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)

Treatment of an organism with UVB light or PUVA (8-methoxypsoralen + UVA light) not only leads to alterations in the irradiated skin but also to systemic immunomodulation, due to the release of several chemical mediators of immunosuppression like prostaglandins, acute-phase proteins, IL-1 inhibitor, alpha-melanocyte-stimulating hormone, propiomelanocorticotropin or other cytokines. A recently described mediator is urocanic acid, which is transformed by UV light in the skin from the trans- to the cis-isomer and that exerts a systemic immunomodulatory effect. In our experiments, treatment with PUVA or with cis-urocanic acid prevents the rejection of rat heart allografts in 50% and 40% of cases, respectively. Control grafts are rejected in fewer than 10 days. PUVA treatment of donor leukocytes before transfusion into the prospective recipient inhibits only their sensitizing, not their graft-protecting, effect on subsequent skin grafts in mice. PUVA treatment also prevents acute lethal GVH disease in mice after irradiation with a sublethal dose of x-rays and transfusion of semiallogeneic spleen cells. Treatment of recipient mice with cis-urocanic acid has the same effect. The humoral immune response to sheep erythrocytes is not influenced by cis-urocanic acid. These results demonstrate that PUVA treatment or its chemical mediator, cis-urocanic acid, may be used in transplantation and hematology as naturally occurring immunosuppressive agents, especially for the control and manipulation of GVH leukemia reaction.
 ...
PMID:Cis-urocanic acid as a mediator of ultraviolet-light-induced immunosuppression. 159 41

We cultured bone marrow cells from patients receiving bone marrow transplantation (BMT) to assay bone marrow fibroblast colony-forming cells (CFU-F) and hematopoietic progenitors (CFU-mix, CFU-C, BFU-E and CFU-E), and compared the mean values obtained from patients with and without graft-versus-host disease (GVHD). The value of CFU-F colonies from 15 patients was always less in patients with acute GVHD Grade II,III than in those with Grade 0,I over the period 30 to 110 days after BMT. The CFU-F colonies from patients with Grade 0,I consisted of approximately the same number of small and large colonies, whereas virtually all CFU-F colonies from patients with Grade II,III were small. Fibroblasts collected from bone marrow cells cultured for 2-3 weeks were incubated with IL-1 (50 U/ml) for 24 h. The concentrations of G-CSF in the culture supernatants from patients with Grade II,III were higher than in those with Grade 0,I. The results of assays of hematopoietic progenitors from 48 patients showed that the number of hematopoietic progenitors decreased as the severity of acute GVHD increased. These results suggest that the myelosuppression seen in GVHD may be associated with reduced numbers of CFU-F in bone marrow.
 ...
PMID:Stromal fibroblastic and hematopoietic progenitors in patients with graft-versus-host disease (GVHD). 172 15

