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)

Fas (APO-1, CD95) is a type I integral membrane protein initially identified by mAbs that induce apoptotic cell death upon binding to certain tumor cells and its belongs to the TNFR family. Fas is expressed on activated lymphocytes and in various tissues including the liver, lung, intestine, and skin. Molecular cloning of Fas ligand (FasL) revealed that it is a type II integral membrane protein homologous to TNF. FasL is predominantly expressed on activated T and NK cells, and mediates Fas divided by target cell lysis by these effector cells. The Fas/FasL system has been also implicated in the pathogenesis of autoimmune diseases, fulminant hepatitis, GVHD, and AIDS. It has been recently reported that human FasL was released as a 26 kD soluble form from COS cells transfected with human FasL cDNA and activated human T cells. In this communication, metalloproteinase-mediated release of FasL and it's clinical relevance are discussed.
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PMID:[Metalloproteinase-mediated release of human fas ligand]. 874 61

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

Graft-versus-host disease (GvHD) is the major limiting toxicity of allogeneic bone marrow transplantation. T cells are important mediators of GvHD, but the molecular mechanisms that they use to induce GvHD are controversial. Three effector pathways have been described for cytotoxic T lymphocytes: one requires perforin and granzymes, the second Fas (APO-1; CD95) and its ligand. Thirdly, secreted molecules (e.g., TNF-alpha, gamma-IFN) can also mediate cytotoxicity. Together, these mechanisms appear to account for virtually all cytotoxicity induced by activated CTL in standard in vitro lytic assays. Using transplants across histocompatibility barriers, we were able to analyze the contributions of these effector molecules to cell-mediated cytotoxicity in vivo in a GvHD model. We found that Fas ligand is an important independent mediator of class II-restricted acute murine GvHD, while perforin/granzyme-dependent mechanisms have only a minor role in that compartment. In contrast, perforin/ granzyme-dependent mechanisms are required for class I-restricted acute murine GvHD, while Fas ligand is not. The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design. In support of this approach, we provide additional data suggesting that specific perforin/granzyme inhibitors should not adversely affect hematopoietic recovery after transplantation.
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PMID:Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. 925 90

The folate antagonist methotrexate (MTX) is extensively used in graft-versus-host disease, rheumatoid arthritis, and other chronic inflammatory disorders. In addition to its antiinflammatory activity associated with increased release of adenosine, MTX exerts antiproliferative properties by inhibition of dihydrofolate reductase and other folate-dependent enzymes. However, the mechanisms of immunosuppressive properties associated with low-dose MTX treatments are still elusive. We report here that MTX (0.1-10 microM) induces apoptosis of in vitro activated T cells from human peripheral blood. PBL exposed to MTX for 8 h, then activated in drug-free medium, underwent apoptosis, which was completely abrogated by addition of folinic acid or thymidine. Apoptosis of activated T cells did not require interaction between CD95 (Fas, APO-1) and its ligand, and adenosine release accounted for only a small part of this MTX activity. Apoptosis required progression of activated T cells to the S phase of the cell cycle, as it was prevented by drugs or antibodies that interfere with IL-2 synthesis or signaling pathways. MTX achieved clonal deletion of activated T cells in mixed lymphocyte reactions. Finally, in vitro activation of PBL taken from rheumatoid arthritis patients after MTX injection resulted in apoptosis. Altogether, the data demonstrate that MTX can selectively delete activated peripheral blood T cells by a CD95-independent pathway. This property could be used as a new pharmacological end point to optimize dosage and timing of MTX administration. It may account for the immunosuppressive effects of low-dose MTX treatments.
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PMID:Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. 966 73