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)

The CD95 (APO-1/Fas) receptor mediates programmed cell death in apoptosis sensitive cells upon oligomerization either by CD95 antibody or by its natural ligand, CD95 ligand (CD95 L). Studies on tissue distribution have shown that CD95 is broadly expressed in normal adult tissues. Furthermore, the spectrum of CD95-expressing cells in inducibly enlarged in the context of chronic inflammation. In contrast, the number of cells capable of expressing CD95 L is strikingly limited to small subsets of lymphocytes and histiocytes and to some specialized normal epithelia. This suggests that cell death via this receptor/ligand system, although possible in almost every tissue and cell type, is limited to very special scenarios one of which is chronic lymphohistiocytic inflammation. The lpr/lpr mouse and the gld/gld mouse are well-known models for autoimmune disorders. Both mutants have abnormal B and T lymphocytes and high titers of autoantibodies. Recently, these mice have been discovered to have functional defects in the murine equivalents of human CD95 and CD95 L, respectively. This suggests that the CD95/CD95 L system might act by preventing autoimmune disease, e.g., by preventing emergence of autoreactive T and B lymphocytes. A human homologue of the lpr mutation has been described as autoimmune lymphoproliferative syndrome. We show that, in mice, CD95/ CD95 L might be operative in experimental graft versus host disease. Further, we suggest a role of this system in early steps of ulcerative colitis. Considering our observations against the background of current literature, CD95/CD95 L is likely to play a dual role in induction and maintenance of peripheral tolerance on the one hand and in tissue damage by chronic inflammation on the other.
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PMID:[CD95 (APO-1/Fas) and CD95-ligand (CD95L). Implications of these apoptosis mediating receptor/ligand systems in the pathogenesis of autoimmune diseases]. 906 94

The increasing use of umbilical cord blood in transplantation has led to a renewed interest in the immunological characterisation of this material. This study addresses the question of whether the CD95 molecule and its ligand are expressed and are functional in mediating cell death in cord blood mononuclear cells. These molecules have a crucial role in the homeostasis of haematopoietic cell populations in the adult and also contribute to graft-versus-host disease. CD95 is the most well studied receptor mediating a signal for cell death by apoptosis and its inducible ligand has been demonstrated to mediate cell death of multiple types of CD95 expressing cells. The object of this study was to examine whether cord blood mononuclear cells could behave either as targets for CD95-mediated cell death or as mediators of cell death due to the expression of CD95L. The results of this study lead us to suggest that cord blood mononuclear cells enjoy some immunological privilege due to the relatively low level of expression of CD95 (in comparison with adult peripheral blood lymphocytes) and the expression of the CD95 ligand.
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PMID:Characterisation of the roles of CD95 and CD95 ligand in cord blood. 971 85

Hydroxy acid-based matrix metalloproteinase (MMP) inhibitors have been shown to inhibit tumor infiltration and growth, endotoxin shock, and acute graft-versus-host disease. Blockade of the release of soluble tumor necrosis factor-alpha (TNF-alpha) and CD95 ligand (CD95L; FasL) from cell-associated forms is reportedly involved in the mechanism of the drug effect. We investigated the effect of a MMP inhibitor, KB-R7785, on host resistance against Listeria monocytogenes infection, in which TNF-alpha is essentially required for the defense, in mice. The administration of KB-R7785 exacerbated listeriosis, while the drug prevented lethal shock induced by lipopolysaccharide and D-galactosamine. KB-R7785 inhibited soluble TNF-alpha production in spleen cell cultures stimulated by heat-killed L. monocytogenes and the drug treatment reduced serum TNF-alpha levels in infected mice, whereas the compound was ineffective on the modulation of interferon-gamma and interleukin-10 production. The effect of KB-R7785 was considered to be dependent on TNF-alpha because the drug failed to affect L. monocytogenes infection in anti-TNF-alpha monoclonal antibody-treated mice and TNF-alpha knockout mice. Anti-CD95L monoclonal antibody was also ineffective on the infection. These results suggest that induction of infectious diseases, to which TNF-alpha is critical in host resistance, should be considered in MMP inhibitor-treated hosts.
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PMID:Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection. 1106 65