Cutaneous graft-versus-host disease (GVHD) provides a unique model for studying the pathogenesis of several important lymphocyte-mediated skin diseases. Morphologic studies have suggested that Ia antigen (Ia)-bearing epidermal Langerhans cells (LC) may be specific targets for destruction in these conditions. Keratinocytes synthesize and express Ia in GVHD and some other lymphocyte-mediated skin disorders; Ia+ keratinocytes, constitutively able to secrete epidermal cell-derived thymocyte activating factor (ETAF)/interleukin 1, may possess antigen-presenting capacity, thus leading to enhanced cutaneous immune responses and disease chronicity. We therefore investigated the fate of Ia+ LC, and the potential antigen-presenting capacity of Ia+ keratinocytes, in a murine model of GVHD. Lethally irradiated C3H/He (H-2k) mice developed acute cutaneous GVHD, and expressed keratinocyte Iak, 8 days after injection of BALB/c (H-2d) bone marrow and spleen cells. Immunofluorescence studies showed a progressive decrease in the density of Ia+ epidermal LC during the evolution of GVHD. This decrease was paralleled by a progressive reduction in the allostimulatory capacity of GVHD epidermal cells (EC) in the allogeneic EC-lymphocyte reaction (ELR). The fall in the density of Ia+ LC, and in EC allostimulatory capacity in both primary and secondary ELRs, was consistently greater in GVHD mice than in mice treated only with x-irradiation. The allostimulatory capacity of GVHD and x-irradiated EC could not be restored by addition of indomethacin or exogenous ETAF to ELR cultures. The decreased allostimulatory capacity was not the result of inhibition of the ELR, since EC from GVHD and x-irradiated mice did not cause suppression when added to control ELR cultures. The capacity of EC to present ovalbumin, purified protein derivative of tuberculin, 2,4,6-trinitrobenzenesulfonic acid coupled to EC, and native cytochrome c (CYTc) to antigen-specific T-cell lines, clones, or hybridomas was reduced in x-irradiated mice and markedly decreased in GVHD mice. The capacity of EC from x-irradiated and GVHD mice to present CYTc fragment 81-104, which does not require further processing or catabolism by accessory cells, was similarly decreased. Taken together, the results indicate that: the function of LC is markedly and progressively impaired in acute GVHD; LC function is also decreased, but to a lesser extent, following x-irradiation alone; and Ia+ keratinocytes from lethally irradiated mice undergoing GVHD do not exhibit antigen-presenting capacity.
 ...
PMID:Immunologic aspects of acute cutaneous graft-versus-host disease: decreased density and antigen-presenting function of Ia+ Langerhans cells and absent antigen-presenting capacity of Ia+ keratinocytes. 242 2

We studied the presence of peripheral-blood- and bone-marrow-derived T-lymphocyte colony formation (CFU-TL) in 28 bone marrow transplant recipients from 1 month to six years after transplantation. Peripheral blood leukocyte and lymphocyte counts were generally normal, and all had morphologic evidence of engraftment without leukemia at the time of study. Both peripheral-blood- and bone-marrow-derived CFU-TL were markedly reduced after transplantation as compared to normal controls, which included bone marrow donors (14.2 +/- 5/4 X 10(4) vs 313 +/- 100/4 X 10(4) [p less than 0.001] and 26 +/- 4/2 X 10(5) vs 1004 +/- 60/2 X 10(5) [p less than 0.001]). Among the patients, four had no detectable bone-marrow-derived CFU-TL when tested less than six months after transplantation. Peripheral blood CFU-TL, while present in all patients, was markedly decreased for more than 12 months after transplantation. After two years, the number of CFU-TL returned to normal in several patients. The abnormalities in CFU-TL were unrelated to diagnosis, age, sex, graft-versus-host disease (GVHD), pretransplant conditioning, or posttransplant immunosuppressive treatment. Patients receiving autologous bone marrow transplants also had decreased CFU-TL. Cocultures of normal peripheral-blood- or bone-marrow-derived mononuclear cells with recipients' mononuclear cells or sera did not inhibit normal CFU-TL growth. Furthermore, the addition of mononuclear cells or sera from normal individuals, or of exogenous interleukin 1 or interleukin 2, did not correct the deficiency of CFU-TL growth by recipient cells. Depletion of T-lymphocytes from bone marrow or peripheral blood in transplant recipients by physical techniques or with a monoclonal antibody (CT-2) and complement had no effect on CFU-TL recovery. Similarly, addition of recipients' T cells to normal peripheral blood or bone marrow mononuclear cells did not suppress CFU-TL. These data indicate that most transplant recipients have a marked reduction in CFU-TL which persists for up to two years after transplantation. This reduction in the growth of T-cell colonies appears to be due to deficient numbers of these cells or an intrinsic defect in their responsiveness to T-cell lymphokines, rather than a result of growth suppression by inhibitory cells or serum factors. This observed defect in CFU-TL may have implications for therapeutic attempts to facilitate immune reconstitution after bone marrow transplantation.
 ...
PMID:Abnormal T-lymphocyte colonies (CFU-TL) following bone marrow transplantation. 353 45

