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)

Lethally irradiated mice reconstituted with histocompatible stem cells from Fas-deficient MRL/lpr mice develop a wasting syndrome reminiscent of chronic graft-versus-host disease. However, reconstitution with double Fas-/Fas ligand (FasL)-deficient stem cells does not result in wasting disease, demonstrating that FasL expression is an important component of the effector mechanisms leading to this syndrome. In the absence of wasting disease double-deficient T cells can induce wild-type B cells to make autoantibodies. These data indicate that autoantibody production is regulated by FasL-expressing T cells, and that Fas-sufficient wild-type B cells differ from Fas-deficient Ipr cells only with regard to their sensitivity to FasL.
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PMID:Double mutant MRL-lpr/lpr-gld/gld cells fail to trigger lpr-graft-versus-host disease in syngeneic wild-type recipient mice, but can induce wild-type B cells to make autoantibody. 1089 16

Allogeneic stem cell transplantation (allo SCT) is now frequently performed for the treatment of haematological malignancies and aplastic anaemia. However, graft-versus-host disease (GVHD) is still the major complication after allo SCT, producing immune deficiency, infection, organ damage and, occasionally, patient death. The antigen-specific signal mediated by the T-cell receptor (TCR) is essential for activation of T-cells; however, additional co-stimulatory signals are required for complete T-cell activation. Therefore, blocking strategies of co-stimulatory signals have been evaluated as targets of therapeutic intervention for GVHD after allo SCT. In a mouse bone-marrow transplantation (BMT) model, the administration of CTLA4-Ig, which blocks the interaction of CD28 on T-cells and B7 molecules on antigen-presenting cells (APCs), can prolong survival of allo BMT recipients, although this effect was not complete. In addition, the anti-CD40L (CD154) monoclonal antibody (mAb), which can interfere with the interaction of CD154 on T-cells and CD40 on APCs, can induce long-term graft survival in the murine model. Combined administration of CTLA4-Ig and anti-CD40L mAb can prevent allograft rejection in primates. Therefore, it seems the most powerful method to prevent the alloimmune response in vivo. The Fas/Fas ligand pathway is also involved in pathogenesis of GVHD. Anti-FasL mAb can reduce the mortality of GVHD and improve intestinal lesions. Recently, it was reported that donor bone marrow treated ex vivo using CTLA4-Ig reconstituted haematopoiesis in vivo with a relatively low risk of GVHD in human allo BMT. Therefore, selective blocking strategies for T-cell co-signalling might be useful for the prevention of GVHD in human allo SCT.
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PMID:T-cell co-signalling molecules in graft-versus-host disease. 1090 5

Death receptors are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Expression and signaling by death receptors and their respective ligands is a tightly regulated process essential for key physiologic functions in a variety of organs, including the skin. Several death receptors and ligands, Fas and Fas ligand being the most important to date, are expressed in the skin and have proven to be essential in contributing to its functional integrity. Recent evidence has shown that Fas-induced keratinocyte apoptosis in response to ultraviolet light, prevents the accumulation of pro-carcinogenic p53 mutations by deleting ultraviolet-mutated keratinocytes. Further- more, there is strong evidence that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of toxic epidermal necrolysis, acute cutaneous graft versus host disease, contact hypersensitivity and melanoma metastasis. With these new developments, strategies for modulating the function of death receptor signaling pathways have emerged and provided novel therapeutic possibilities. Specific blockade of Fas, for example with intravenous immunoglobulin preparations that contain specific anti-Fas antibodies, has shown great promise in the treatment of toxic epidermal necrolysis and may also be useful in the treatment acute graft versus host disease. Likewise, induction of death signaling by ultraviolet light can lead to hapten-specific tolerance, and gene transfer of Fas ligand to dendritic cells can be used to induce antigen specific tolerance by deleting antigen-specific T cells. Further developments in this field may have important clinical implications in cutaneous disease.
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PMID:Death receptors in cutaneous biology and disease. 1095 Dec 28