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

T cells with natural killer cell phenotype and function (NKT cells) have been described in both human and murine tissues. In this study, culture conditions were developed that resulted in the expansion of CD8(+) NKT cells from bone marrow, thymus, and spleen by the timed addition of interferon-gamma (IFN-gamma), interleukin 2 (IL-2), and anti-CD3 monoclonal antibody. After 14 to 21 days in culture, dramatic expansion of CD3(+), CD8(+), alphabetaT-cell receptor(+) T cells resulted with approximately 20% to 50% of the cells also expressing the NK markers NK1.1 and DX5. The CD8(+) NKT cells demonstrated lytic activity against several tumor target cells with more than 90% lysis by day 14 to day 21 of culture. Cytotoxicity was observed against both syngeneic and allogeneic tumor cell targets with the greatest lytic activity by the cells expressing either NK1.1 or DX5. The expanded CD8(+) NKT cells produce T(H)1-type cytokines with high levels of IFN-gamma and tumor necrosis factor alpha. Expansion of the CD8(+) NKT cells was independent of CD1d. Ly49 molecules were expressed on only a minority of cells. A single injection of expanded CD8(+) NKT cells was capable of protecting syngeneic animals from an otherwise lethal dose of Bcl1 leukemia cells. Expanded CD8(+) NKT cells produced far less graft-versus-host disease (GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8(+) NKT cells as compared to splenocytes were injected. This reduction in GVHD was related to IFN-gamma production since cells expanded from IFN-gamma knock-out animals caused acute lethal GVHD, whereas cells expanded from animals defective in fas ligand, fas, IL-2, and perforin did not. These data indicate that CD8(+) NKT cells expanded in this fashion could be useful for preserving graft-versus-leukemia activity without causing GVHD.
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PMID:Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. 1134 13

Allogeneic immune responses, which are initiated by dendritic cells (DCs) of both donor and host origins, remain a major obstacle in organ transplantation. Presentation of intact major histocompatibility complex (MHC) molecules by allogeneic DCs and allogeneic peptides by syngeneic DCs leads to complex allogeneic immune responses. This study reports a novel strategy designed to suppress both pathways. A stable DC line XS106 (A/J mouse origin) was transfected with CD95L cDNA and fused with splenic DCs purified from allogeneic BALB/c mice. The resulting "killer" DC-DC hybrids: (1) expressed CD95L and MHC class I and class II molecules of both A/J and BALB/c origins, while maintaining otherwise characteristic surface phenotypes of mature DCs; (2) inhibited MHC class I- and class II-restricted mixed leukocyte reactions between the parental strains by triggering apoptosis of alloreactive T cells; and (3) abolished delayed-type hypersensitivity responses of A/J (and BALB/c) mice to BALB/c-associated (and A/J-associated) alloantigens when injected intravenously into A/J (and BALB/c) mice. The onset of graft-versus-host disease in (BALB/c x A/J) F1 hosts receiving A/J-derived hematopoietic cell transplantation was suppressed significantly (P <.001) by killer DC-DC hybrid treatment. These results form both technical and conceptual frameworks for clinical applications of CD95L-transduced killer hybrids created between donor DCs and recipient DCs in the prevention of allogeneic immune responses following organ transplantation.
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PMID:Immunosuppressive properties of CD95L-transduced "killer" hybrids created by fusing donor- and recipient-derived dendritic cells. 1171 89

Fas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versus-host disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-alpha, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-alpha. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an inhibitor of caspase-8, the upstream caspase coupled to CD95 death signaling. Vascular lesions are likely to play an important role in the pathogenesis of allogeneic immune responses and of other diseases involving circulating CD95L-expressing cells or smCD95L, and the prevention of CD95-mediated death signaling in endothelial cells may have therapeutic implications in these diseases.
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PMID:CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications. 1192 85