Peripheral blood mononuclear leukocytes (cells of marrow donor origin) from 89 patients were collected at various times after allogeneic marrow transplantation, stimulated in vitro by phytohemagglutinin, and assayed for the production of interleukin 2 (IL-2). This was done by testing culture supernatants for their ability to induce proliferation of human lymphoblasts and/or IL-2-dependent cultured murine cytotoxic cells. Supernatants from cultures of patient cells were compared with those of marrow donor cells. Supernatants produced by cells from most short-term marrow recipients (30-101 days postgrafting), regardless of the presence or absence of acute graft-versus-host disease (GVHD), and those from most long-term patients with chronic GVHD (103-1932 days postgrafting) had significantly lower-than-normal IL-2 activity, whereas cells from most long-term marrow recipients without GVHD (353-1934 days postgrafting) had essentially normal IL-2 activity. Additionally, we tested the ability of monocytes from 35 marrow recipients to produce interleukin 1 (IL-1) in response to lipopolysaccharide as compared with monocytes from marrow donors or normal unrelated individuals. IL-1 activity in culture supernatants of patient cells, regardless of the time of testing after marrow grafting and the status of GVHD, was found not to differ from that in supernatants of normal cells. These findings suggest that impaired T cell functions seen in some (but not all) marrow recipients are probably not due to IL-1 but to IL-2 deficiency or to the mechanism that causes IL-2 deficiency.
 ...
PMID:Cellular interactions in marrow-grafted patients. III. Normal interleukin 1 and defective interleukin 2 production in short-term patients and in those with chronic graft-versus-host disease. 388 Sep 62

Immunotherapy can be defined as treatment directed at augmenting host immune defence mechanisms. Non-antimicrobial therapies and immunoprophylaxis in bone marrow transplantation (BMT) can be subdivided into three broad categories: passive immunotherapy with intravenous immunoglobulin (IVIG); cytokine therapy; and anti-endotoxin-directed treatments. Most studies using IVIG in BMT are prophylactic and suffer from variability in study design, type of IVIG and dosing regimens. Various effects on viral and bacterial infections and graft-versus-host disease (GVHD) have been reported but few if any have shown benefit in terms of improved patient survival. Moreover the immunomodulatory effect of immunoglobulin G preparations is frequently overlooked. With the exception of cytomegalovirus (CMV) pneumonitis, there is little evidence of benefit in the treatment of established infections and the relative benefits of hyperimmune preparations are poorly established. The development of haemopoietic growth factors has led to the widespread use of cytokines in BMT. The benefits of these agents both in the prevention of fever and infection and as adjuvants to standard antimicrobial therapy in established infection (e.g. invasive mycoses) are rapidly becoming apparent. Both human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and granulocyte colony-stimulating factor (rhG-CSF) have been shown to accelerate granulocyte recovery following BMT and reduce fever days, antibiotic usage and hospitalization. RhGM-CSF appears superior in these respects. The roles of interleukin 1 (IL1), IL3, IL6 and interferons are also under evaluation. As with the much publicised studies using anti-endotoxin antibodies as therapy in sepsis, there is little evidence of benefit in the few studies performed in BMT patients.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Immunotherapy and immunoprophylaxis in bone marrow transplantation. 756 Sep 54

Cord blood has been used successfully for stem cell transplantation in several haematological conditions: Fanconi's anaemia, leukaemia and Wiskott-Aldrich syndrome. On account of the low incidence of GVHD observed following cord blood transplantation, it has been suggested that cord blood be used for HLA-matched, or perhaps one or two antigens mismatched, and unrelated stem cell transplantation. Based on an extensive immunophenotype-functional correlation, we determined that cord blood contains mainly immature unprimed T lymphocytes that are predominantly suppressor cells. Recent findings suggest that dysregulated production of cytokines (IL-1, IL-2, TNF alpha) plays a role in GVHD. We showed that T cells in cord blood express receptors for IL-2, TNF alpha, but no receptors for IL-1. Similarly, NK cells, one of the effector cells of GVHD, express receptors for TNF alpha and gamma IFN but do not express receptors for IL-1, nor IL-2R alpha-chain (CD25) although IL-2R beta-chain is expressed. The potential for activation of T lymphocytes and NK cells therefore exists in the context of bone marrow transplantation. However, the high number of suppressor cells in cord blood most likely modulate the activation of lymphocytes and NK cells thereby minimizing GVHD.
 ...
PMID:Phenotypic analysis of functional T-lymphocyte subtypes and natural killer cells in human cord blood: relevance to umbilical cord blood transplantation. 777 9