To determine the role of perforin-mediated cytotoxic T lymphocyte (CTL) effector function in immune regulation, we studied a well-characterized mouse model of graft-versus-host disease (GVHD). Induction of acute GVHD using perforin-deficient donor T cells (pfp-->F1) initially resulted in features of acute GVHD, e.g., engraftment of both donor CD4(+) and CD8(+) T cells, upregulation of Fas and FasL, production of antihost CTL, and secretion of both Th1 and Th2 cytokines. Despite fully functional FasL activity, pfp donor cells failed to totally eliminate host B cells, and, by 4 weeks of disease, cytokine production in pfp-->F1 mice had polarized to a Th2 response. Pfp-->F1 mice eventually developed features of chronic GVHD, such as increased numbers of B cells, persistence of donor CD4 T cells, autoantibody production, and lupuslike renal disease. We conclude that in the setting of B- and T-cell activation, perforin plays an important immunoregulatory role in the prevention of humoral autoimmunity through the elimination of both autoreactive B cells and ag-specific T cells. Moreover, an ineffective initial CTL response can evolve into a persistent antibody-mediated response and, with it, the potential for sustained humoral autoimmunity.
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PMID:Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. 1099 84

Several bone marrow cells and lymphocyte subpopulations, known as "veto cells," were shown to induce transplantation tolerance across major histocompatibility antigens. Recently, it has been suggested that anti-third party CTLs depleted of alloreactivity are endowed with marked veto activity and therefore might potentially facilitate bone marrow allografting without graft versus host disease (GVHD). The veto mechanism is still obscure. While early studies emphasized the role of CD8-mediated apoptosis, more recent evidence indicates a role for Fas-FasL. In the present study we show, by using blocking anti-CD8 antibody, by generating CTLs from FasL or perforin mutated mice, and by gene transfer of FasL, that the veto activity of anti-third party CD8+ CTLs is dependent upon the simultaneous expression of both CD8 and FasL.
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PMID:Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. 1107 Jan 69

Death receptors are a growing family of transmembrane proteins which can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. The best studied to date is Fas (CD95). Expression and signalling by Fas and its ligand (FasL, CD95L) is a tightly regulated process essential for key physiological functions in a variety of organs, including the maintenance of immune homoeostasis. Recently, strong evidence has shown that dysregulation of Fas expression and/or signalling contributes to the pathogenesis of toxic epidermal necrolysis and acute graft-versus-host disease. With these new developments, strategies for modulating the function of Fas signalling have emerged and opened up novel therapeutic possibilities. Specific blockade of Fas, for example with intravenous immunoglobulin preparations containing specific anti-Fas antibodies, has shown great promise in the treatment of toxic epidermal necrolysis and may also be useful in the treatment of acute graft-versus-host disease. Further developments in this field may have important clinical implications for the treatment of such diseases.
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PMID:Fas-mediated cell death in toxic epidermal necrolysis and graft-versus-host disease: potential for therapeutic inhibition. 1110 36

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. One strategy to treat GVHD is to equip donor T cells with a conditional suicide mechanism that can be triggered when GVHD occurs. The herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir system used clinically has several limitations, including immunogenicity and cell cycle dependence. An alternative switch based on chemically inducible apoptosis was designed and evaluated. A chimeric human protein was expressed comprising an extracellular marker (DeltaLNGFR), the Fas intracellular domain, and 2 copies of an FK506-binding protein (FKBP). Primary human T lymphocytes retrovirally transduced with this construct could be purified to homogeneity using immunomagnetic beads. Genetic integrity of the construct was ensured by redesigning repetitive sequences. Transduced T cells behaved indistinguishably from untransduced cells, retaining the ability to mount a specific antiallogeneic immune response. However, they rapidly underwent apoptosis with the addition of subnanomolar concentrations of AP1903, a bivalent "dimerizer" drug that binds FKBP and induces Fas cross-linking. A single 2-hour treatment eliminated approximately 80% of T cells, and multiple exposures induced further apoptosis. T cells were eliminated regardless of their proliferation state, suggesting that the AP1903/Fas system, which contains only human components, is a promising alternative to HSV-tk for treating GVHD.
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PMID:A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. 1122 67

