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)

Hematopoietic growth factors were found as factors stimulating hematopoietic colony formation in in vitro culture system using bone marrow cells as a source of hematopoietic progenitor cells. Erythropoietin, a growth factor stimulating erythroid lineage has now been clinically used as an therapeutic agent for anemia of chronic renal failure. Macrophage colony-stimulating factor (M-CSF), a growth factor stimulating the production of leukocytes including monocytes and neutrophils has been clinically used as an agent for leukopenic patients after anti-cancer therapy. M-CSF improves a survival rate after bone marrow transplantation (BMT) through the reduction of mortality rate associated with BMT such as bleeding, engraftment failure and GVHD. M-CSF accelerated platelet production when injected to thrombopenic patients with solid tumor after anticancer therapy. Granulocyte CSF (G-CSF) is a most powerful agent for various kinds of neutropenia such as neutropenia after anti cancer therapy, neutropenia after BMT, aplastic anemia, chronic neutropenia of children and myelodysplastic syndrome. However, since G-CSF stimulates growth of leukemic cells in vitro, careful observations should be required when clinically used on leukemic patients. Clinical studies of granulocyte-macrophage CSF (GM-CSF) and interleukin 3 (IL-3) are now in progress, in which a promoting activity of leukocyte production of these factors is evaluated.
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PMID:[Clinical application of hematopoietic growth factor (IL-3, G-CSF, GM-CSF, and EPO)]. 127 40

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.
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PMID:The effects of cyclosporin A on non-T cell components of the immune system. 150 9

Natural suppressor (NS) cells, which nonspecifically suppress immune responses, are present in the spleen following exposure to radiation, chronic graft-versus-host disease, or cancer and in normal bone marrow. A model system is described which allows the study of cytokines activating and inhibiting NS cells, cytokines mediating NS activity, and NS effects on cytokine synthesis. Recombinant interleukin-3 (rIL-3) and granulocyte-macrophage colony-stimulating factor (rGM-CSF) efficiently activated NS cells present in normal bone marrow and were effective at concentrations as low as 5 U/ml. At high concentrations, GM-CSF, but not IL-3, did not activate NS cells. Recombinant interferon-gamma (rIFN-gamma) blocked the activation of bone marrow NS cells by rIL-3, but did not down-regulate NS cells once activated. The NS cells secreted one or more soluble suppressor factors, which blocked IL-2 synthesis and also inhibited IL-2-dependent T cell proliferation in the presence of excess IL-2.
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PMID:Cytokine regulation of bone marrow natural suppressor cell activity in the suppression of lymphocyte function. 153 70

In murine models, L-leucyl-L-leucine methyl ester (LLME) is effective as an ex vivo purging agent for the prevention of graft-versus-host disease. However, reduction of progenitor cells by LLME raises concerns about the engraftment potential of LLME-treated marrow. Therefore, the effects of LLME on human marrow were investigated. Concentrations of LLME from 0.005 mM to 5 mM were used to examine the effects of LLME on marrow cells. Concentrations of LLME less than or equal to 0.05 mM had no effect on recovery of nucleated marrow cells, mononuclear cells (MNC), myeloid cells or monocytes. At 0.5 mM, nucleated marrow cell recovery was 25%, and MNC recovery was 93%. As determined by cytochemical stains, 0.5 mM LLME eliminated myeloid cells and monocytes. At 0.005 mM, LLME had little effect on marrow progenitor cells; progenitor cell recovery with 0.05 mM LLME was 35% for granulocyte-macrophage colony forming units (CFU-GM) and 23% for erythroid burst forming units (BFU-E) (p less than 0.05 compared to 0.005 mM). At higher LLME concentrations, recoveries of both CFU-GM and BFU-E were less than 1%. To determine if earlier hematopoietic cells remained after treatment with LLME, progenitor cell experiments were repeated with 0.5 mM LLME using recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) or recombinant human interleukin 3 (rhIL-3) plus or minus recombinant human mast cell growth factor (rhMGF) as sources of colony-stimulating activity. In this system, both IL-3 and GM-CSF induced rare progenitor cells (less than 6/5 x 10(4) cells plated).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of L-leucyl-L-leucine methyl ester on human marrow and protection of progenitor cells by IL-1. 164 32

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

The treatment of severe aplastic anemia has been modified recently by the demonstration that Cyclosporine A is active alone or in combination leading to more than 50% response rate. Combination or sequential treatments with ATG seem to be better than such drug separately but this must be studied in randomized studies. Long term follow-up is necessary to assess the rate of malignant transformation. Growth factors have been recently introduced. G or GM-CSF seem to be active. IL-3 has not been proven to be effective in very small non randomized study. Allogeneic bone marrow transplantation is the best treatment with a matched related donor, progress must be achieved in methods of conditioning and GVH prophylaxis when a matched unrelated donor is used.
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PMID:Recent treatments of aplastic anemia. The International Group on SAA. 181 8

