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)

Pentoxifylline (PTX) has recently been shown to modulate TNF-alpha production and to reduce the incidence and severity of all major complications after BMT, including mucositis, veno-occlusive disease, renal insufficiency, hypertension, and graft-versus-host disease. To analyze in detail the effect of PTX on immune complications after BMT, we investigated the immunomodulatory effect of PTX on immune responses in vitro. The continuous presence of PTX significantly reduced the proliferative response of PBMC to PHA stimulation and to alloantigens in a dose-dependent manner. Starting at concentrations of 100 micrograms/ml, PTX was able to inhibit and, at 1000 micrograms/ml, completely block mitogen-induced proliferation. Maximal inhibition of more than 90% (91 +/- 4%) was also observed at PTX concentrations of 1000 micrograms/ml in the mixed lymphocyte culture (MLR) and by addition on day 0. However, lower but still significant suppression (13 +/- 7%) was achieved at concentrations of 10 micrograms/ml PTX. The inhibitory capacity of PTX was increased by mAbs against TNF-alpha (34 +/- 5% additional suppression at 100 micrograms/ml PTX) and not reversed by the addition of rTNF-alpha. The effect of PTX on the generation of CTLs in vitro was studied in the cell-mediated lymphotoxicity assay. PTX (100 micrograms/ml) significantly inhibited (P = 0.0178) the in vitro generation of CTLs when PTX was added to the culture on day 0. PTX also showed profound modulatory properties in the NK assay, with a reduction of 23 +/- 3% in specific lysis at 10 micrograms/ml PTX and maximal reductions of 88 +/- 3% at 1000 micrograms/ml PTX. Immunomodulatory properties of PTX were not only associated with blockage of TNF-alpha, as shown by decreased mRNA expression and TNF-alpha values in the culture supernatants, but also with an impaired production of other cytokines and secondary messages such as IFN-gamma and neopterin. PTX treatment, however, did not affect IFN-alpha or IL-1 beta production, and IL-6 release was even increased. PTX, therefore, has profound immunomodulatory properties in vitro, which are associated with selective inhibition of cytokine release and can be enhanced by the addition of mAbs against TNF-alpha, but not reversed by the addition of rTNF-alpha.
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PMID:Immune response modulation by pentoxifylline in vitro. 833 42

Whereas T lymphocytes are essential for the initiation of acute graft-versus-host disease (aGVHD), it is not at all clear whether they or other cells or noncellular factors actually mediate the characteristic lesions. This report describes the in vivo effects of human NK cells, T cells, and cytokines on the induction of aGVHD in 4 Gy sublethally irradiated C.B-17 scid/scid (SCID) mice. Human NK and T lymphocytes were obtained separately by antibody- and complement-mediated negative selection from the peripheral blood of normal donors and expanded in medium containing rIL-2 and irradiated autologous feeder cells. The characteristics of the two groups of cells were analyzed before injection into SCID mice. Cytofluorometric phenotyping demonstrated that 70-95% of NK-enriched cells expressed CD3-, CD16+, CD56+, and CD8-dim+; ninety-seven per cent of T cells expressed CD3+, TCR-alpha/beta+, CD4+, or CD8-bright+. Analysis of K562 and Daudi cultured target cell lines demonstrated 40-50% higher cytotoxicity by NK-enriched cells as compared with activated T lymphocytes. TNF-alpha cytokine production was greatly increased in activated NK cells (250 pg/ml) as compared with T cells (25 pg/ml) and fresh PBMC (12.5 pg/ml). IFN-gamma was increased in both NK and T cells. After i.v. injection of 1-5 x 10(7) cells into irradiated SCID mice, minor to severe skin lesions, diarrhea, and weight loss occurred in NK- but not the T cell-injected animals. In NK-injected animals, thinning and focal loss of epithelium with pyknotic nuclear change and degeneration and loss of skin appendages were observed. Single cell necrosis, crypt abscess formation, and loss of glandular epithelium developed in the colon of NK but not in T cell-injected animals. These findings are very similar to allogeneic aGVHD in SCID mice injected with C57BL/6 mouse splenocytes. Immunohistological staining with anti-human CD56, CD3, TNF-alpha, and IFN-gamma antibodies demonstrated CD56+ cells in association with TNF-alpha and IFN-gamma secretion in the bowel of NK-injected animals. CD3+ cells were not found in the same tissues. These findings were not observed in T cell-injected and control mice. In summary, aGVHD-like lesions were induced by transplantation of xenogeneic human activated NK cells into SCID mice. We hypothesize that cytokines released from human NK cells play a central role in the pathogenesis of clinical aGVHD.
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PMID:Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into SCID mice. 835 98

