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)

Although chronic graft-versus-host disease (GVHD) remains a frequent complication of bone marrow transplantation (BMT), the pathogenesis remains unclear. We examined the potential role of cytokines in mediating chronic GVHD. Skin samples from seven patients with cutaneous chronic GVHD, six post-BMT controls and six normal controls were evaluated by reverse transcription polymerase chain reaction for the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha), Th1-associated cytokines IL-2 and interferon-gamma (IFN-gamma), Th2-associated cytokines IL-4, IL-5 and IL-10, and fibrosis-associated cytokines platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). IFN-gamma transcription was significantly more frequent in cutaneous chronic GVHD (86%) vs post-BMT and normal controls (17% (P = 0.03) and 0 (P = 0.005), respectively). IL-2 transcription was more frequent in chronic GVHD (28%) and post-BMT controls (50%) vs normal controls (17%). TNF-alpha mRNA was frequent in chronic GVHD (71%) and post-BMT controls (83%), but not significantly more than in normal controls (50%). Transcription of IL-1alpha, IL-4, IL-5 and IL-10 was infrequent in all three groups. PDGF and TGF-beta mRNA were detected in the majority of all samples. The frequent transcription of IFN-gamma in cutaneous chronic GVHD supports its potential role in mediating the associated tissue injury. While the cellular sources of these cytokines are uncertain, their expression and secretion in situ may propagate the cytotoxic cascade and perpetuate the tissue injury. Better understanding of the contribution of FN-gamma and other cytokines to the pathogenesis of chronic GVHD may allow the design of more specific and more effective therapy.
 ...
PMID:Cytokine expression in human cutaneous chronic graft-versus-host disease. 880 19

Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells that secrete gamma-interferon (IFN-gamma). IFN-gamma induces the production of inflammatory cytokines, e.g., tumor necrosis factor-alpha and interleukin (IL)-1, which are the distal mediators of GVHD. We demonstrate that the transplantation of polarized type 2 murine T cells (i.e., cells secreting IL-4 but not IFN-gamma) together with T-cell-depleted bone marrow results in a significant increase in survival (P<0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR-->CBA/J). Further analysis demonstrated that increased survival in recipients of polarized type 2 T cells correlated with diminished production of both IFN-gamma and tumor necrosis factor-alpha but with increases in IL-4 2 weeks after transplantation. Despite improved survival, histologic changes of GVHD were evident in oral mucosal and hepatic tissues at 7 weeks after bone marrow transplantation. These data provide further evidence that inflammatory cytokines in the immediate posttransplant period are pivotal to the development of mortality but that they do not correlate with individual target organ damage.
 ...
PMID:Transplantation of polarized type 2 donor T cells reduces mortality caused by experimental graft-versus-host disease. 893 72

Dendritic cells (DC), as professional antigen-presenting cells, play a major role in stimulating naive T cell responses in vivo and in vitro, and may exacerbate or modulate T lymphocyte-mediated reactions, such as interactions between a hematopoietic graft and the recipient, eg GVHD and graft-versus-leukemia. Here, we describe a two-stage cell culture system for expansion of functionally active human DC from CD34+ marrow precursors. Optimal outgrowth was achieved by initially culturing CD34+ cells for 5 days in medium containing GM-CSF, MGF and TNF-alpha. Substitution of CD40L and IL-4 for TNF-alpha during a subsequent 5-day subculture increased DC content, such that by 10 days the cultures contained approximately 40% DC as determined by immunophenotype and morphology. An increase in DC purity to 84% at 10 days was achieved by immunomagnetic separation for CD1a+ cells from 5-day cultures and subculturing these cells in medium with IL-4 and CD40L. Reversing the sequence of growth factors during culture and subculture decreased the yield and purity of DC. Expression of CD80 and CD86 was enhanced by adding CD40L and IL-4, and the DC showed stimulatory activity in MLC. In conclusion, we have described a simple two-stage culture system to generate functional DC from CD34+ marrow precursors.
 ...
PMID:In vitro expansion and characterization of dendritic cells derived from human bone marrow CD34+ cells. 893 57

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
 ...
PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

