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)

Immunomodulatory properties are attributed to apoptotic cells. These properties have been used to modulate allogeneic immune responses in experimental transplantation settings. In independent studies, apoptotic cell infusion has been shown to favor hematopoietic cell engraftment, to increase heart graft survival, and to delay the lethal onset of graft-versus-host disease (GVHD). The goal of this review was to discuss how apoptotic cell infusion interferes with graft rejection or host rejection (i.e., GVHD) and to focus on the potential mediators or "perpetuators" involved in apoptotic cell-induced immunomodulation. Particular emphasis on apoptotic cell phagocytosis, transforming growth factor (TGF)-beta secretion, and regulatory T cell induction was performed. Stimulating "naturally" immunosuppressive molecules (i.e., TGF-beta) or immunomodulatory cells ("alternatively-activated" macrophages, certain dendritic cell subsets, or regulatory T cells) in a physiological manner by using apoptotic cell infusion can be a promising way to induce tolerance.
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PMID:Mediators involved in the immunomodulatory effects of apoptotic cells. 1763 10

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematological malignancies and inherited diseases. However, acute graft-versus-host-disease (aGVHD) is a major life-threatening complication after allo-HCT and there are few therapeutic options for severe steroid-refractory aGVHD. Preliminary studies on co-transplantation of mesenchymal stem cells (MSCs) have shown an improvement in or resolution of severe aGVHD. However, the mechanism underlying this immunosuppressive effect has not been elucidated. Most of the data suggest that the immunosuppressive effect involves soluble factors such as IL-6 or TGF-beta as well as cell-cell contact dependence. MSCs interact either directly with T cells or indirectly via other immune cells such as dendritic cells and NK cells. Here we review the immunomodulatory function of MSCs in allo-HCT and their potential usefulness in the treatment or prevention of severe acute GVHD.
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PMID:Mesenchymal stem cells for treatment and prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation. 1950 66

Extracorporeal photochemotherapy (ECP) is a well established treatment for both cutaneous T cell lymphoma (CTCL) and graft-versus-host disease (GVHD). However, the general effector mechanism is not fully settled. Twenty-four patients with CTCL and 14 patients with GVHD were included to assess the relative numbers of regulatory T cells (Treg) and any change in the serum cytokine profile during 6 months of ECP therapy. The relative amount of Treg cells was twice as high in CTCL compared to GVHD and healthy controls. TGF-beta was on average three times higher in GVHD than in CTCL. Both patient groups had a small but significant increase in TGF-beta after treatment. Our results indicate a strengthened Treg function as a result of ECP. Elevated TGF-beta may indicate high Treg activation in GVHD, whereas an increased number of Treg cells in CTCL could be interpreted as a response that is involved in down-regulating the lymphoma cells.
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PMID:Cutaneous T cell lymphoma and graft-versus-host disease: a comparison of in vivo effects of extracorporeal photochemotherapy on Foxp3+ regulatory T cells. 1977 1

Systemic sclerosis (SSc) is a fibrosing connective tissue disease with significantly increased mortality. Therapeutic options to treat fibrosis are limited. The small molecule tyrosine kinase inhibitor imatinib and related drugs such as dasatinib and nilotinib target simultaneously two of the major profibrotic pathways, TGFbeta- and PDGF- signaling. Imatinib, dasatinib and nilotinib inhibit collagen synthesis in cultured fibroblasts and have potent anti-fibrotic effects in animal models of different fibrotic diseases. Moreover, several case reports, case series and uncontrolled studies on patients with SSc, mixed connective tissue disease, nephrogenic systemic fibrosis and in particular sclerodermatous graft versus host disease (cGvHD) report regression of fibrosis and good tolerability. However, the results of larger controlled trials, which are currently ongoing, are needed before any conclusions on efficacy and tolerability can be drawn. Until the results of these trials are available, we discourage off-label use of Imatinib in single patients.
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PMID:Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. 1999 44

Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs.
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PMID:Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. 2023 66

Graft-versus-host disease (GVHD) is a frequent and life threatening complication of allogeneic haematogenesis stem cell transplantation (aHSCT). The correlation of CD4(+)CD25(+) regulatory T cells (Tregs) in the patients after aHSCT to the occurrence and severity of acute and chronic GVHD (aGVHD and cGVHD) is not fully investigated. Here, we examined the levels of CD4(+)CD25(+) Tregs by assessment of CD4(+)CD25(high) and CD4(+)CD25(+)CD127(low) in peripheral blood, and the levels of serum TGF-beta and TNF-alpha in 56 patients at early immune reconstitution following aHSCT. Our data showed a significant reduction in the frequency of Tregs in patients with grades II-IV aGVHD and extensive cGVHD compared to healthy controls. Moreover, a decreased level of CD4(+)CD25(+) Tregs was correlated to increased severity of GVHD. The levels of CD4(+)CD25(+) Tregs in non-GVHD groups were however significantly higher than that in healthy controls. A significant decrease in the levels of TGF-beta and a significant increase the levels of TNF-alpha was also seen with increased severity of GVHD. This study suggested that measurement of CD4(+)CD25(+) Tregs along with serum TGF-beta and TNF-alpha at early immune reconstruction after aHSCT may indicate the onset and severity of both aGVHD and cGVHD.
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PMID:Decrease of CD4(+)CD25(+) regulatory T cells and TGF-beta at early immune reconstitution is associated to the onset and severity of graft-versus-host disease following allogeneic haematogenesis stem cell transplantation. 2040 84

