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)

Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8(+) T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8(+) T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-beta dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-beta activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8(+) T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-beta-dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8(+) T cells during GVHD pathogenesis.
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PMID:TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. 1589 78

Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.
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PMID:Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion. 1596 5

Peripheral tolerance is mediated by multiple mechanisms such as anergy and/or active suppression of effector T cells by T regulatory (Tr) cells. Among the CD4(+) Tr cells, T regulatory type 1 cells (Tr1) have been shown to down-modulate immune responses through production of the immunosuppressive cytokines IL-10 and TGF-beta. Tr1 cells maintain peripheral tolerance, control autoimmunity, and prevent allograft rejection and graft versus host disease (GvHD). Cellular therapy with ex vivo generated Tr1 cells has been proven to be effective in several preclinical models of T cell-mediated pathologies and therefore, represents a promising approach for clinical application. This review will summarize the new findings on Tr1 cells, the recent development of methods for their ex vivo expansion, and their potential clinical relevance as cellular therapy.
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PMID:Tr1 cells: from discovery to their clinical application. 1646 9

As a functionally and phenotypically distinctive T cell subpopulation, CD4+CD25+ regulatory T cells are anergic and retain their ability to suppress antigen-driven response of CD4+CD25- cells in a contact-dependent manner or through a way of secreting immunosuppressive cytokines such as IL-10 and TGF-beta. Graft-versus-host disease (GVHD) is one of the major complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recently, some researches on the relationship between donor CD4+CD25+ regulatory T cells and GVHD severity produced two contradictory conclusions: one is CD4+CD25+ regulatory T cells that can prevent GVHD efficiently; the other is that GVHD is associated with the increased numbers of peripheral blood CD4+CD25+ regulatory T cells. The answer to this question will provide a new idea for clinic therapy of GVHD. In this review some new research progresses in the related area, such as the CD4+CD25+ regulatory T cells, the phenotype, characteristics, immunoregulatory mechanisms of CD4+CD25+ regulatory T cells, as well as the relation of CD4+CD25+ with GVHD were presented.
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PMID:[CD4+CD25+ regulatory T cells and their function in graft-versus-host disease--review]. 1663 27

Induction of apoptosis and changes to cytokine secretion patterns have been implicated in the mechanism of action of extracorporeal photopheresis (ECP). Lymphocyte apoptosis is initially detected in significant numbers prior to re-infusion and by 48 h post-ECP the majority of treated lymphocytes are apoptotic. The early apoptosis involves changes to mitochondrial function, reversal of the Bcl-2/Bax ratio and externalisation of phosphatidylserine. Apoptotic lymphocytes, observed from 20 h post-ECP, are associated with enhanced levels of CD95 and Fas-ligand. For cutaneous T cell lymphoma (CTCL), processing of the apoptotic lymphocytes, by suitable antigen presenting cells (APCs), is suggested to induce a clonal cytotoxic response which targets the malignant T cell population. Increased levels of TNFalpha and IFNgamma, observed post-ECP in monocytes and lymphocytes, respectively, are thought to further contribute to the proposed anti-tumour reaction seen in CTCL. However, down-regulation of pro-inflammatory cytokines and enhanced anti-inflammatory responses have been reported following ECP treatment. These immune responses may contribute to the tempering of the inflammatory conditions, such as graft versus host disease, which respond to ECP. Furthermore, untreated monocytes exposed to ECP-treated lymphocytes have also demonstrated a shift in monocyte cytokine-secretory pattern, toward one associated with immune tolerance. Recently, a mechanism of ECP-induced immune tolerance has been linked to the stimulation of the anti-inflammatory cytokines IL10 and TGFbeta by T regulatory cells, following the infusion of ECP-treated CD11c(+) APCs. Ultimately, the multifaceted responses, induced by ECP, may explain the diversity of clinical conditions that benefit.
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PMID:Extracorporeal photopheresis: a focus on apoptosis and cytokines. 1679 26