The low incidence of graft-versus-host disease following clinical use of umbilical cord blood compared to adult bone marrow as a source of stem cells for bone marrow reconstitution, leads to questions concerning the level of immunocompetence of newborn T cells. The maturation and functional status of newborn CD4+ T cells, which are almost exclusively CD45RA+ naive T cells, compared with their adult phenotypic counterparts, is poorly understood. We examined the proliferative response to mitogens and cytokines of CD4/CD45RA+ T cells from adults and newborns, with and without accessory cells. Newborn CD4/CD45RA+ T cells demonstrated a distinct proliferative response profile which was determined by the number of accessory cells present in co-cultures with various stimuli. Newborn CD4/CD45RA+ T cells were particularly responsive to interleukin (IL)-4, IL-4 plus anti-CD2 monoclonal antibodies (mAb) and IL-4 plus phytohemagglutinin (PHA), whereas adult CD4/CD45RA+ T cells were unresponsive under similar conditions. The mitogenic responses of newborn and adult CD4/CD45RA+ T cells to PHA and anti-CD2 mAb, which were equivalent, were directly proportional to the number of accessory cells present, whereas the responsiveness to cytokines was inversely proportional to the number of co-cultured accessory cells. Anti-CD2 responses were much more sensitive to low numbers of accessory cells than PHA. The particular sensitivity of newborn CD4/CD45RA+ T cells to IL-4 represents an antigen-independent T cell activation response which could help promote a Th2 immune response resulting in the newborn.
 ...
PMID:Antigen-independent responsiveness to interleukin-4 demonstrates differential regulation of newborn human T cells. 897 81

Cord blood transplantations successfully reconstituted hemopoiesis in patients treated with myeloablative therapies. These transplantations were associated with a low rate of acute graft-versus-host disease (aGVHD), a major life-threatening complication of allo-transplantation. The physiopathology of aGVHD implies the recognition of host alloantigens by donor T cells but also involves a cytokine cascade. In this cascade, interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) produced by donor T cells and monocytes/macrophages play a major effector role. Therefore, we investigated whether the lower percentage of aGVHD in cord blood transplants could be related to a lower ability to produce these cytokines in vitro compared with adult blood. Mononucleated cells (MNCs) isolated from term cord blood and adult peripheral blood were stimulated with a combination of lipopolysaccharide and phytohemaglutinin and incubated for 96 hours. Levels of IL-1beta, IL-2, IL-3, IL-4, IL-6, TNF-alpha, IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured in the supernatants after various times of incubation. The productions of IL-1beta, IL-6, and GM-CSF were similar in stimulated cord and adult blood and IL-3 levels, though lower and delayed in cord blood, were not statistically different. On the other hand, we found markedly lower levels of IFN-gamma, TNF-alpha, and IL-4 in cord blood throughout the incubation period. The stimulated levels of IL-2 were similar in cord and adult samples throughout the first 48 hours of incubation but became significantly lower in cord blood after 72 and 96 hours. We suggest that the cytokine production pattern that characterizes cord blood could provide an explanation for the lower occurence of aGVHD following cord blood transplants.
 ...
PMID:Comparative cytokine production by in vitro stimulated mononucleated cells from cord blood and adult blood. 901 9

We have investigated cytokine mRNA expression in the peripheral blood mononuclear cells of 20 patients who received allogeneic hematopoietic stem cell transplants to assess the cytokine network after transplantation. IL-4 mRNA expression decreased in five of five (100%) patients with > or = grade III (severe) acute GVHD and increased in 10 of 22 (45%) patients without severe GVHD. In contrast, IL-12 mRNA expression increased in two of two (100%) patients with severe GVHD, but increased in only six of 18 (33%) patients without severe GVHD. Furthermore, IL-10 and/or IL-13 mRNA expression increased in 19 of 22 (86%) patients without severe GVHD, but increased in only one of three (33%) patients with severe GVHD. In patients with allogeneic PBSCT who had severe acute GVHD, the cytokine mRNA expression in patients with allogeneic PBSCT, who had no severe GVHD, showed a similar pattern to that in patients with allogeneic BMT. IL-4 mRNA expression increased in three of five (60%) patients and IL-10 and/or IL-13 mRNA expression increased in five of five (100%) patients. In contrast, IL-12 mRNA expression increased in only one of three (33%) patients. Serum IL-4 concentration in allogeneic PBSCT patients in the early engraftment phase was relatively high, while serum IL-12 concentration was low. These findings suggest that severe GVHD may be related to the cytokine imbalance between type 1 helper T (Th1) cells and type 2 helper T (Th2) cells.
 ...
PMID:The important balance between cytokines derived from type 1 and type 2 helper T cells in the control of graft-versus-host disease. 908 37

