Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.69 (BMT)
 2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor-alpha (TNF-alpha), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 x DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti-TNF-alpha antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60%< survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti-TNF-alpha antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT.
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PMID:Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. 1019 54

The present studies were designed for investigation of the requirements for cytotoxic function in donor T-cells transplanted to support engraftment after infusion of allogeneic bone marrow. The experiments examined the capacity of donor CD8 T-cells lacking Fas ligand and/or perforin function to facilitate donor B6 congenic (B6-Ly5.1) BM engraftment across major histocompatibility complex class I/II barriers after transplantation. T-cell-depleted BM cells from B6-Ly5.1 donors were transplanted into sublethally irradiated (5.5 Gy) BALB/c recipients together with different lymphocyte populations from wild-type B6 (B6-wt) donors or donors lacking functional cytotoxic pathways. Early presence of lineage-committed donor progenitor cells was assessed by the presence of day 5 splenic colony-forming units-granulocyte-macrophage (CFU-GM). Recipients of BMT without donor T-cells did not demonstrate significant CFU-GM activity 5 days post-BMT. Lineage-committed progenitor cells in recipient spleens could be supported by addition to the BM of wild-type (B6-wt) and cytotoxically single- (perforin, B6-pko or FasL, B6-gld) or double-deficient (B6-cdd) CD8 T-cells. However, B220+-enriched B-cells could not support the presence of day 5 donor CFU-GM. For further assessment of the capacity of cytotoxically impaired T-cells to participate in the engraftment process, the ability of these and normal CD8 cells to support the homing of donor cells to the BM was examined after infusion of carboxyfluorescein diacetete succinimidyl ester-labeled progenitors. In a syngeneic model lacking resistance, cytotoxically impaired donor T-cells supported increased numbers of progenitor cells in the marrow equivalent to the support provided by wild-type donor T-cells. Examination of peripheral chimerism indicated that during the first month after B6-->BALB/c BMT, donor chimerism was detected in BMT recipients receiving unfractionated T-cells or CD8+ T-cells from B6-wt donors, and chimerism was maintained at least 80 days after BMT. In contrast, B6-cdd unfractionated or CD8+ T-cells failed to maintain long-term B6 donor chimerism in the host. Experiments with highly enriched populations of positively selected CD8+ T-cells from B6-pko, B6-gld, or B6-cdd donors demonstrated that although each of these T-cell populations could promote the initial presence of donor CFU-GM early post-BMT, B6-pko and B6-cdd CD8+ T-cell populations were not able to support long-term peripheral chimerism. These results demonstrate that donor T-cells lacking major cytotoxic effector pathways have functions that support initial donor progenitor cell presence in the host hematopoietic compartment after BMT. They also demonstrate that support of long-term donor BM engraftment requires CD8+ T-cells with intact cytotoxic, that is, perforin, function. Finally, syngeneic B6-->B6 BMT suggests activation of CD8+ T-cells posttransplantation apparently is required to support enhanced progenitor cell activity. This study provides new findings concerning the role of cytotoxic function in the process of facilitating allogeneic donor BM engraftment.
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PMID:The contribution of cytotoxic and noncytotoxic function by donor T-cells that support engraftment after allogeneic bone marrow transplantation. 1246 77

To evaluate the implications of soluble Fas ligand (sFasL) in acute graft-versus-host disease (aGVHD) and discriminating symptoms of aGVHD from those of infection, plasma levels of sFasL were assessed in 84 plasma samples from 13 patients who had undergone allogeneic BMT by using a sandwich enzyme-linked immunological assay (ELISA). Plasma sFasL levels of the patients before BMT and at different time points during the post-BMT period were measured. Three points were concluded: (1) Plasma sFasL levels were higher in patients with grade II-IV aGVHD than in those with grade 0 or I aGVHD. (2) Plasma sFasL levels in patients with infection were not statistically different from those in patients without infection. (3) In seven patients with grade II-IV aGVHD, the plasma sFasL levels at pre-BMT were much lower than those of the six patients with 0 or I grade aGVHD. sFasL may be useful for the diagnosis of aGVHD and for differentiating aGVHD from other BMT related complications such as infection.
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PMID:Plasma Soluble Fas Ligand Levels in Hemopathic Patients Undergoing Allogeneic Bone Marrow Transplantation. 1257

In order to explore a new special and effective way to prevent graft versus host disease (GVHD) after allogenic bone marrow transplantation (allo-BMT), the stem cell antigen-1 (Sca-1) + early hematopoietic cells (EHC) from BALB/c mouse (H-2d) were introduced with exogenous mouse Fas ligand (mFasL) cDNA gene by the retrovirus-mediated gene transfer and expanded for one week, and then they were co-cultured with the spleen mononuclear cells (SMNC) from BAC mouse (H-2dxb) as one way mixed lymphocyte reaction (OWMLR). The cytotoxicity of treated BAC mouse SMNC against Na2 51CrO4 labeling SMNC from BALB/c mouse was observed. The bone marrow mononuclear cells (BMMNC) from BAC mouse treated by the above methods were transplanted into lethally-irradiated congenic BALB/c mice to observe the occurrence of GVHD. The results showed that the SMNC from BAC mouse after OWMLR with exogenous mFasL cDNA gene-transduced hematopoietic cells (HC) from BALB/c mouse in a ratio of 1 to 5 exhibited an obvious inhibition of the cytotoxicity against the BALB/c mouse spleen cells at different effector/target ratios as compared to the control group (P<0.01). The grade I GVHD or no GVHD and the 80% survival rate at day 60 post-BMT were observed in the BALB/c mouse receiving BAC mouse BMMNC treated with similar way, while the grade II - III GVHD and the 20% survival rate were noted in the control group (P<0.01). It is suggested that the attenuation of GVHD in allo-BMT recipient could be successfully achieved through FasL-Fas pathway in an H-2 haplotype disparate mouse combination.
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PMID:Attenuation of GVHD for allo-bone marrow transplantation recipient by FasL-Fas pathway in an H-2 haplotype disparate mouse combination. 1558 91

Fas (CD95) is a member of the TNF-receptor family expressed on a wide range of cells. Interaction of Fas with its receptor, Fas ligand (Fas-L), stimulates an intracellular cascade of events that leads to apoptosis. Because apoptosis of inflammatory cells plays a key role in atherosclerosis we sought to determine the role of Fas in the development of atherosclerosis by repopulating the bone marrow cells of atherosclerosis-prone low density lipoprotein receptor null (LDL-R-/-) mice with either cells from lpr mice (lpr-BMT) that have defective Fas expression or from control mice (WT-BMT). The lpr-BMT mice exhibited no peripheral blood Fas expression 4 weeks after BMT. After consuming an atherogenic diet for 16 weeks, lpr-BMT mice developed atherosclerotic lesions characterized by smaller fibrous area with thinner fibrous cap and less TUNEL-positive staining compared to WT-BMT mice, although overall lesion size in lpr-BMT mice was similar to that of WT-BMT mice. Examination of a series of human atherosclerotic lesions revealed that many Fas-positive cells were colocalized with CD68-positive macrophages. Although apoptotic cells were rarely observed in the foam cell-rich fatty streak lesions, apoptotic CD68-positive macrophages in advanced lesions were detected in areas rich with inflammatory cells near the necrotic core. These observations suggest that Fas expression by the macrophages in atherosclerotic lesions can influence the plaque morphology towards a more fibrous type.
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PMID:Defective Fas Expression on Bone Marrow Derived Cells Alters Atherosclerotic Plaque Morphology in Hyperlipidemic Mice. 2632 29