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)

After bone marrow transplantation many T-lymphocyte functions, including the production of cytokines (CK), such as interleukin 2, are severely depressed for months. The monocyte-derived cytokines tumor necrosis factor alpha and interleukin 6 are molecules central to immune functions. Moreover, they may be involved in graft-versus-host disease and in graft-versus-leukemia reaction. Hence, we have studied the reappearance of these CKs after BMT by analyzing whole blood cultures stimulated in vitro with lipopolysaccharide for 6 hr, followed by testing for the secretion of TNF in the WEHI 164/actinomycin D cytotoxicity bioassay and for IL-6 in the 7 TD 1 proliferation assay. We performed sequential studies in 6 children who were transplanted for aplastic anemia or leukemia with allogeneic bone marrow. We found that the production of both CKs can be induced as early as 10-14 days post BMT at the very beginning of engraftment, indicating that the regenerating monocyte system is recovering rapidly after BMT. Depletion and neutralization experiments confirmed that monocytes are the cellular source of the LPS-induced CK secretion after BMT. Control levels were reached 3 to 4 weeks post BMT. When analyzing the endotoxin-induced CK production in a larger panel of BMT patients after complete reconstitution, we could not detect any impact of acute or chronic GvHD, or of allogeneic or autologous BMT, nor did treatment with cyclosporine A (CsA) show any suppressive effect. Thus, our data show that the CK production of the monocyte/macrophage lineage is quite resistant to factors that do influence other cell lineages of the immune system during BMT. The coincident appearance of monocyte-derived cytokines and of GvHD suggests a role for these cytokines in GvHD in man.
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PMID:Recovery of monocytes after bone marrow transplantation--rapid reappearance of tumor necrosis factor alpha and interleukin 6 production. 192 48

Interleukin 10 (IL-10) is a potent inhibitor of proliferative T cell responses toward alloantigens, and suppresses the production of pro-inflammatory cytokines which are important in cellular activation and recruitment to sites of inflammation. Because of these properties, we hypothesized that high IL-10 production in patients prior to BMT may predict a better outcome. To investigate this, peripheral blood mononuclear cells (PBMNC) were obtained from 58 recipients (11 autologous, 25 related donor (RD), and 22 unrelated donor (URD)), prior to conditioning therapy. PBMNC were cultured for 24 h in the presence and absence of lipopolysaccharide (LPS) and culture supernatants were assayed for IL-10 using an ELISA method. Spontaneously produced and LPS-stimulated IL-10 levels were correlated with the development of transplant-related complications (TRC) including grade II-IV acute GVHD, veno-occlusive disease, idiopathic pneumonia syndrome and multi-organ dysfunction syndrome, and with death before day 100. For the autologous group, there were no TRC and only one death prior to day 100; therefore, no statistical comparisons to IL-10 levels could be made. In the RD group, 36% developed one or more TRC and 24% died before day 100; however, there were no statistically significant associations between spontaneous or LPS-induced IL-10 levels. In URD patients 41% developed TRC and 55% died prior to day 100. In this group, higher levels of spontaneous IL-10 production were associated with a lower overall occurrence of TRC (P = 0.03) and early death (P = 0.04). Our data would indicate that higher levels of IL-10 production prior to URD BMT may predict fewer TRC, as well as early deaths. The hypothesis that high IL-10 production prior to BMT may decrease complications following URD BMT warrants further testing.
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PMID:High spontaneous IL-10 production in unrelated bone marrow transplant recipients is associated with fewer transplant-related complications and early deaths. 1038 51

Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-alpha (TNF-alpha) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-alpha to the development of IPS has not been elucidated. Using a lethally irradiated parent --> F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-alpha, elevated numbers of donor-derived TNF-alpha-secreting T cells, and increased pulmonary macrophage production of TNF-alpha to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-alpha(-/-) donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-alpha-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-alpha secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-alpha resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS. Collectively, these data demonstrate that donor TNF-alpha is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-alpha in the evolution of this process.
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PMID:Donor-derived TNF-alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation. 1506 18

Acute graft versus host disease (aGVHD) after allogeneic bone marrow transplantation (allo-BMT) predominantly involves a Th1-type cytokine response. Interestingly, the Th2-cytokine, Interleukin-13 (IL-13), produced by alloreactive donor T cells in vitro was recently shown to correlate with clinical aGVHD severity. Using an established mouse model, we show that the systemic cytokine milieu following allo-BMT with IL-13-/- donors is characterized by decreases in serum Th2 cytokines and an increase in serum TNFalpha, and ultimately correlates with higher aGVHD mortality compared to allogeneic controls. In vitro studies further demonstrate that both exogenous and T cell-derived IL-13 can regulate TNFalpha production by macrophages following lipopolysaccharide stimulation. Thus, donor-derived IL-13 may have a role in modulating inflammatory cytokine release that is associated with aGVHD.
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PMID:The absence of donor-derived IL-13 exacerbates the severity of acute graft-versus-host disease following allogeneic bone marrow transplantation. 1745 19

Extracorporeal photopheresis (ECP) is emerging as a therapy for graft-versus-host-disease (GVHD), but the full mechanism of action and the impact on immunity have not been fully established. After murine minor histocompatibility antigen-mismatched bone marrow (BM) transplantation (allo-BMT), coinfusion of ECP-treated splenocytes with T cell-replete BM attenuated GVHD irrespective of the donor strain of the ECP-treated splenocytes, and was associated with increased numbers of regulatory T cells. Coculture of myeloid dendritic cells (DCs) with ECP-treated splenocytes resulted in increased interleukin (IL)-10 production after submaximal stimulation with lipopolysaccharide. Furthermore, male myeloid DCs exposed to ECP-treated splenocytes were less potent at inducing CD8(+) HY responses when used as a vaccine in vivo. The efficacy of ECP-treated splenocytes was enhanced when administered just before delayed donor lymphocyte infusion following T cell-depleted allo-BMT, allowing for the administration of sufficient numbers of T cells to respond to myeloid DC vaccination in the absence of a thymus. Finally, the therapeutic effect of ECP-treated splenocytes was lost in recipients of IL-10-deficient BM. We demonstrate that ECP-treated splenocytes attenuate GVHD irrespective of the source of ECP-treated cells via a mechanism that likely involves modulation of DCs and requires IL-10 produced by BM-derived cells. Importantly, the attenuation of GVHD by ECP-treated splenocytes permits donor lymphocyte infusion-dependent responses to DC vaccines after allo-BMT.
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PMID:Extracorporeal photopheresis attenuates murine graft-versus-host disease via bone marrow-derived interleukin-10 and preserves responses to dendritic cell vaccination. 2121 99