Cytokines are believed to cause a number of inflammatory diseases. We have investigated the role of 3 inflammatory cytokines, IL-1, IL-2, and TNF alpha, during graft-versus-host disease (GVHD), a paradigm disease of cytokine dysregulation in vivo. Measuring cytokine mRNA transcripts with a quantitative polymerase chain reaction technique, we demonstrate that IL-1 transcript levels are increased several hundred-fold in GVHD target organs, whereas TNF alpha transcripts increase only 4- to 6-fold. Kinetic studies during the first month after transplant unexpectedly show that GVHD never induces IL-2 transcripts in the skin and only induces IL-2 transcripts in the spleen during the first week, whereas levels of IL-1 transcripts continue to increase throughout the entire 4 weeks. Administration of an IL-1 receptor antagonist after the termination of the IL-2 response and after the establishment of GVHD significantly increases long-term survival, confirming the central role of IL-1 as an effector molecule of GVHD and suggesting new therapeutic strategies for this disorder.
 ...
PMID:Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens. 827 27

The dynamics of changes in the metabolic and functional activities of thymus, lymph node and spleen lymphocytes and spleen macrophages of AKR mice was examined during the preleukemic period. The MTT colorimetric assay was used to determine the mitochondrial enzyme activity of viable cells, the local xenogeneic GVH reaction and the IL-2 assay for measuring T cell responses, and the IL-1 assay as an indicator of macrophage activity. In the early preleukemic period (at 1.5 months of age), lymphocyte dehydrogenase enzyme hyperactivity was accompanied by a highly increased production of IL-2, positive local xenogeneic GVH reaction and increased IL-1 production. Later on, at the age of 4-5 months, AKR mice demonstrated a progressive decrease in the metabolic activity of lymphocytes, negative local GVH reaction and reduction or lack in IL-2 and IL-1 production. This early hyperreactivity and late, gradually evolving, areactivity of lymphocytes and macrophages was not found in other, non-leukemic strains of mice (RFM, CBA, C57BL).
 ...
PMID:Transient early metabolic and functional hyperreactivity and late areactivity of lymphocytes in preleukemic AKR mice. 835 39

IL-1ra is the first described naturally occurring receptor antagonist of any cytokine or hormone-like molecule. IL-1ra is a member of the IL-1 family by three criteria: amino acid sequence homology of 26 to 30% to IL-1 beta and 19% to IL-1 alpha; similarities in gene structure; and common gene localization to human chromosome 2q14. Two structural variants of IL-1ra exist: sIL-1ra, a secretory molecule produced by monocytes, macrophages, neutrophils, fibroblasts, and other cells; and icIL-1ra, an intracellular molecule produced by keratinocytes and other epithelial cells, macrophages, and fibroblasts. IL-1ra production by monocytes, macrophages, and neutrophils may be regulated in a differential fashion with IL-1 beta. Human IL-1ra binds to both human IL-1RIs and IL-1RIIs on cell surfaces, although with 100-fold greater avidity to IL-1RIs. IL-1ra may bind preferentially to soluble IL-1RIs and not at all to soluble IL-1RIIs. IL-1ra competitively inhibits binding of both IL-1 alpha and IL-1 beta to cell surface receptors without inducing any discernible intracellular responses. All three forms of IL-1 may bind to IL-1 receptors in a similar fashion but IL-1ra may lack the secondary interactions necessary to trigger cell responses. A 100-fold or greater excess of IL-1ra over IL-1 may be necessary to inhibit biological responses to IL-1 both in vitro and in vivo. The roles of sIL-1ra and icIL-1ra in normal physiology or in host defense mechanisms remain unclear. The administration of IL-1ra blocks the effects of IL-1 in some animal models of septic shock, inflammatory arthritis, graft-versus-host disease, and inflammatory bowel disease. The preliminary results of clinical trials in humans indicate possible efficacy of IL-1ra in sepsis syndrome, rheumatoid arthritis, and GVHD.
 ...
PMID:Interleukin-1 receptor antagonist. 837 62


1 2 3 4 5 Next >>