Serum levels of soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-6 were studied in patients who developed veno-occlusive disease of the liver (VOD) after allogenic bone marrow transplantation (BMT). sIL-2R increased by a mean of 366% in 10 VOD patients. This was significantly higher than in control patients (n = 12) undergoing BMT without major complications (103%, P = 0.002) or in patients (n = 10) with grade II or III acute graft-versus-host disease (aGVHD) (139%, P = 0.003). Peak sIL-2R levels occurred on day 17 +/- 4 (mean +/- SD) after BMT in VOD patients versus on day 29 +/- 11 in patients with grades II-III aGVHD (P = 0.006). Mean maximum sIL-2R values in VOD patients were 4548 +/- 1420 (+/- SD, U/ml), which was significantly higher than the value of 2123 +/- 1023 U/ml in control patients undergoing BMT without major complications (P < 0.001). In patients with grade II or III aGVHD, mean maximum sIL-2R levels were 3076 +/- 2264 U/ml. Serum levels of TNF-alpha, IFN-gamma, and IL-6 were also increased during VOD and aGVHD, with peak levels occurring at the same time as peak sIL-2R levels in most patients. We found no difference in peak levels between VOD and acute GVHD patients. To conclude, an early dramatic increase in sIL-2R was seen in patients with VOD. Inflammatory cytokines like IL-6, TNF-alpha, and IFN-gamma also increased during VOD and aGVHD.
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PMID:Increased levels of soluble interleukin-2 receptor in veno-occlusive disease of the liver after allogenic bone marrow transplantation. 852 24

In this study, we have investigated cytokine (IL-1 beta, IL-2, IL-5, IL-6, IFN-gamma, TNF-alpha) and T cell surface molecule (IL-2 receptor, CD28, CTLA-4) gene expression in two way mixed lymphocyte cultures (MLC) enhanced by concanavalin A (ConA) to assess whether this is a useful predictive method for severe graft-versus-host disease (GVHD) and graft failure in allogeneic bone marrow transplantation (allo BMT) patients. Our present study revealed increased mRNA expression of IL-2, IL-5 and IFN-gamma using this assay in patients with delayed engraftment followed by graft failure and patients who developed grade III acute GVHD. Elevated IL-2 and IFN-gamma levels in MLC medium were also observed in these patients. Concerning T cell surface molecule gene expression in our modified MLC, IL-2 receptor gene expression was not altered so much in allo BMT patients, however, CD28 and CTLA-4 gene expression were elevated in patients with graft failure and severe acute GVHD. The elevated expression of cytokines (IL-2, IL-5 and IFN-gamma) and T cell surface molecules (CD28 and CTLA-4) mRNA in our modified MLC, in patients who developed severe lethal transplantation-related complications may suggest an important role for these molecules in inducing a strong alloresponse. Therefore, the detection of increased gene expression of those molecules, in our modified MLC system, appeared to be useful for predicting transplantation-related complications in allo BMT patients. In addition, this modified MLC assay may also be useful for the selection of the most compatible related and unrelated donors.
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PMID:Transplantation-related complications predicted by cytokine gene expression in the mixed lymphocyte culture in allogeneic bone marrow transplants. 857 69

We examined whether the use of G-CSF would affect the outcome of allogeneic marrow transplantation in humans and mice. Retrospective analysis of 24 patients who had received allogeneic marrow grafts from HLA-identical siblings revealed that the incidence of chronic but not acute graft-versus-host disease (GVHD) was lower in the patients receiving G-CSF than in those not given G-CSF (18% vs. 80%, P = 0.02). There was a difference in serum TNF-alpha levels during the first 3 months after transplant between these two groups. Four out of the ten patients who were not given G-CSF showed elevated serum TNF-alpha levels, whereas there was only one patients with an increased TNF-alpha level among eleven patients who were given G-CSF. With the use of murine acute and chronic GVHD models, we also observed that administration of G-CSF improved the survival of minor GVHD, but not major GVHD, mice. Taken together, these findings suggest that G-CSF down-regulates allogeneic immune responses and is active in modulating alloreactivity in vivo.
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PMID:Modulation of allogeneic immune responses by filgrastim (recombinant human granulocyte colony-stimulating factor) in bone marrow transplantation. 858 69