The introduction in 1974 of psoralens UVA (PUVA) therapy followed in 1987 by extracorporeal photopheresis (ECP) has launched UV light in medicine field. A significant number of potential mechanisms could be linked to the basic cellular UV action (i.e., DNA damage and subsequent cells apoptosis). Phagocytosis by macrophages and dendritic cells (DCs) leads, through a receptor-mediated process, to their modulation. A state of antigen-specific tolerance is induced by induction of Treg cells, inhibition of DCs, which remain at a an immature state, inhibition of production of the proinflammatory cytokines IL-2, IFN-gamma, TNF-alpha and IL-12, and induction of production of cytokines IL-10, TGF-beta and IL-1Ra. Beside cutaneous T-cell lymphoma, use of ECP remains experimental except for graft-versus-host disease, especially the chronic-resistant form. The sparing action of corticosteroids as described in studies on transplantation deserves further attention.
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PMID:UV-induced immunosuppressive and anti-inflammatory actions: mechanisms and clinical applications. 2063 42

The TiO(2) nanotube layers fabricated by electrochemical anodization have received considerable attention in dentistry and orthopedic medicine due to their increased osseointegration compared with the unanodized titanium. The molecular mechanisms underlying the interactions between nanotubes and osteoblasts is unknown. To examine this, the mRNA expression profile of MG-63 osteoblast-like cells cultured on the TiO(2) nanotubes was explored by DNA microarray. The differentially expressed genes were identified by bioinformatics analysis. Gene ontology (GO) and Go-map network analysis indicated that the TiO(2) nanotubes enhanced osteoblast proliferation and differentiation and decreased osteoblast adhesion and immunization. The expressions of genes were mainly increased in pathways influencing cell proliferation and differentiation (Cell cycle, Terpenoid backbone biosynthesis, and TGF-beta signaling) and were decreased in pathways controlling cell immunization (Cell adhesion molecules (CAMs), Allograft rejection, and Graft-versus-host disease). Signal network analysis generated from differentially expressed genes suggested that CTNNB1 (beta-catenin) was the central gene for increasing osteoblast proliferation and differentiation, and IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma) was the central gene for repressing osteoblast immunization on nanotube layers. These two genes were further confirmed by quantitative PCR. The identified signal pathways and central genes in the study are well correlated with osteoblast phenotype. Furthermore, microarray-based bioinformatics analysis is a powerful tool in efficiently understanding molecular mechanisms underlying the interactions between osteoblasts and the nanotube layers.
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PMID:Microarray-based bioinformatics analysis of osteoblasts on TiO2 nanotube layers. 2226 Nov 77

The balance between immunostimulation and immunoregulation in T cell immunity is achieved by maintaining specific ratios of Th1, Th2, Th3 and Tr1 cells. Here, we investigate levels of type 1 (IFN-gamma; NK1), type 2 (IL-13; NK2), type 3 (TGF-beta; NK3) and regulatory (IL-10; NKr) cytokines in peripheral blood to assess the cytokine profiles of natural killer (NK) cells following human allogeneic hematopoietic stem cell transplantation (allo-HSCT). NK2 and NK3 cell expansion was observed after allo-HSCT; levels of NKr cells reached donor levels at day 15, though levels of NK1 cells were consistently lower than donor levels until day 60 after allo-HSCT. Multivariate analysis showed that a higher level of NK1 cells by day 15 was associated with a lower overall risk of acute graft-versus-host disease (GVHD) (HR 0.157, P=0.010) as well as II-IV acute GVHD (HR 0.260, P=0.059). Furthermore, higher levels of NK1 cells by day 15 were correlated with lower rates of cytomegalovirus (CMV) reactivation (HR 0.040, 0.005-0.348, P=0.003). These results indicate that rapid reconstitution of NK cells, especially NK1 cells, can help prevent the development of GVHD as well as CMV reactivation after allogeneic transplantation.
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PMID:Rapid reconstitution of NK1 cells after allogeneic transplantation is associated with a reduced incidence of graft-versus-host disease. 2954 91


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