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

Immune homeostasis is important for the protection of a host from pathogen aggression, as well as for preventing autoimmunity. Dendritic cells (DCs), the most potent antigen presenting cells, are critical in innate, adaptive immunity and in central tolerance. Recently, their involvement in peripheral tolerance has been shown. Whether DCs induce immunity or tolerance depends on their state of maturation. Different subsets of tolerogenic DCs have been identified in vivo, either in physiological, or pathological conditions, such as tumors, or GVHD. Moreover, tolerogenic DCs can be generated in vitro, by using different culture conditions, such as IL-10 or TGF-beta. In our study, we obtained tolerogenic DCs, by culturing them in the presence of human mesenchymal stem cells (MSCs).
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PMID:The regulatory role of dendritic cells in the immune tolerance. 1682 8

Quiescent T cells express Tob, an APRO gene family member, which functions as a transcriptional regulator. Subtractive hybridization identified Twisted gastrulation (Tsg) as one of the genes suppressed by Tob. Tsg is a secreted protein that interacts with Drosophila decapentaplegic (Dpp) and its vertebrate orthologs BMP2/4 and regulates morphogenetic effects in embryos. Here, we report the expression and function of Tsg in human T cells. Tsg mRNA was almost undetectable in unstimulated T cells and was up-regulated after activation by TCR/CD3 and either CD28, IL-2, or PMA. Tsg protein had no effect on responses of primary T cells to TCR/CD3 stimulation but had a potent inhibitory effect on proliferation and cytokine production of primed alloreactive CD4+ cells. Surprisingly, Tsg did not affect phosphorylation of the BMP-specific Smad1 but induced phosphorylation of the TGF-beta-specific Smad2 and mediated DNA binding on Smad3/4 consensus-binding sites, suggesting that it acted downstream of TGF-beta. In vitro association assays revealed a direct interaction of Tsg and TGF-beta proteins. Thus, Tsg functions as an agonist synergizing with TGF-beta to inhibit T-cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases.
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PMID:Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-beta signaling in activated T lymphocytes. 1716 48

TGF-beta is a pluripotent cytokine that is capable of inducing the expression of Foxp3 in naive T lymphocytes. TGF-beta-induced cells are phenotypically similar to thymic-derived regulatory T cells in that they are anergic and suppressive. We have examined the cytokine and costimulatory molecule requirements for TGF-beta-mediated induction and maintenance of Foxp3 by CD4(+)Foxp3(-) cells. IL-2 plays a non-redundant role in TGF-beta-induced Foxp3 expression. Other common gamma-chain-utilizing cytokines were unable to induce Foxp3 expression in IL-2-deficient T cells. The role of CD28 in the induction of Foxp3 was solely related to its capacity to enhance the endogenous production of IL-2. Foxp3 expression was stable in vitro and in vivo in the absence of IL-2. As TGF-beta-induced T regulatory cells can be easily grown in vitro, they may prove useful for the treatment of autoimmune diseases, for the prevention of graft rejection, and graft versus host disease.
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PMID:Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. 1737 55

Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation and is a major source of morbidity and mortality. Two main forms of GVHD occur: cytotoxic GVHD (Cyt GVHD), in which TNFalpha is a critical cytokine in epithelial injury, and sclerodermatous GVHD (Scl GVHD), in which TGFbeta plays a major role in fibrosis. To understand the critical early events in GVHD and scleroderma, we are studying a murine model that uses differences in minor histocompatibility antigens to generate Scl GVHD. We asked the question: what is the immune environment in this model that promotes fibrosis rather than the epithelial injury of Cyt GVHD? We found that in Scl GVHD, cutaneous CD4+ T cells produced IFNgamma and IL-2 but not TNFalpha, also absent by gene array analysis. The role of cutaneous CD4+ T cells in Scl GVHD may not be an active process through production of TGFbeta, but may rather be a passive one due to lack of antigen-presenting cell (APC) support for CD4+ T cells and failure to produce TNFalpha, a potent inhibitor of TGFbeta-induced fibrosis as well as inducer of keratinocyte apoptosis. These APC-T cell interactions and the cytokine environment promote fibrosis rather than cytotoxic epithelial injury in skin in Scl GVHD.
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PMID:Absence of cutaneous TNFalpha-producing CD4+ T cells and TNFalpha may allow for fibrosis rather than epithelial cytotoxicity in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. 1742 41


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