Depletion of T lymphocytes from allogeneic bone marrow transplants successfully prevents the development of graft-versus-host disease (GvHD) but is associated with impaired engraftment, immunosuppression, and abrogation of the graft-versus-leukemia effect. We therefore explored the possibility of selectively eliminating alloreactive T cells by CD95/CD95L-mediated activation-induced cell death (AICD) in a major histocompatibility complex allogeneic murine model system. Activation of resting or preactivated T lymphocytes from C3H/HeJ (H-2(k)) mice was induced with irradiated BALB/cJ (H-2(d)) mouse-derived stimulators. Substantial decrease (> or = 80%) of proliferative and lytic responses by activated alloreactive T cells was subsequently achieved by incubating the mixed lymphocyte culture with an agonistic monoclonal antibody to CD95, and residual T cells recovered did not elicit alloreactivity upon challenge to H-2(d). Depletion of alloreactive T lymphocytes by AICD was specific because reactivity to an I-A(d)-restricted ovalbumin (OVA) peptide by OVA-specific CD4(+) T cells mixed into the allogeneic T-cell pool and subjected to induction of AICD in the absence of OVA peptide could be preserved. Adoptive transfer of donor-derived allogeneic T lymphocytes, depleted from alloreactive T cells by AICD in vitro, in the parent (C3H/He) to F(1) (C3H/He x BALB/c) GvHD model prevented lethal GvHD. The results presented suggest that alloreactive T cells can effectively be depleted from allogeneic T cells by induction of AICD to prevent GvHD and might introduce a new strategy for the separation of GvH-reactive T cells and T cells mediating antiviral and possibly graft-versus-leukemia effects.
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PMID:Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death. 1192 98

Death receptors (DRs) are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Eight human DRs (Fas, TNF-R1, TRAMP, TRAIL-R1, TRAIL-R2, DR-6, EDA-R and NGF-R) have been identified. The best studied to date is Fas (CD95). Expression and signaling 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 homeostasis. Recently, strong evidence has shown that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of tissue destructive diseases such as graft-versus-host disease, toxic epidermal necrolysis, multiple sclerosis and stroke. With these new developments, strategies for modulating the function of Fas signaling have emerged and provided novel protein-based therapeutic possibilities that will be discussed herein. Selective triggering of DR-mediated apoptosis in cancer cells is an emerging approach that is being intensely investigated as a mode of cancer therapy. Local administration of Fas agonists, and more promisingly, systemic use of soluble recombinant forms of TRAIL have shown efficacy in preclinical models of the disease. Developments in this field that may have important clinical implications for the treatment of cancer are reviewed.
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PMID:Protein-based therapeutic approaches targeting death receptors. 1265

Antithymocyte globulins (ATGs), the immunoglobulin G (IgG) fraction of sera from rabbits or horses immunized with human thymocytes or T-cell lines, are used in conditioning regimens for bone marrow transplantation, in the treatment of acute graft-versus-host disease, in the prevention or treatment of acute rejection in organ transplantation, and in severe bone marrow aplasia. In nonhuman primates, ATGs induce rapid, dose-dependent, T-cell depletion in peripheral lymphoid tissues, where apoptotic cells can be demonstrated in T-cell zones. We show here that increasing ATG concentrations in vitro resulted in reduced lymphocyte proliferative responses, associated with a rapid increase in the percentage of apoptotic cells. Apoptosis did not require prior exposure to interleukin-2, nor did it result in CD178/CD95 or tumor necrosis factor/tumor necrosis factor receptor (TNF/TNF-R) interactions; it was therefore clearly different from activation-induced cell death. Cytochrome c release, caspase-9, and caspase-3 activation were not implicated, excluding a direct involvement of the intrinsic mitochondrial pathway. The cysteine protease inhibitor E64d and cathepsin-B-specific inhibitors conferred significant protection, whereas apoptosis was associated with the release of active cathepsin B into the cytosol. These data demonstrate a role for cathepsin B in T-cell apoptosis induced by ATGs at concentrations achieved during clinical use.
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PMID:Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion. 1289 46


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