It appears that part of the confusion surrounding the lineage of NS cells could be due, in part, to the presence of more than one cell population in normal BM. Whether other cell populations exist in other organ compartments, or can be induced, is presently unknown. This is of particular interest in allogeneic BMT where various lymphocyte depletion techniques have been employed to reduce the incidence of AGVHD. When CCE is used for depletion, the NS lymphocyte component is entirely removed. Since the incidence of AGVHD is significantly reduced with CCE lymphocyte-depleted rat and human BM, it appears that this subpopulation need not be present to abrogate AGVHD. Quite surprisingly, preliminary studies in rats indicates that this lymphocyte subpopulation may actually induce acute syngeneic GVHD (Fischer et al., 1989). That a cell(s) in the clonogenic compartment has the ability to suppress or down-regulate a variety of immune responses is not altogether surprising. This cell is better thought of as an auto-regulatory cell which has the ability to control the cellular interactions in its immediate micro-environment. Indeed, R/O NSCA can be augmented by GM-CSF, IL-3, and CsA (NoGa et al., 1988a). In vitro, this cell differentiates into the mono-myeloid series using a variety of stimulatory agents and can acquire tumoricidal activity. The ability to express NSCA is lost however, being present only during a brief window of early maturation. Only IL-3 can sustain NSCA in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Elutriation of bone marrow delineates two distinct natural suppressor cell populations. 213 33

Injection of parental C57BL/10 spleen cells into unirradiated immune-competent (B10 x B10.BR)F1 hosts has been demonstrated to produce a graft-vs.-host-induced immune deficiency in T cell-mediated functions, including mitogen or alloantigen stimulated proliferation or cytotoxic T cell generation. The production of T cell-derived lymphokines affecting hematopoiesis was also altered during GVH. During the first two weeks of GVH, IL-3 and particularly GM-CSF were produced spontaneously; in subsequent weeks, the spontaneous production dropped to normal or subnormal levels. CSF content in concanavalin A-stimulated splenic supernatants was reduced at weeks 1-2, and declined to less than 5% of normal levels by 3-4 weeks of GVH. This decline in CSF content was correlated with a decrease in immune function as assessed by concanavalin A-stimulated IL-2 production and by generation of cytotoxic T lymphocytes. Concurrent with the recovery of immune function during GVH weeks 8-15, mitogen-stimulated production of CSF returned to normal levels. In addition to the decrease in CSF production identified in acute suppressive GVH, CSF content in concanavalin A-stimulated splenic supernatants was also decreased in chronic stimulatory GVH, generated in the strain combination (B6 x B6bm1)F1----(B6bm1 x B6bm12)F1. This decrease in CSF production correlated with a decrease in self-restricted T helper cell function. Finally, a decrease in both immune function and CSF production capacity was observed in the acute GVH following allogeneic (minor histocompatibility loci) bone marrow transplantation into irradiated hosts.
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PMID:Alterations in T cell-derived colony-stimulating factors associated with GVH-induced immune deficiency. 218 11

We have recently demonstrated that IL-3 and GM-CSF content in concanavalin A--stimulated splenic cultures was severely depressed for several weeks in mice undergoing an acute graft-vs.-host reaction (GVHR). Several factors contributed to this decrease in CSF levels at different points in the first 10 weeks of GVH. Myeloid lineage cells, both GM-CFU and Mac-1+ cells, increased in the spleen during GVH weeks 3-6, and (125I)-GM-CSF binding by spleen cells increased 10 fold--hence CSF content in supernatants was probably reduced by local consumption during these weeks. During GVH weeks 3-12, levels of all T cells--and of L3T4+ T cells, in particular--were reduced, limiting production of T cell derived lymphokines. Finally, during the first six weeks of GVH, immune suppression was found in cocultures of normal F1 and GVH spleens. Furthermore, during weeks 3-5, nonspecific suppression was found, affecting CSF production not only by normal host spleens but also by parental donor or unrelated spleen cells as well.
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PMID:Factors contributing to the decrease in concanavalin A-induced colony-stimulating factors in acute suppressive graft-versus-host disorder. 218 12

The major immunological reactions after an allogeneic bone marrow transplantation (BMT) are graft rejection and graft-versus-host disease (GVHD). GVHD can be prevented by T-cell depletion of the allogeneic BM graft, but the beneficial effect of T-cell depletion on the incidence of GVHD is counterbalanced by a higher incidence of graft failure. One option for the prevention of graft rejection after T-cell-depleted BM grafts is the administration of cytokines. Before applying cytokines after an allogeneic BMT, we considered it desirable to learn whether cytokines would alter the susceptibility of donor BM cells to host T cells. An in vitro assay was developed to investigate the role of the cytokines interleukin-1 (IL-1), IL-3, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) on the interaction between allosensitized, cytotoxic-T cells (CTLs) and T-cell-depleted BM cells. CTLs primed against the BM donor suppressed the formation of colonies consisting of granulocytes and macrophages (colony-forming unit GM). Colony formation was not inhibited by CTLs sensitized against a third party. Accordingly, the number of colonies scored in cocultures with CTLs sensitized to third party antigens were designated as 0% inhibition. A 66% inhibition of colony formation was observed for untreated BM cells at an effector:target (E:T) ratio of 1:1. Pretreatment of the BM cells with the cytokines G-CSF, GM-CSF, IL-1, and IL-3 resulted in a 38% (P = .001), 53%, 66%, and 68% inhibition of colony formation, respectively, at E:T ratios of 1:1. G-CSF reduced the susceptibility of BM cells over a range from 4:1 to 1:16 (E:T ratios). GM-CSF had only significant influence at the lower E:T ratios (1:4 and 1:16). These in vitro data indicate that G-CSF could protect BM cells from killing by allosensitized CTLs and suggest that administration of these cytokines might potentially reduce the susceptibility of T-cell-depleted allogeneic BM grafts to host T-cell-mediated rejection.
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PMID:Granulocyte colony-stimulating factor (CSF) but not interleukin-1 (IL-1), IL-3, and granulocyte-macrophage CSF protect bone marrow progenitor cells from suppression by allosensitized cytotoxic T cells. 752 93


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