In order to evaluate anti-human Fas antibody, we have established a new graft-versus-host disease (GVHD) model wherein splenocytes of human Fas transgenic mice (hFas-TgM) were transferred to immune-deficient SCID mice. In this model, although host SCID cells are not activated by or responsive to graft hFas-TgM cells, graft hFas-TgM cells are activated by and responsive to host SCID cells and thus cause GVHD symptoms. SCID mice that received hFas-TgM splenocytes had increased human Fas-positive lymphocytes in lymph nodes, decreased in body weight, and developed skin diseases, including rash and alopecia. Administration of novel anti-human Fas antibody HFE7A, which did not induce liver toxicity after administration to mice, decreased the level of the human Fas-positive lymphocytes, blocked the decrease of body weight, and suppressed development of skin diseases in this model. These results indicate that induction of apoptosis to activated graft cells with nontoxic anti-Fas antibody could reduce GVHD symptoms.
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PMID:Therapeutic effect of novel anti-human Fas antibody HFE7a on graft-versus-host disease model. 1135 29

Cross-tolerization of T lymphocytes after apoptotic cell uptake by dendritic cells may be involved in self-tolerance maintenance. Furthermore, immunosuppressive properties are attributed to apoptotic cells. This study evaluated the consequences of apoptotic leukocyte administration in a restrictive engraftment model of murine bone marrow (BM) transplantation. Sublethally irradiated recipients received a limited number of allogeneic BM, with or without irradiated apoptotic leukocytes of different origins. No graft-versus-host disease was observed. Whereas only a low proportion of mice receiving BM cells alone engrafted, addition of apoptotic irradiated leukocytes, independently of the origin (donor, recipient, third-party mice, as well as xenogeneic peripheral blood mononuclear cells), significantly enhanced engraftment. Similar results were obtained after infusion of leukocytes rendered apoptotic by UVB irradiation or by anti-Fas monoclonal antibody stimulation, thus confirming the role of apoptotic cells in engraftment facilitation. Overall, these results suggest that apoptotic leukocytes can nonspecifically facilitate allogeneic BM engraftment. Such a simple approach could be of interest in BM transplantation settings involving an important HLA donor/recipient disparity, a T-cell-depleted graft, or reduced conditioning regimen intensity.
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PMID:Intravenous injection of apoptotic leukocytes enhances bone marrow engraftment across major histocompatibility barriers. 1141 84

Cytotoxic lymphocytes largely comprise CD8(+) cytotoxic T cells and natural killer cells and form the major defense of higher organisms against virus-infected and transformed cells. A key function of cytotoxic lymphocytes is to detect and eliminate potentially harmful cells by inducing them to undergo apoptosis. This is achieved through two principal pathways, both of which require direct but transient contact between the killer cell and its target. The first, involving ligation of TNF receptor-like molecules such as Fas/CD95 by their cognate ligands, results in mobilization of conventional, programmed cell-death pathways centered on activation of pro-apoptotic caspases. This review concentrates on the second pathway, in which the toxic contents of secretory vesicles of the cytotoxic lymphocyte are secreted toward the target cell, and some toxins penetrate into the target cell cytoplasm and nucleus. In addition to invoking a powerful stimulus to caspase activation, this "granule-exocytosis mechanism" provides a variety of additional strategies for overcoming inhibitors of the caspase cascade that may be elaborated by viruses. The key molecular players in this process are the pore-forming protein perforin and a family of granule-bound serine proteases or granzymes. The molecular functions of perforin and granzymes are under intense investigation in many laboratories including our own, and recent advances will be discussed. In addition, this review discusses the evidence pointing to the importance of perforin and granzyme function in pathophysiological situations as diverse as infection with intracellular pathogens, graft versus host disease, susceptibility to transplantable and spontaneous malignancies, lymphoid homeostasis, and the tendency to auto-immune diseases.
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PMID:Unlocking the secrets of cytotoxic granule proteins. 1143 81


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