Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gliotoxin, an epipolythiodioxopiperazine, is a fungal metabolite that causes genomic DNA degradation preferentially in certain blood cell types including T lymphocytes and macrophages. Gliotoxin has previously been used to treat murine allogeneic bone marrow prior to transplantation into irradiated recipients, and in this situation the drug prevents development of graft-versus-host disease, and permits the establishment of allogeneic bone marrow chimeras. We have examined the nature of the cells that survive gliotoxin treatment and report here that gliotoxin selectively spares a unique class of haemopoietic stem cell that forms large (HPP) colonies in the presence of mixtures of M-CSF and IL-3. We confirm that the cells which survive gliotoxin treatment are capable of reconstituting the haemopoietic system in allogeneic lethally irradiated mice.
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PMID:Gliotoxin treatment selectively spares M-CSF- plus IL-3-responsive multipotent haemopoietic progenitor cells in bone marrow. 170 26

A phase I dose escalation trial of recombinant human macrophage colony-stimulating factor (rhM-CSF) in combination with conventional antifungal therapy was conducted in 24 marrow transplant recipients with invasive fungal infection. Daily doses ranged from 100 to 2,000 micrograms/m2/d. Toxicity, such as constitutional symptoms, directly ascribed to rhM-CSF was not observed; however, transient, dose-related thrombocytopenia was observed. Patients who received 2,000 micrograms/m2/d of rhM-CSF had a mean reduction in platelet count of 61,000/mm3 during the rhM-CSF infusion period, which was significant when compared with patients who received lower doses of rhM-CSF (P = .008). Fourteen of the 16 patients who received rhM-CSF after undergoing allogeneic bone marrow transplantation had no change in the severity of graft-versus-host disease (GVHD) while receiving rhM-CSF. One had an increase in the severity of GVHD and one had a decrease. There were no effects on neutrophil, monocyte, or lymphocyte counts. Six patients had resolution of their infections, 12 were not evaluable for response, and six did not respond. Ten patients survived 100 days after initiation of rhM-CSF and 14 died. Further trials with rhM-CSF to assess antifungal activity are indicated.
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PMID:Phase I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections. 186 51

In a randomised, double-blind trial 20 patients with leukaemia received human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and 20 received placebo, for 14 days after allogeneic, matched sibling, bone-marrow transplantation. The neutrophil count recovered to 0.5 x 10(9)/l 3 days earlier in the GM-CSF group than in the placebo group (not significant), and the median neutrophil count at 14 days was significantly higher in the GM-CSF group (1.90 vs 0.46 x 10(9)/l). The lymphocyte count was significantly higher in the GM-CSF than in the placebo group between days 10 and 15 after transplantation, but this difference was not associated with a higher incidence of graft-versus-host disease. There was no evidence that GM-CSF was associated with a greater incidence of leukaemic relapse. The GM-CSF group had lower haemoglobin concentrations and platelet counts and higher plasma urea, creatinine, and bilirubin than the placebo group. The duration of hospital stay was the same for both patient groups. Further studies are now indicated to assess the overall effect of GM-CSF on outcome after allogeneic bone-marrow transplantation.
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PMID:Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial. 197 80

A randomized, double-blind placebo-controlled phase III clinical trial was performed to study the effects of human urinary macrophage colony-stimulating factor (hM-CSF) after allogeneic and syngeneic bone marrow transplantation (BMT) in 60 hM-CSF treated and 59 placebo control patients. HM-CSF was administered at a daily dose of 2 x 10(5) units/kg from day 1 to day 14 after BMT. Significant differences between hM-CSF and control patient were found in the recovery time to greater than 0.5 x 10(9) granulocytes/l and the survival rate during the initial 120 d without retransplantation. There was no difference in the incidence or grade of graft-versus-host disease (GVHD). There was no difference in the rate of leukaemic relapse at 24-36 months after BMT in patients with acute lymphocytic, acute nonlymphocytic, or monocytic leukaemia. The results of this trial show that human M-CSF improves the outcome of BMT without any influence on the occurrence of leukaemic relapse or GVHD.
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PMID:Double-blind test of human urinary macrophage colony-stimulating factor for allogeneic and syngeneic bone marrow transplantation: effectiveness of treatment and 2-year follow-up for relapse of leukaemia. 226 13

