute rejection in renal transplantation. In the bone marrow transplant where each polymorphism is taken as a risk factor for GVHD necessitates prospective testing of non-HLA gene polymorphism and hence, transplant outcome. Various typing methods are now available to identify the non-HLA genetic polymorphisms. A scenario can be envisaged where polymorphisms associated with transplant outcome are tested prior to transplantation at the same time as HLA typing.
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PMID:MHC non -HLA gene polymorphisms in transplantation. 1830 97


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