UMLS:C0018133 - FACTA Search

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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)

Hematopoietic reconstitution by bone marrow transplantation (BMT) is used as therapy for the treatment of various malignancies and genetic blood disorders. Allogeneic BMT is the most common application of this treatment but is frequently associated with graft-versus-host disease (GVHD). Recent clinical studies have shown that sibling transplant using umbilical cord blood (UCB) is an acceptable alternative to BMT and may involve fewer problems with GVHD. We have investigated the in vitro alloreactive capacity of UCB as it relates to allogeneic transplantation. Initial screening assays demonstrated that UCB T cells were functionally immature. It was not possible to generate significant levels of alloantigen-specific cytotoxic T lymphocytes (CTL) in either primary or secondary mixed lymphocyte cultures. Limiting dilution analyses revealed that cord blood T cells were 10-1000 x less alloreactive in terms of proliferative T cells (PTLp) and cytotoxic T cells (CTLp) compared with adult peripheral blood lymphocytes (PBL). However, UCB was equivalent to adult PBL in terms of natural killer (NK) and lymphokine-activated killer (LAK) cell precursors. Analysis of cells from alloantigen-stimulated MLC revealed that UCB generated primarily CD4+ and CD16+ cells that made little or no IL-4, IL-6, TNF-alpha or IFN-gamma on antigenic stimulation. Cold target inhibition analyses revealed that alloantigen-stimulated cord blood T cells had a fine specificity similar to NK cells. From these in vitro results cord blood would seem to be unlikely to mediate severe GVHD reactions in vivo and should be suitable for allogeneic transplantation.
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PMID:Analysis of the alloreactive capacity of human umbilical cord blood: implications for graft-versus-host disease. 785 29

In patients with acute graft-versus-host disease (GVHD), IL-6 gradually increased > 14 days before clinical onset of acute GVHD and decreased when acute GVHD disappeared. Interferon-gamma (IFN gamma) levels increased < 14 days before clinical acute GVHD and decreased at the disappearance of acute GVHD. Tumor necrosis factor-alpha (TNF alpha) levels increased almost simultaneously with the onset of acute GVHD and also decreased when it disappeared. However, these results do not necessarily mean that the increased levels of IL-6, IFN gamma and TNF alpha induced acute GVHD; they merely show that acute GVHD is observed more frequently in patients with increased IL-6, IFN gamma and TNF alpha levels than in those with normal levels. Although increased IL-6 levels were also observed in patients without acute GVHD, concomitant increase of IFN gamma and TNF alpha was not detected in such cases, showing that IL-6 can be increased by even graft-versus-host reaction (GVHR) which may not develop into clinical acute GVHD. Taken together, acute GVHD appeared to be induced by synergistic interaction of IL-6, IFN gamma and TNF alpha, consistent with a cytokine cascade. A similar interaction of IL-6 and TNF alpha was also observed in chronic GVHD. Although IFN gamma levels were slightly increased in chronic GVHD and sometimes aggravated the disease status, IL-6 and TNF alpha appeared to be more closely involved in the induction of chronic GVHD. In autologous BMT, increased cytokine levels were not observed unless IL-2 was administered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. 792 Mar 9

To determine the degree of graft versus host disease (GVHD) prophylaxis that might be necessary if cord blood (CB) transplantation is more widely applied, we compared human cord blood mononuclear cell (CBMC) and adult peripheral blood mononuclear cell (PBMC) proliferative responses and stimulatory capabilities; to examine the utility of UVB irradiation for GVHD prophylaxis, we compared proliferative responses, antigen-presenting cell (APC) stimulatory functions, and cytokine production by untreated and UVB-irradiated CBMCs. The two cell types, CBMC and PBMC, proliferated equally both in response to phytohemagglutinin (PHA) and alloantigen in mixed lymphocyte culture (MLC). Cord blood stimulatory function in MLC was significantly (P < 0.05) reduced to 60% of PBMC stimulatory capability. Ultraviolet-B irradiation at a dose of 100 J/m2 of CBMCs significantly (P < 0.01) inhibited PHA stimulation by 79.4%, reduced responder activity in MLC by 75.8%, and inhibited stimulatory activity in MLC by 55.6% as compared with the activity shown by untreated CBMCs. The same dose of UVB preserved 59.9% of CFU-GM and 65.9% of BFU-E colony growth as compared with untreated CBMCs. Production of lymphokines (IL-2, GM-CSF, LIF, and gamma-IFN) by PHA-stimulated CBMCs was decreased, but monokine (IL-1 beta and IL-6) production was unchanged. We conclude that UVB irradiation at a dose of 100 J/m2 inhibits CB lymphocyte activation and preserves the cellular growth potential of CB hematopoietic progenitor cells.
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PMID:The effect of UVB irradiation on proliferative activity and cell growth potential of cord blood. 807 20