Graft-versus-host (GVH) reaction has a curious unsolved area in the immunopathogenesis and pathophysiology of the immunohematopoietic system, and GVH disease remains one of the major obstacles in clinical allogeneic bone marrow transplantation. T lymphocytes and T lymphocyte subpopulations are now recognized to be initiators of this GVH reaction and disease. Also, T lymphocytes are known to be accessory cells in the regulation of hematopoiesis, and produce a variety of lymphokines relevant to hematopoiesis. Admittedly, remarkable hematopoietic changes can be found in GVH reaction, but the cellular mechanisms underlying these changes are so complex they have yet to be fully elucidated. In fact, elevated serum levels of myeloid and erythroid colony-stimulating activities were found in mice suffering from GVH disease in which marked granulopoiesis and suppression of erythropoietic differentiation were seen. In addition, each granulocyte/macrophage colony-stimulating factor (GM-CSF) or burst-promoting activity (BPA) could be detected in sera from patients with GVH disease following allogeneic bone marrow transplantation. There seems to be at least two mechanisms involved in the control of hematopoiesis with either humoral or local environmental factor, probably via the T lymphocytes or T lymphocyte subpopulations activated by alloantigens or autologous non-T cells.
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PMID:Hematopoietic factors in graft-versus-host reaction. 332 29

Human dendritic cells (DC) generated from CD34+ hematopoietic progenitors cultured in the presence of granulocyte macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha are related to Langerhans cells (DLC) and have been shown to induce a strong proliferation of allogeneic CD4+ T cells. The present study shows that recombinant human IL-10 (h-IL-10) inhibits the primary and secondary proliferative responses of both CD4+ and CD8+ T cells induced by allogeneic CD1a+ DLC. The alloreaction induced by DLC generated after 5-18 days of culture of CD34+ HPC was equally inhibited by h-IL-10, thus indicating that DLC were sensitive to h-IL-10 at all stages of differentiation. This is further indicated by the h-IL-10-induced inhibition of the T cell alloreaction mediated by interdigitating DC freshly isolated from tonsils. h-IL-10 specifically acted on DLC as it did not affect the proliferation induced by Epstein-Barr virus lymphoblastoid cell lines (EBV-LCL) nor that induced by immobilized anti-CD3. The inhibitory effect of h-IL-10 was not due to the production of suppressive factors by the DLC, as the addition of DLC and IL-10 did not inhibit EBV-LCL-induced T cell proliferation. Rather, the inhibition of cytokine production (IL-2, GM-CSF, TNF, IFN-gamma) observed after 24 h of co-culture may explain the inhibition of T cell DNA synthesis detected 3 days later. The h-IL-10-induced inhibition of human DC mediated alloreaction advocates considering the use of h-IL-10 in the prevention of transplant rejection and graft versus host disease, phenomena initiated by DC.
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PMID:Interleukin 10 inhibits T cell alloreaction induced by human dendritic cells. 752 90

The use of hematopoietic growth factors after allogeneic bone marrow transplantation (BMT) was investigated either in a preclinical canine model or in patients. G-CSF administration in dogs after high-dose total body irradiation (TBI) and transplantation of DLA-identical littermate marrow significantly accelerated recovery of peripheral blood neutrophils, monocytes and lymphocytes, but not of platelet counts, without significantly increasing the risks of graft failure or graft-versus-host disease (GVHD). GM-CSF given to patients after HLA-identical sibling BMT was well tolerated at doses < or = 250 micrograms/m2/day and resulted in significantly faster neutrophil recovery compared with matched historical controls. Risks of graft failure, GVHD or relapse were not increased. When GM-CSF was given after matched or 1-antigen mismatched unrelated BMTs, the number of febrile days and septic episodes within the first 28 days was reduced even though neutrophil recovery was not accelerated. Incidences of graft failure, GVHD or relapse were not increased. In recipients of BMT with invasive fungal infections, M-CSF in combination with conventional anti-fungal therapy may have a beneficial effect on survival. Treatment with GM-CSF in patients with graft failure appears to result in improved survival without increasing the risks of GVHD or relapse.
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PMID:Hematopoietic growth factors after allogeneic marrow transplantation in animal studies and clinical trials. 772 31