We analysed 35 risk factors for acute GVHD in 291 consecutive recipients of HLA-identical sibling marrow transplants from 1975 to 1993. Of these, 16% developed moderate-to-severe acute GVHD following transplantation. In multivariate analysis, GVHD prophylaxis with monotherapy (MTX or CsA) (P = 0.015) seropositivity for several herpes viruses in the donor (P = 0.015) and seropositivity for CMV in the recipient (P = 0.037) before the transplants as well as early engraftment (P = 0.016), were the principal risk factors for GVHD. A high serum TNF-alpha level during conditioning therapy was also a significant risk factor in 75 recipients (P = 0.005). The risk of grades II-IV acute GVHD increased with the number of risk factors. Thus the cumulative incidence of acute GVHD was 1%, if no risk factor was present, 4% with one, 9% with two, 21% with three and 44% in patients with four risk factors. Factors reported to correlate with acute GVHD, such as age, diagnosis, female donor to male recipient, relative response and donor-responding capacity in MLC, MNS blood group antigen, splenectomy and bone marrow cell dose were not associated with acute GVHD in this study. Five-year survival was 24% in patients with grades II-IV GVHD vs 62% in patients with grades 0-I GVHD (P = 0.0001).
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PMID:Risk factors for acute graft-versus-host disease in 291 consecutive HLA-identical bone marrow transplant recipients. 875 Feb 64

The dynamics of different peripheral blood lymphocyte subpopulations (CD3+, CD4+, CD8+, CD22+, DR+, CD25+ and CD16+) and levels of serum cytokines TNFa and IL1 beta were evaluated in 10 patients with allogeneic bone marrow transplantation (BMT). It was established that initially low levels of practically all the lymphoid subsets studied came back to normal in patients with favorable post-BMT course, while, in unfavorable post-BMT course (GVHD or relapse), the levels of said lymphoid subsets remained unchanged or even dropped. Post-BMT increase in serum TN alpha level can be of prognostic value for GVHD development whereas serum IL1 beta level does not correlate with post-BMT course.
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PMID:[Immunologic monitoring and immune reconstitution in recipients of allogeneic bone marrow]. 892 56

The mechanism of action of intravenous immunoglobulins (IVIg) for prevention of graft rejection and graft-versus-host disease (GVHD) is poorly understood. Recently, it has been shown that these preparations contain natural antibodies directed toward interferon (IFN)-gamma. During mixed lymphocyte reaction (MLR), which constitutes an in vitro model of allograft rejection and GVHD, T cell recognition of HLA differences induces IFN-gamma release. This cytokine promotes T cell proliferation and acts as a macrophage-activating factor to provoke tumor necrosis factor-alpha secretion. The aim of the present work is to investigate the influence of IVIg on IFN-gamma production occurring during MLR and its subsequent impact on T cell proliferation and tumor necrosis factor (TNF)-alpha secretion. We tested IVIg preparations for the presence of anti-IFN-gamma and anti-TNF-alpha antibodies. High amounts of anti-IFN-gamma, but not anti-TNF-alpha antibodies, were found. IVIg addition at the initiation of culture resulted in IFN-gamma secretion blockade. Likewise, lymphocyte proliferation and TNF-alpha secretion were inhibited. This inhibition was reversed by the addition of recombinant human IFN-gamma. Furthermore, the inhibitory properties of IVIg were mimicked by an IFN-gamma-specific neutralizing monoclonal antibody. We conclude that the capacity of IVIg to inhibit proliferation and TNF-alpha release during MLR is due to IFN-gamma blockade by natural antibodies. This immunosuppressive mechanism could contribute to the effect of IVIg on prophylaxis of organ graft rejection and GVHD after allogeneic bone marrow transplantation.
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PMID:Blockade of proliferation and tumor necrosis factor-alpha production occurring during mixed lymphocyte reaction by interferon-gamma-specific natural antibodies contained in intravenous immunoglobulins. 893 74

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.
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PMID:In vitro expansion and characterization of dendritic cells derived from human bone marrow CD34+ cells. 893 57

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We examined here the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c x C57BL/6) F1 that received C57BL/6 spleen cells markedly reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.
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PMID:A metalloproteinase inhibitor prevents lethal acute graft-versus-host disease in mice. 922 53


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