The potential of recombinant glycosylated human interleukin-6 (rhIL-6) for enhancing immunohematopoietic reconstitution and survival after syngeneic and semiallogeneic bone marrow transplantation (BMT) in BALB/c mice subjected to total body irradiation (TBI) was investigated. rhIL-6 produced enhanced reconstitution of white blood cells as assessed on days 8 and 14 after syngeneic BMT and of platelets as assessed on day 10. Moreover, rhIL-6 treatment produced significant improvement of survival in lethally irradiated mice receiving either syngeneic or semiallogeneic BMT with limiting number of BM cells. This effect of IL-6 was not seen with large BM cell inocula producing high survival by themselves. rhIL-6 showed no toxic effects and did not affect the survival of mice that were lethally irradiated but not reconstituted by BM cells. However, the sensitivity of mice to sublethal irradiation was increased by rhIL-6 in the absence of BM cell transplantation. In experimental conditions inducing graft-versus-host disease (GVHD), in which lethally irradiated (BALB/c x C57BL/6)F1 mice received mixtures of BM and spleen cells from C57BL/6 donors, rhIL-6 was found to enhance GVHD manifestations. No consistent enhancement of T-cell in vitro proliferative responses to allogeneic spleen cells or T- and B-cell-dependent mitogens were seen in the splenocytes obtained from recipients of syngeneic or semiallogeneic BMT. Our data suggest that rhIL-6 may be useful in BMT procedures to enhance thrombopoiesis and hematologic recovery, as well as to increase overall survival rates. In addition, the potentiation of GVHD, which is considered to correlate with graft-versus-leukemia effects, may be of interest in enhancing GVHD-dependent antitumor effects in protocols combining radiochemotherapy with BMT.
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PMID:Potential use of interleukin-6 in bone marrow transplantation: effects of recombinant human interleukin-6 after syngeneic and semiallogeneic bone marrow transplantation in mice. 812 61

Cytokine gene expression in peripheral blood mononuclear cells during the development of graft-versus-host disease (GVHD) in patients who underwent allogeneic bone marrow transplantation (allo BMT) was analysed using a semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR). The expression of interleukin (IL)-1 beta, IL-6, and tumour necrosis factor (TNF)-alpha mRNA was increased during the development of GVHD and the degree of this increment depended on the severity of the disease. IL-2 expression was not detected at all and interferon-gamma expression was not much changed during GVHD. In patients with hepatic veno-occlusive disease (VOD), another transplantation-related complication, the expression of IL-1 beta and TNF-alpha mRNA was increased but IL-6 mRNA expression showed little increase. These findings suggest that IL-1 beta, IL-6 and TNF-alpha produced by peripheral blood mononuclear cells play an important role in the development of GVHD. Furthermore, liver dysfunction due to GVHD or VOD may be distinguishable by this type of cytokine analysis. Analysis of cytokine mRNA expression in peripheral blood mononuclear cells after allogeneic bone marrow transplantation may provide important information concerning the immune response and the cytokine network system in marrow transplant patients.
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PMID:Cytokine gene expression in peripheral blood mononuclear cells during graft-versus-host disease after allogeneic bone marrow transplantation. 813 79

Plasma concentrations and peripheral blood cells containing cytoplasmic cytokines were monitored during the post-transplant period in 10 patients who had received allogeneic bone marrow transplants (BMT) for the correction of inherited genetic disorders. The presence of CD14-positive cells containing cytoplasmic interleukin-1 alpha and beta in the peripheral blood was indicative of acute graft-versus-host disease (GVHD). Plasma concentrations of IL-1 alpha, IL-1 beta and TNF-alpha were significantly raised in the GVHD group when compared with the uneventful days. There was, however, poor temporal correlation between the plasma concentrations and clinical manifestations of acute GVHD. Cells containing cytoplasmic IL-6 were present in the peripheral blood when patients had clinically suspected and/or microbiologically confirmed infection. The results from this study demonstrate that analysis of peripheral blood cells for cytoplasmic IL-1 alpha and IL-1 beta are better markers of acute GVHD than is monitoring plasma concentrations of these cytokines.
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PMID:Monitoring cytokine production in peripheral blood during acute graft-versus-host disease following allogeneic bone marrow transplantation. 813 47

We assessed the origin of peripheral blood cells and bone marrow cells obtained from 15 patients after allogeneic bone marrow transplantation (allo BMT) by sensitive two-step polymerase chain reaction (PCR) amplification of MCT118, a variable number of tandem repeats regions (VNTR), that can be used to detect the DNA pattern of a minor cell population of only 1% without using radioisotopes. Mixed chimerism(MC) was detected in the haematopoietic cells of 3 patients. Two patients developed relapse of leukaemia after the detection of MC and one patient died of bone marrow hypoplasia 7 months after BMT. These findings indicate the clinical usefulness of this method to monitor patients with MC. Also, we analyzed cytokine gene expression in peripheral blood mononuclear cells during the development of graft-versus-host disease (GVHD) in patients who underwent allo BMT using a semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR). The expression of interleukin(IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha mRNA was increased during the development of GVHD and the degree of this increment depended on the severity of the disease. These findings suggest that IL-1 beta, IL-6, and TNF-alpha produced by peripheral blood mononuclear cells play an important role in the development of GVHD. Therefore, analysis of MC and cytokine mRNA expression using the PCR technique after allogeneic bone marrow transplantation provide important information for treatment and monitoring of marrow transplant patients.
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PMID:[Clinical application of gene technology to monitor bone marrow transplantation]. 815 60