We studied peripheral blood CD4-CD8- gamma/delta T cells in recipients of allogeneic marrow grafts, using three-color immunofluorescence and flow cytometry, and investigated changes in their numbers in relation to the administration of hematopoietic growth factors or chronic graft-versus-host disease (GVHD). In the early post-bone marrow transplantation (BMT) period, the relative and absolute numbers of peripheral CD4-CD8- gamma/delta T cells in 22 allogeneic marrow graft recipients in relation to the use of hematopoietic growth factors were studied. During the first 4 weeks, increased numbers of CD4-CD8- gamma/delta T cells were observed in recipients of either recombinant human granulocyte colony-stimulating factor (rhG-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF). However, 4-8 weeks after BMT, the number of these cells was similar in both groups whether or not growth factors had been administered. At a later stage after BMT (3-12 months), peripheral CD4-CD8- gamma/delta T cells from 43 allogeneic BMT recipients were studied. These cells were markedly decreased in patients with chronic GVHD, and this decrease correlated closely with the clinical signs of chronic GVHD. These results suggest that CD4-CD8- gamma/delta T cells may play an important role in the recovery of neutrophils associated with growth factors during the very early post-BMT period, and in the immunodeficient state of chronic GVHD at a later stage after BMT.
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PMID:Transition of T cell receptor gamma/delta expressing double negative (CD4-/CD8-) lymphocytes after allogeneic bone marrow transplantation. 788 6

Major histocompatibility complex (MHC) antigens, termed HLA in man, provide the major barrier to transplantation. Clinical manifestations of the host-versus-graft reaction are generally referred to as rejection and those of the graft-versus-host (GVH) reaction as graft-versus-host disease (GVHD). GVHD can occur after transplantation of marrow or solid organs or transfusion of blood products. GVHD involves antigen-presenting cells, which are recognized by T lymphocytes via the T-cell receptor. CD4 and CD8 serve as accessory molecules. This interaction results in T-cell activation, expression of interleukin-2 receptors (IL-2R) and the production of IL-2 followed, generally, by clonal proliferation and differentiation associated with lymphokine secretion and dysregulation that may involve interferon-gamma; tumor necrosis factor-alpha; IL-2, -3, -4, -5, -6, and -9; granulocyte macrophage colony-stimulating factor (GM-CSF); and other factors. Effector cells such as cytotoxic T cells, natural killer (NK) cells, and macrophages become activated, mostly by bone marrow-derived lymphohemopoietic cells, and contribute to cell and tissue death. Many of the cytokines also alter vascular endothelium; conceivably these changes also affect homing of cells and allogeneic interactions. Another factor is the administration of in vivo GVHD prophylaxis, which may modify both undesirable (GVHD-inducing) and desirable (tolerance-inducing) mechanisms. Exogenous hematopoietic growth factors and cytokines recently introduced into clinical trials may interfere with endogenous feedback loops in a positive or negative fashion. Adverse reactions have been observed with IL-2 and with interferon. Potentially beneficial effects have been reported with the use of soluble IL-1R or IL-1R-antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Graft-versus-host disease: host and donor views. 830 4

Secretion of different cytokines may be an important T-cell effector mechanism for bone marrow engraftment, graft versus host disease and graft versus leukaemia effects after allogeneic bone marrow transplantation (BMT). Cytokine secretion and autocrine proliferative capacity of T-cell clones derived from leukaemia patients 3-6 weeks after allogeneic bone marrow transplantation were investigated. Only a minority of post-transplant T-cell clones (23/120; 19%) was capable of undergoing autocrine proliferation. By contrast, 21/65 (32%) normal control clones from the marrow donors derived under the same conditions were autocrine proliferative. All clones were interleukin-2 (IL-2) responsive. A majority (12/17; 71%) of autocrine proliferating post-transplant clones secreted detectable IL-2. Compared with control clones, CD4+ T-cell clones derived early after BMT produced decreased levels of interleukin-4 (IL-4) and interleukin-6 (IL-6), whereas secretion of interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) showed no significant difference. The small number (n = 8) of posttransplant CD8+ clones showed decreased production of IL-3, IL-4 and IL-6 compared with control clones, but normal secretion of GM-CSF. Neither CD4+ nor CD8+ T-cell clones secreted interleukin-7 (IL-7).
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PMID:Secretion of IL-2, IL-3, IL-4, IL-6 and GM-CSF by CD4+ and CD8+ TCR alpha beta+ T-cell clones derived early after allogeneic bone marrow transplantation. 832 61


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