The role of IFNgamma in the development of infection-driven interstitial pneumonitis in a model of murine graft-versus-host disease was investigated. Mice were given either syngeneic or allogeneic bone marrow transplants along with lung Pneumocystis carinii infections and were treated with either control mAb or anti-IFNgamma mAb. At day 21 after transplant, lung weights were elevated nearly twofold in all groups. By day 41, mice in all groups had cleared the P. carinii but only the mice given allogeneic transplants and anti-IFNgamma had increased lung weights. Increased lung weights in the anti-IFNgamma-treated mice corresponded to alveolar infiltration of eosinophils, neutrophils, and multinucleated giant cells and exacerbated interstitial pneumonitis compared with mice treated with control antibody. Intracellular staining indicated that there were 3- to 10-fold more CD4+ cells producing IFNgamma than those producing IL-4 in the lung lavages of mice given either syngeneic or allogeneic transplant. Treatment of transplanted mice with anti-IFNgamma resulted in a significant decrease in IFN-gamma-producing CD4+ and CD8+ cells in the lung lavages but no change in the number of IL-4-producing CD4+ cells. These data indicate that IFNgamma is critical for controlling the development of P. carinii-driven interstitial pneumonia after either syngeneic or allogeneic bone marrow transplant in mice.
 ...
PMID:Neutralization of interferon-gamma exacerbates pneumocystis-driven interstitial pneumonitis after bone marrow transplantation in mice. 912 7

Patients with a relapse of chronic myeloid leukemia (CML) after allogeneic bone marrow transplantation can be successfully treated with blood mononuclear cells from the original bone marrow donor. However, the antileukemic effect of this treatment is often accompanied by graft-versus-host disease (GVHD). Treatment with cytotoxic T-lymphocyte (CTL) lines or clones that are specifically generated against leukemic antigen-presenting cells from the patient, may separate antileukemic effects from GVHD. In this report we demonstrate that after culturing CD34-positive cells purified from bone marrow of patients with chronic phase CML in medium containing human serum, GM-CSF, TNF alpha, and IL-4 up to 28% of the cultured cells were dendritic cells, characterized by morphology, phenotypic analysis, and their efficient capacity to stimulate allogeneic T lymphocytes. The expression of HLA and costimulatory molecules and the stimulatory capacity of the dendritic cell-enriched cell suspensions were optimal between days 7 and 10 after onset of the cultures. Fluorescence in situ hybridization revealed that all cultured dendritic cells contained the CML specific t(9;22) translocation. PCR analysis showed expression of the translocation specific bcr-abl mRNA. These leukemic dendritic cells may enhance the induction and proliferation of CTL lines and clones with more specificity for the leukemic cells.
 ...
PMID:Generation of dendritic cells expressing bcr-abl from CD34-positive chronic myeloid leukemia precursor cells. 912 81

The feasibility of transplanting peripheral blood mononuclear cells (PBMC) from granulocyte colony-stimulating factor (G-CSF)-treated normal human donors to myeloablated allogeneic hosts has been demonstrated recently. The current work examined the ability of recombinant G-CSF to alter peripheral blood T-cell function and graft-versus-host disease (GVHD) in a murine model of allogeneic G-CSF-mobilized PBMC transplantation. Administration of recombinant G-CSF to C57BL/Ka mice markedly increased the capacity of PBMC to reconstitute lethally irradiated syngeneic hosts. T- and B-lineage lymphocytes were depleted about 10-fold in the bone marrow of the treated mice, and the T-cell yield in the blood was increased about fourfold. The ability of PBMC or purified CD4+ and CD8+ T cells to induce acute lethal GVHD in irradiated BALB/c mice was reduced after the administration of G-CSF. This was associated with decreased secretion of interferon gamma and interleukin-2 (IL-2) and an increased secretion of IL-4. The donor cell inoculum, which was most successful in the rescue of irradiated allogeneic hosts, was the low-density fraction of PBMC from G-CSF-treated mice. These low-density cells were enriched for CD4-CD8-NK1.1+ T cells and secreted about 10-fold more IL-4 than the unfractionated cells from the G-CSF-treated donors.
 ...
PMID:Granulocyte colony-stimulating factor reduces the capacity of blood mononuclear cells to induce graft-versus-host disease: impact on blood progenitor cell transplantation. 920 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>