In a previous study, we found that total body irradiation (TBI) was essential to induce acute graft-versus-host disease (GVHD) after allogeneic H-2-incompatible splenocyte (SP) transplantation in SCID mice. SCID mice (H-2d) conditioned with cyclophosphamide and transplanted intravenously (IV) with 5 x 10(7) C57BL/6 (H-2b) SP developed chronic GVHD within 3 months posttransplant without any evidence of preceding acute GVHD. In this study, SCID mice were conditioned with 4 Gy TBI or non-TBI regimens, either BuCy2 (busulfan 4 mg/kg/d + cyclophosphamide 100 mg/kg/d for 2 days) or Cy5 (cyclophosphamide 100 mg/kg/d for 5 days), and then transplanted IV with 5 x 10(7) SP. The TBI-conditioned mice were further divided into tree transplant groups: (1) TBI and SP administered the same day (TBI + D0 SP), (2) SP administered 4 days post-TBI (TBI + D4 SP), and (3) SP administered 7 days post-TBI (TBI + D7 SP). The severity of GVHD was compared among these groups by clinical and histologic grading. Twenty-eight of 28 mice treated with TBI + D0 SP died of acute GVHD, with overwhelming diarrhea by day 15 posttransplantation. Sixteen mice treated with either TBI + D4 SP or TBI + D7 SP developed acute GVHD, but none of them died of this disorder during 30 days posttransplantation. The mice conditioned with non-TBI regimens developed chronic GVHD within 3 months without showing any detectable signs of acute GVHD. Serum and in situ colonic cytokines were determined by enzyme-linked immunosorbent assay and immunohistology respectively. TBI itself significantly increased both serum and colonic tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-6 when compared with non-TBI regimens and normal controls. TNF-alpha appeared in the serum and colon 4 hours post-TBI and peaked in 24 hours, followed by increasing IL-1 alpha and then IL-6 levels. TNF-alpha and IL-1 alpha decreased rapidly within 3 to 5 days post-TBI if no allogeneic cells were transplanted. Histoincompatible transplantation augmented cytokine release, which remained elevated on day 10 in these animals. Mice treated with TBI + D0 SP developed the most severe acute GVHD and had the highest levels of TNF-alpha, IL-1 alpha, and IL-6. The BuCy2-conditioned mice had the lowest cytokine levels and developed no acute GVHD. When the mice transplanted with TBI + D0 SP were treated immediately with recombinant soluble human TNF receptor (rhuTNFR:Fc) 100 micrograms/d intraperitoneally and for the subsequent 15 days acute GVHD mortality was significantly reduced from 100% to 50% (P < .001).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. 816 3

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

UVB irradiation (700 J/m2) of bone marrow cells (UVB-BMC) before transplantation into lethally gamma-irradiated (10.5 Gy) allogeneic rats prevents graft-versus-host disease (GVHD) and induces a stable complete lymphohematopoietic chimerism. To better understand the underlying mechanism of the development of stable chimerism and induction of tolerance to donor organs in this model, we examined if the addition of T cells or dendritic cells (DC), as antigen presenting cells (APC), would restore the immunogenicity of UVB-BMC in in vitro mixed lymphocyte reaction (MLR) and induce in vivo bone marrow (BM) graft rejection. Whereas gamma-irradiated, unfractionated BMC induce allogeneic T cells to proliferate, UVB irradiation of BMC abolishes the stimulatory capacity of such cells in a primary MLR. Addition of purified T cells, CD4+ T cells, CD8+ T cells or B cells, respectively, failed to restore the capacity of UVB-BMC to stimulate allogeneic T-cell proliferation. In contrast, the addition of only a small number of splenic accessory cells or purified DC, which by themselves were relatively ineffective in stimulating T-cell proliferation, restored the accessory function and the allostimulatory capacity of UVB-BMC. To define the molecular defect induced by UVB irradiation, cytokines were added as costimulatory factors to primary MLRs and the results showed that the addition of interleukin (IL)-2 or IL-6 but not IL-1 or interferon gamma (IFN-gamma) restored the stimulatory capacity of UVB BMC. This finding suggests that UVB may alter the production, and/or utilization of IL-2 and IL-6 either at the membrane or cytoplasmic level. Parallel in vivo studies showed that addition of DC to UVB BM inoculum resulted in failure of BM engraftment, whereas addition of T cells led to development of fatal GVHD, thus suggesting that UVB modulation of accessory cells reduces graft immunogenicity and prevents BMT rejection, while modulation of T cells prevents GVHD. Our data provide evidence that UVB modulation of APC and mature T cells contained within BMC is potentially useful in preventing GVHD without endangering successful engraftment and may serve as a model for induction of adult chimerism and tolerance without the development of GVHD.
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PMID:Prevention of graft-versus-host disease and bone marrow rejection: kinetics of induction of tolerance by UVB modulation of accessory cells and T cells in the bone marrow inoculum. 845 11

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